TNFα is mainly produced by activated macrophages, T lymphocytes, and natural killer (NK) cells, but is also expressed at lower levels by fibroblasts, smooth muscle cells, and tumor cells. The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication and respond to sepsis via IL1 & IL6 producing cells.

In this section, we present the members of TNF superfamily and the receptors in the table 1(table 1a and 1b).

Tumor Necrosis Factor receptors

The portrait of all the receptors in the TNF Superfamily is large and complicated (Table 1b), including the official genome nomenclature site, which introduced the TNFSF and TNFRSF numbering system^[1].

Table 1b TNF Receptor SuperFamily

A tumor necrosis factor (TNF)-alpha inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The inhibitor, including etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab, all bind to the cytokine TNF and inhibit its interaction with the TNF receptors^[2].

As a cytokine, TNF is involved with the inflammatory and immune response and can bind to TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). It occurs in numerous forms, both monomeric and trimeric, as well as soluble and transmembrane^[3]. Etanercept is a fusion protein of two TNFR2 receptor extracellular domains and the Fc fragment of human IgG1. It inhibits the binding of both TNF-alpha and TNF-beta to cell surface TNFRs. Infliximab is a chimeric monoclonal antibody that includes a murine variable region and constant human region. It binds to the soluble and transmembrane forms of TNF-alpha and inhibits the binding of TNF-alpha to TNFR^[4].

The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects^[5].

TNF can bind two receptors, TNFR1 (TNF receptor type 1) and TNFR2 (TNF receptor type 2) [6]. TNFR1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNFR2 is found typically in cells of the immune system, and respond to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNFR1, the role of TNFR2 is likely underestimated. Upon binding, TNF triggers the activation of numerous pathways including the NFκB and MAPK signaling pathway.

Accumulating evidences have revealed that dysregulation of TNF production was implicated in a variety of human diseases including Alzheimer’s disease^[7], cancer^[8], major depression^[9], psoriasis^[10] and inflammatory bowel disease (IBD). Its complex functions in the immune system include the stimulation of inflammation, cytotoxicity, the regulation of cell adhesion, and the induction of cachexia.

[1] Carl F. Ware. TNF Superfamily 2008[J]. Cytokine Growth Factor Rev, 2008 (3-4): 183–186

[2] Valerie Gerriets1; Steve S. Bhimji2. Tumor Necrosis Factor (TNF), Inhibitors[J]. StatPearls Publishing, 2018 Jan

[3] Meroni PL, Valentini G, et al. New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis[J]. Autoimmun Rev. 2015 (9): 812-29

[4] Komaki Y, Yamada A, et al. Efficacy, safety and pharmacokinetics of biosimilars of anti-tumor necrosis factor-α agents in rheumatic diseases; A systematic review and meta-analysis[J]. Autoimmun. 2017 (79): 4-16

[5] N Scheinfeld. A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab[J]. Journal of Dermatological Treatment, 2004 (15): 280–294

[6] Arianne L. Theiss, James G. Simmons, et al. Tumor Necrosis Factor (TNF) Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts via TNF Receptor 2[J]. The journal of biological chemistry, 2005 (43): 36099 -36109

[7] Swardfager W, Lanctôt K, et al. A meta-analysis of cytokines in Alzheimer’s disease[J]. Biol Psychiatry, 2010 (68): 930–941

[8] Locksley RM, Killeen N, et al. “The TNF and TNF receptor superfamilies: integrating mammalian biology[J]. Cell, 2001 (104): 487–501

[9] Dowlati Y, Herrmann N, et al. A meta-analysis of cytokines in major depression[J]. Biol Psychiatry, 2010 (5): 446–457

[10] Victor FC, Gottlieb AB. TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis[J]. Drugs Dermatol, 2002 (3): 264–75

[11] Balkwill, F. (2002). Tumor necrosis factor or tumor promoting factor[J]. Cytokine & Growth Factor Reviews, 2002 (13): 135–141

[12] Galban, S., Fan, J., et al. von Hippel-Lindau protein-mediatedrepression of tumor necrosis factor alpha translation revealed through use of cDNA arrays[J]. Molecular & Cellular Biology, 2003 (23): 2316–2328

[13] Tsan, M.-F. Toll-like receptors, inflammation and cancer[J]. Seminars in Cancer Biology, 2005 (16): 32–37

[14] Kulbe, H., Hagermann T, et al. The inflammatory cytokine TNF-a upregulates chemokine receptor expression on ovarian cancer cells[J]. Cancer Research, 2005 (65): 10355–10362

[15] Balkwill, F. The significance of cancer cell expression of CXCR4[J]. Seminars in Cancer Biology, 2004 (14): 171–179

[16] Korneev KV, Atretkhany KN, et al. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis[J]. Cytokine, 2017 (89): 127–135

[17] Ma X, Xu S. TNF inhibitor therapy for rheumatoid arthritis[J]. Biomed Rep, 2012 (2): 177–184.

[18] Narayanan Parameswaran, Sonika Patial. Tumor Necrosis Factor-α Signaling in Macrophages[J]. Crit Rev Eukaryot Gene Expr, 2010 (2): 87–103.

[19] Ulrike Billmeier, Walburga Dieterich, et al. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases[J]. World J Gastroenterol, 2016 (42): 9300–9313

[20] Konstantinos Papamichael, Adam S Cheifetz. Defining and predicting deep remission in patients with perianal fistulizing Crohn’s disease on anti-tumor necrosis factor therapy[J]. World J Gastroenterol. 2017 (34): 6197–6200

The members of interleukin are wealthy which are named IL-1~IL-38.

The interleukin receptors can be classified as type I, type II and other type. The type II interleukin receptors include interleukin-10, 20, 22, 28 receptors, the other type include interleukin-1, 8 receptors, the rest of them are type I interleukin receptors.

Table 1. Interleukin Family and Receptors

In this part, we display several interleukin pathways, including IL-1, IL-10, IL-12, IL-17 and IL-7 signaling pathway.

Interleukin is important for transmitting information, activating and regulating immune cells, mediates the activation, proliferation and differentiation of T cells and B cells.

Interleukin-1 contains IL-1α and IL-1β. While the former is produced by diverse cells, the later one is produced by some specific tissues. IL-1β is cleaved by caspase-1 which is formed by proteins termed as “the inflammasome”. It can lead to pain and short-time sleep, so that they study the relationship between fatigue and IL-1^[2]. IL-1 also can simulate the nitric oxides, chemokines, cytokines and adhesion molecules that destroy the cartilage, while the IL-1 receptor antagonist can inhibit the destruction of IL-1 through the completion of the same receptor. The study helps us to understand the pathology of these diseases^[3].

Interleukin-2 is popular object in the past 36 years as it is important for the immunotherapy of many diseases including cancers. But the adverse of taking it is fearful^[4].Thus, timing of IL-2 administration and different T cells status are crucial to IL-2 therapies^[5].

Interleukin-10 is an anti-inflammatory cytokine. In the meanwhile, IL-10 suppresses the immune responses by modulating the T cells and antigen-presenting cells. By controlling the receptor of IL-10, we can resolve the chronic viral infection^[6]. The research was published in The Journal of Experimental Medicine in 2006.

Interleukin-18 is a regulator of cancer and autoimmune diseases. As a member of IL-1 family, it plays essential roles in inflammation process. It can cooperate with IL-12 to activate cytotoxic T cells (CTLs) and natural killer (NK) cells to produce IFNγ which may contribute to tumor immune. In addition, it can work with IL-23 to induce the secretion of IL-17. It has pros and cons effects in the treatment of many diseases^[7].

Inflammation is a productive conduct to stimuli such as pathogens and damage cells. Its characters are heat, redness, swelling, pain and loss of function, sometimes accompanied with fever. Inflammasome activation leads to activation of caspase-1, resulting in the induction of apoptosis and the secretion of pro-inflammatory cytokines including IL-1β and IL-18[8]. Without inflammation, we can’t prevent harm from stimuli, but it can lead to chronic infection such as rheumatoid arthritis. Inflammation plays a key role in chronic inflammatory systemic diseases (CISD). There are overlaps between different CISD.

[1]Pellegrini M, Calzascia T, et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology[J]. Cell, 2011(144): 601-603

[2]Megan E. Roerink, Marieke E. van der Schaaf, et al. Interleukin-1 as a mediator of fatigue in diseases: a narrative review[J]. Journal of Neuroinflammation, 2017(14): 16

[3]Claire J, Marjolaine G, et al. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation[J]. Vitamins and Hormones, 2006(74): 371-403

[4]Dhupkar P, Gordon N. Interleukin-2: old and new approaches to enhance immune-therapeutic efficacy[J]. Adv Exp Med Biol, 2017(995): 33-51

[5]Blattman JN, Grayson JM, et al. Therapeutic use of IL2 to enhance antiviral T-cell responses in vivo[J]. Nat Med, 2003(9): 540-547

[6]Eirnaes M, Filippi CM, et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade[J].J Exp Med, 2006(203): 2461-2472

[7]Esmailbeig M, Ghaderi A. Interleukin-18: a regulator of cancer and autoimmune diseases[J]. Eur Cytokine Netw, 2017(28): 127-140

[8]Yi YS. Role of inflammasomes in inflammatory autoimmune rheumatic diseases[J]. Korean J Physiol Pharmacol, 2018(1): 1-15

[9]Lockshin B, Balaqula Y, et al. Interleukin-17, inflammation, and cardiovascular risk in patients with psoriasis[J]. J Am Acad Dermatol, 2018, accepted

[10]Mathews RJ, Robinson JI, et al. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment)[J]. Ann Rheum Dis, 2014(73): 1202-1210

[11]Jenko B, Praprotnik S, et al. NLRP3 and CARD8 polymorphisms influence higher disease activity in rheumatoid arthritis)[J]. J Med Biochem, 2016(35): 319-323

[12]Sui J, Li H. NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum, 2012(64): 647-654

[13]Joosten LA, Netea MG, et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1)[J]. Arthritis Rheum, 2009(60): 3651-3662

[14]Zhang L, Dong Y, et al. Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis)[J]. Int Immunopharmacol, 2013(17): 489-494

[15]Roberts TL, Idris A, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA)[J]. Science, 2009(323): 1057-1060

[16]Tsai PY, Ka SM, et al. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation)[J]. Free Radic Biol Med, 2011(51): 744-754

[17]Ka SM, Lin JC, et al. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation)[J]. Arthritis Res Ther. 2015(17): 331

[18]Danese S, Vermeire S, et al. Randomised trial and open-label extensive study of an anti-interleuki8n-6 antibody in crohn’s disease(ANDANTW I and II)[J]. Gut, 2017, doi:10.1136

Colony-stimulating factors (CSFs) activate intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell (usually white blood cells. For red blood cell formation, see erythropoietin). CSFs circulate in the blood, acting as hormones, and are also secreted locally. General speaking, CSFs include macrophage colony-stimulating factor (CSF1), Granulocyte–macrophage colony-stimulating factor (CSF2), granulocyte colony-stimulating factor (CSF3) and interleukin-3 (IL-3; also known as multi-CSF). But in some extent, CSFs also involve erythropoictin (Epo) and thrombopoietin (Thpo) for their ability of stimulating the formation of red blood.

In this section, we list the common colony-stimulating factors and corresponding receptors in the below Table 1.

Table 1. CSFs and receptors

CSFs later became apparent that they could also affect more mature populations in these lineages, promoting their survival and/or proliferation, activation and differentiation, all of which could be relevant to inflammation. The effects of Csf gene deficiency in mice and of specific neutralizing monoclonal antibodies (mAbs) have spurred a reassessment of the roles that these CSFs have in steady-state haematopoiesis. Each of these CSFs can play a part in the host response to tissue injury and infection, which has potential implications for inflammatory and autoimmune diseases^[5][6]. Roles for the different CSFs and their targeting, particularly GM-CSF and CSF1, are increasingly being investigated in preclinical models and clinical trials of inflammatory and autoimmune diseases. In this part, we will introduce the primary CSFs and inflammation.

Colony stimulating factors are used in patients who are undergoing cancer treatment that causes low white blood cell counts (neutropenia) and puts the patient at risk of infection. Colony stimulating factors tend to reduce the time where patients are neutropenic. In this part, we numerate several latest researches about colony stimulating factors.

• Several days ago, Baig H’s team have revealed that prophylactic granulocyte colony-stimulating factor use is appropriately highest for high-risk regimens and lowest for low-risk regimens yet still potentially underused in high risk regimens, overused in low-risk regimens, and not appropriately targeted in intermediate-risk regimens, indicating a need for further education on febrile neutropenia risk evaluation and appropriate granulocyte colony-stimulating factor use.
• George DM, et al. have published one paper that named “Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors” in the journal of PLoS One, on 7 September 2018. The paper suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. At the same time, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets.
• Ashrafi F1, a researcher from department of internal medicine of Isfahan University of Medical Sciences in Isfahan, has demonstrated that G-CSF and biosimilar pegylated G-CSF are effective in reducing cytopenia in breast cancer patients treated with dose-dense chemotherapy, but side effects induced by pegylated G-CSF (Pegagen) are higher.

1] Burgess, A. W. & Metcalf, D. The nature and action of granulocyte-macrophage colony stimulating factors[J]. Blood. 1980(56)947–958

[2] Metcalf, D. Hematopoietic cytokines[J]. Blood. 2008, 111, 485–491

[3] Masek-Hammerman, K. et al. Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus[J]. Clin. Exp. Immunol. 2016, 183, 258–270

[4] Michaelson MD, Bieri PL, et al. CSF-1 deficiency in mice results in abnormal brain development[J]. Development. 1996, 122:2661-2672

[5] Théry C, Hétier E, et al. Expression of macrophage colonystimulating factor gene in the mouse brain during development[J]. J Neurosci Res. 1990, 26:129-133

[6] Ahmed N. Advanced glycation endproducts–role in pathology of diabetic complications[J]. Diabetes Res Clin Pract. 2005, 67:3-21

[7] Michaelson MD, Bieri PL, et al. CSF-1 deficiency in mice results in abnormal brain development[J]. Development. 1996, 122:2661-2672

[8] Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation[J]. Curr Opin Immunol. 2006, 18:39-48

[9] Chow F, Ozols E, et al. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury[J]. Kidney Int. 2004, 65:116-128

[10] Wautier MP, Boulanger E, et al. AGEs, macrophage colony stimulating factor and vascular adhesion molecule blood levels are increased in patients with diabetic microangiopathy[J]. Thromb Haemost. 2004, 91:879-885

[11] Wei Liu1, Ge Z Xu1, et al. Macrophage colony-stimulating factor and its receptor signaling augment glycated albumininduced retinal microglial inflammation in vitro[J]. BMC Cell Biology. 2011, 12:5

[12] John A. Hamilton, Andrew D. Cook, et al. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases[J]. Nature. 2016;12(16):53-70

[13] Adrian Achuthan, Andrew D. Cook,, et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation[J]. The Journal of Clinical Investigation. 2016;126(9):3453–3466

[14] Achuthan A. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation[J]. J Clin Invest. 2016;126(9):3453–3466.

[15] Cornish, A. L., Campbell, I. K., et al. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis[J]. Nat. Rev. Rheumatol. 2009, 5, 554–559.

[16] Eyles, J. L., Roberts, A. W., et al. Granulocyte colony-stimulating factor and neutrophils — forgotten mediators of inflammatory disease[J]. Nat. Clin. Pract. Rheumatol. 2006, 2, 500–510.

[17] Wright, H. L., Moots, R. J, et al. The multifactorial role of neutrophils in rheumatoid arthritis[J]. Nat. Rev. Rheumatol. 2014, 10, 593–601.

[18] Stark, M. A. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17[J]. Immunity 2005, 22, 285–294.

[19] Joshi, A. Transcription factor, promoter, and enhancer utilization in human myeloid cells[J]. J. Leukoc. Biol. 2015, 97, 985–995.

Interferon, also known as IFN, is a kind of cytokines which plays important roles in viral defense, tumor inhibition and disease treatment through cytotoxic T cells, NK cells and DC cells, etc. Interferon, produced mainly by monocytes and macrophages and positioned at different cells’surface, regulates cell growth, cell differentiation, immunoediting. CUSABIO has produced various interferon related products, including proteins, antibodies and Elisa kits.

The IFN family is consist of three main classes of cytokines, type I IFNs, type II IFN and type III IFN. Among of them, type I IFN and type II IFN are well-studied.

Type I interferon

Type I interferon includes interferon α(which can be further divided into 13 different subtypes(IFN-α1, -α2, -α4, -α5, -α6, -α7, -α8, -α10, -α13, -α14, -α16, -α17 and -α21), β, ε, к, and ω in human. All type I IFNs bind a identical common cell-surface receptor, which is known as the type I IFN receptor. The receptor for type I interferons has multichain structures, which is composed of at least two different submits, IFNAR1 and IFNAR2. Amounting research results demonstrate that type I IFNs plays a key role in microbial infection. However, each member of type I IFNs also has its unique biologic functions. For the instance, although both IFN-α and IFN-β are elicited by Cl-13 infection, losing of IFN-β signaling is the primary factor that initiates early clearance of LCMV persistent infection by blocking IFNAR. in the stage of early viral clearance, the result of blocking IFN-β similar to that observed by blocking the IFNAR despite the presence of high levels of IFN-α; The study of Ng, C.T et al. reports that blockade of at least six forms of IFN-α can not accelerate viral clearance^[1]. However, IFN-α was key to controlling viral spread, as only IFN-α blockade altered early viral dissemination, manifesting that the roles played by IFN-β as compared to IFN-α in controlling viral infection are different^[2].

Type II Interferon

Type II interferon, only including interferon gamma, also known as IFN γ, is a cytokine that is critical for innate and adaptive immunity against viral, some protozoal and bacterial infections. Comparing with type I interferon, the protein does not exist marked structural homology. The receptor for type II interferons also has multichain structures, which is composed of two different submits, IFNGR1 and IFNGR2. IFN γ is Produced by lymphocytes, activated by specific antigens or mitogens, and has an antiviral activity and important immunoregulatory functions. It is a potent activator of macrophages, and has antiproliferative effects on transformed cells. IFN γ is an important mediator of immunity and inflammation that utilizes the JAK-STAT signaling pathway to activate the STAT1 transcription factor. In addition, emerging evidence shows that it can enforce the antiviral and antitumor effects of the type I interferons.

Type III Interferon

Type III interferon includes interferon λ, which can be further divided into 4 distinct subtypes, IFNλ1, IFNλ2, IFNλ3 and IFNλ4 in human. However, IFNλ1-λ4 are pseudogenes in mice, which prevents the function study of these cytokines in this animal model ^[3][4].

The members of interferon family are shown in the table 1.

Table 1. The member of IFNs family

In the past two decades, accumulating evidences have revealed the mechanism of the interferon signaling pathway. Since the original discovery of the classical JAK-STAT signaling pathway, it has become clear that the connection and cooperation of multiple distinct signalling cascades are required for the generation of responses to interferons, including the mitogen-activated protein kinase p38 cascade and the phosphatidylinositol 3-kinase cascade. In this part, we focus on the most fundamental classical signaling pathway^[5]. According to different type of interferon and corresponding receptors, we introduce the relevant signaling pathway, respectively.

Type I IFN Signaling Pathway

Almost all cell types particularly plasmacytoid dendritric cells(pDC) upon virus recognition can produce type I interferon. The receptors of type I interferon make up of IFNAR1 and IFNAR2. They stimulate the JAK-STAT pathway, resulting in the expression of IFN-stimulated genes(ISG), which are related to the antiviral host defense. An important transcriptional complex, induced by type I IFNs, is the ISG factor 3 (ISGF3) complex. The mature ISGF3 complex is consist of the phosphorylated STAT1 and STAT2, and combine with IRF9, which does not suffer tyrosine phosphorylation. This complex is the only complex that binds specific elements (known as IFN-stimulated response elements(ISREs)) that are present in the promoters of certain ISGs, then initiating their transcription. Overall, IFNα can be used to treat hepatitis B and C infections, while IFNβ can be used to treat multiple sclerosis. The receptors of type III interferon differ from the former one, but they have the common signaling pathway. Type III interferon plays critical roles in the antiviral host defense, predominantly in the epithelial tissues.

Figure 1 Type I IFN Signaling Pathway

Type II IFN Signaling Pathway

Type II interferon(interferon gamma) is produced by activating T cells, natural killer cells and macrophages et al. upon the stimuli of cytokines like interleukin 12. The receptors of type II interferon make up of IFNGR1 and IFNGR2. The transcription of type II IFN (IFN γ)-dependent genes is regulated by GAS elements, and STAT1 is the most important IFN γ-activated transcription factor for the regulation of these transcriptional responses. After binding to the type II IFN receptor by IFN γ, JAK1 and JAK2 are activated and then phosphorylate STAT1 on the tyrosine residue. Then phosphorylated STAT1 combines with another and forms STAT1–STAT1 homodimers , which translocate to the nucleus and bind GAS elements to initiate transcription. Comparing with type I IFNs, IFN γ does not induce to form ISGF3 complexes, and thereby cannot induce the transcription of genes which have only ISREs in their promoter. In addition to having antiviral activity, type II interferon has important immunoregulatory functions as it is a potent activator of macrophages and T helper 1 cells, at the same time, it has antiproliferative, antiviral and antitumor effects.

Figure 2 Type II IFN Signaling Pathway

Interferon is so important that it is related to many diseases and the application of it should be highlighted.

In this part, we are listing some latest researches about interferon.

#1 The research of Elitza S. Theel et al. suggested that the necessary transition to the QFT-Plus assay would be associated with a minimal difference in assay performance characteristics though comparison of the QuantiFERON-TB Gold Plus and QuantiFERON-TB Gold In-Tube Interferon-γ eelease assays in Patients at Risk for Tuberculosis and in healthcare workers. Please click here to obtain the article.

#2 Li F et al. demonstrated that mice deficient in E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria F. novicida, Mycobacterium, and Listeria by limiting bacterial dissemination. In the absence of HECTD3, type I IFN response was impaired during bacterial infection both in vivo and in vitro. These results indicated that HECTD3 mediated TRAF3 polyubiquitination and type I interferon induction during bacterial infection.

#3 Pulmonary, a researcher from critical care & sleep medicine of department of medicine in state university of New York, found that macrophages could be effectively immune-stimulated by aerosol therapy by repurposing IFN γ as an inhaled aerosol and targeting directly to the lung to treat a host of diseases affected by dysregulated immunity.

[1] Ng, C.T., Sullivan, B.M., et al. Blockade of Interferon Beta, but Not Interferon Alpha, Signaling Controls Persistent Viral Infection[J]. Cell Host Microbe.2015, 17, 653-661.

[2] Cherie T. Ng,1 Juan L. Mendoza, et al. Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes[J]. Cell. 2016, 164, 349-352.

[3] Nan Y, Wu C, et al. Interferon independent non-canonical STAT activation and virus induced inflammation[J]. Viruses, 2018(4): Apr.

[4] Kathrin S, Julia D, et al. Interferon α subtypes in HIV infection[J]. Cytokines Growth Factor Rev, 2018 Feb.

[5] Leonidas C. Platanias. Mechanisms of type I and type II interferon mediated signaling[J]. Nat Rev Immunol.2005 5(5):375-86.

[6] Aqbi HF, Wallace M, et al. IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape, and progression[J]. J Leukoc Biol, 2018 Feb.

[7] Hotter D, Kirchhoff F. Interferons and beyond: Induction of antiretroviral restriction factors[J]. J Leukoc Biol, 2018(3): 465-477.

[8] Flynn JL, Chan J, et al. An essential role for interferon γ in resistance to mycobacterium tuberculosis infection[J]. J Exp Med, 1993(6): 2249-2254.

[9] Rozman P, Svajger U. The tolerogenic role of IFN-γ[J]. Cytokines Growth Factor Rev, 2018 Apr

[10] Dumitrescu L, Constantinescu CS, et al. Recent developments in interferon-based therapies for multiple sclerosis[J]. Expert Opin Biol Ther, 2018 Apr.

[11] Helmo FR, Alves EAR, et al. Intrauterine infection, immune system and premature birth[J]. J Matern Fetal Neonatal Med, 2018(9): 1227-1233.

[12] Amato MP, Portaccio E. Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs[J]. CNS Drugs, 2015(3): 207-220.

[13] Almas S, Vance J, et al. Management of multiple sclerosis in the breastfeeding Mother[J]. Mul Scler Int, 2016: 6527458.

[14] Hale TW, Siddiqui AA, et al.Transfer of interferon beta-1a into human breastmilk[J]. Breastfeed Med, 2012 (2):123-125.

[15] Shepard, C. W., et al. Global epidemiology of hepatitis C virus infection[J]. Lancet Infect. 2005, 5, 558-567.

[16] Robek, M. D., Boyd, et al. Lambda interferon inhibits hepatitis B and C virus replication[J]. J. Virol. 2005, 79, 3851-3854.

[17] Jordan J. Feld and Jay H. Hoofnagle. Mechanism of action of interferon and ribavirin in treatment of hepatitis C[J]. Nature.2005, 436(7053):967-72.

According to the database from Wikipedia, we conclude the classification of growth factors in the Table 1, which includes gene name, Uniprot ID and corresponding receptors.

Table 1. The Classification of Growth Factors

Fibroblast Growth Factors (FGFs) and Receptors

a. Fibroblast growth factors

The fibroblast growth factors are a family of cell signaling proteins, also known as potent regulators of cell proliferation, differentiation and function, which are critically important in normal development, tissue maintenance, wound repair and angiogenesis. FGFs are also associated with several pathological conditions. Mutations in FGF genes are associated with various diseases such as cardiovascular disease, osteoarthritis, hepatocellular carcinoma, intervertebral disc homeostasis and hypophosphatemia^[11][12][13].

FGFs bind heparan sulfate glycosaminoglycans (HSGAGs), which facilitates dimerization (activation) of FGF receptors (FGFRs). There are 22 members of the FGF family in humans from FGF-1 to FGF-23 except for FGF-15 which exists in the mouse. All FGFs except for four members (FGF11-FGF14) bind to FGF Receptors. Because FGF11-FGF14, also known as fibroblast growth factor-homologous factors or FHF1-FHF4, share significant sequence and structural homology with FGFs, and the manner of binding HS is similar to the FGFs. In contrast, Olsen et al. And Mohammadi et al. Who analysed FHF-mediated FGFR activation showed that FHFs are incapable of activating any of the four FGFRs, likely as a result of the structural incompatibility of the FGFR interacting region^[14][15]. According to the present stage of knowledge, FHFs act as intracellular signaling molecules that function independently of FGFRs, via interaction with islet brain-2 scaffold protein and voltage-gated sodium channels, as discussed in detail later^[16]. Based on phylogenetic analysis, the human FGF family can be further divided into seven subfamilies; FGF1-FGF2, FGF4-FGF6, FGF 3/7/10/22, FGF 8/17/18, FGF 9/16/20, FGF 11-FGF14, and FGF 19/21/23. Some other research discoveries showed that FGF24 and 25 are exist in zebra fish, but no data is available about their mammalian counterparts^[17][18].

b. Fibroblast growth factors receptors

The fibroblast growth factor receptors, also known as FGFRs, are receptors that bind to members of the fibroblast growth factor family of proteins. FGFRs are single-pass transmembrane receptors with extracellular ligand-binding domains and an intracellular tyrosine kinase domain that have intracellular tyrosine kinase activity, and belong to the family of receptor tyrosine kinases (RTK)^[19]. Activation of RTKs by their respective ligands induces kinase activation that in turn initiates intracellular signaling networks that ultimately orchestrate key cellular processes, such as cell proliferation, growth, differentiation, migration, and survival. In this way, RTKs play pivotal biological roles during the development and adult life of multicellular organisms. FGFRs are associated with several pathological conditions, such as cancer cell migrations^[20], tumor initiation and progression^[21], carcinogenesis^[22], congenital skeletal dysplasias^[23], et al. Mutations in FGFR genes are associated with various diseases such as breast cancer^[24], bladder cancer^[25], gastric cancer^[26], clear-cell renal cell carcinoma^[27], developmental corruption and malignant disease^[28], et al.

The FGFRs includes four genes encoding closely related transmembrane, tyrosine kinase receptors (termed FGFR1 to FGFR4). A typical FGFR consists of a signal peptide that is cleaved off, three immunoglobulin (Ig)–like domains, an acidic box, a transmembrane domain, and a split tyrosine kinase domain.

Transforming growth factors & receptors

TGF-β Signaling Pathway

In TGF-β signaling pathway, the family members of TGF-βs include TGF-betas, activins and bone morphogenetic proteins (BMPs), which are structurally related secreted cytokines found in various species ranging from insects to mammals. TGF-β signaling pathway is involved in many cellular processes, including cell growth, cell differentiation, apoptosis, cellular homeostasis, et al.

Fig. 1. The image of TGF-β signaling pathway

The mechanism includes four parts, Ligand binding, Receptor recruitment and phosphorylation, CoSMAD binding, and Transcription. TGF-beta family ligands binds to the type II receptor and recruits Type I, whereby type I receptor is phosphorylated and activated by type II receptor. Then, the type I receptor phosphorylates receptor-activated Smads(R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads combine with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins.

VEGF Signaling Pathway

When a VEGF binds to its receptor, the receptor can transiently exert its kinase activity and form a complex with an intracellular tyrosine or serine/threonine kinase. Then, the activated receptors result in the activation of other proteins in the signaling pathway and the production of various second messengers. Finally, these signals are transmitted into the nucleus and induce the expression of specific genes.

Fig. 2. The image of VEGF signaling pathway

Now, although the evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells also is not very much, it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to form receptor dimer, then, followed by intracellular activation of the PLCγ; Subsequently, PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3′ -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.

Wnt Signaling Pathway

The Wnt signaling pathway is a group of signal transduction pathway made of proteins that pass signals into a cell through cell surface receptors.

Wnt signaling diversifies into three main branches: 1. The canonical Wnt pathway, also known as classical, activates target genes through stabilization of β-catenin in the nucleus. The function of this pathway during embryonic development has been originally elucidated by experimental analysis of axis development in the frog Xenopus laevis and of segment polarity and wing development in the fly Drosophila melanogaster. 2. The planar cell polarity pathway involves RhoA and Jun Kinase (JNK) and controls cytoskeletal rearrangements. Its main role is the temporal and spatial control of embryonic development, as exemplified in the polar arrangement of cuticular hairs in Drosophila or the convergent-extension movements in Xenopus embryos. 3. The Wnt/Ca2+ pathway is stimulated by Wnt 5a and Wnt 11 and involves an increase in intracellular Ca2+ and activation of Ca2+-sensitive signalling components, such as calmodulin-dependent kinase, the phosphatase calcineurin, and the transcription factor NF-AT.

• Komaki Y’s team have revealed that hepatocyte growth factor facilitates esophageal mucosal repair and inhibits the submucosal fibrosis in a rat model of esophageal ulcer. If you want to know more information, please click here to view the article.
• Regeenes R1, Silva PN, et al. have demonstrated that fibroblast growth factor receptor 5 (FGFR5) is a co-receptor for FGFR1 that is up-regulated in beta-cells by cytokine-induced inflammation. If you want to know more information, please click here to view the article.
• Breit A1, Miek L, et al. have found that insulin-like growth factor-1 acts as a zeitgeber on hypothalamic circadian clock gene expression via glycogen synthase kinase-3β signaling. If you want to know more information, please click here to view the article.

[1] Stauber DJ, DiGabriele AD, et al. Structural interactions of fibroblast growth factor receptor with its ligands[J]. Proceedings of the National Academy of Sciences of the United States of America. 2000, 97 (1): 49–54

[2] Santos-Ocampo S, Colvin JS, et al. Expression and biological activity of mouse fibroblast growth factor-9[J]. The Journal of Biological Chemistry. 1996, 271 (3): 1726–31

[3] Ornitz DM, Xu J, et al. Receptor specificity of the fibroblast growth factor family [J]. The Journal of Biological Chemistry. 1996, 271(25):15292-15297

[4] Duchesne L, Tissot B, et al. N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding [J]. The Journal of Biological Chemistry. 2006, 281(37):27178-27189

[5] Davidson D, Blanc A, et al. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis[J]. The Journal of Biological Chemistry. 2005, 280(21):20509-20515

[6] Chellaiah A, Yuan W, et al. Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity[J]. The Journal of Biological Chemistry. 1999, 274 (49): 34785–94

[7] Pavel Krejci, Jirina Prochazkoval, et al. Molecular pathology of the fibroblast growth factor family[J]. Hum Mutat. 2009, 30(9): 1245–1255

[8] Laureys G, Barton DE, et al. Chromosomal mapping of the gene for the type II insulin-like growth factor receptor/cation-independent mannose 6-phosphate receptor in man and mouse[J]. Genomics.1988, 3 (3): 224–9

[9] Ojeda, S. R.; Ma, Y. J., et al. The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty[J]. Molecular Psychiatry. 1997, 2 (5): 355–358

[10] Gilchrist, R., Lane, M., et al. Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality[J]. Human Reproduction Update. 2008, 14(2), pp.159-177

[11] Yun, Y.-R., Won, J. E., et al. Fibroblast growth factors: biology, function, and application for tissue regeneration[J]. Tissue Eng. 2010, 218142

[12] Coleman SJ, Grose RP, et al. Fibroblast growth factor family as a potential target in the treatment of hepatocellular carcinoma[J]. J Hepatocell Carcinoma. 2014, 29;1:43-54

[13] Ellman MB, An HS, et al. Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis[J]. Gene. 2008, 15;420(1):82-9

[14] Olsen SK, Garbi M, et al. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs[J]. J Biol Chem. 2003, 278:34226–34236

[15] Mohammadi M, Dikic I, et al. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction[J]. Mol Cell Biol. 1996; 16:977–989

[16] Goldfarb M. Fibroblast growth factor homologous factors: evolution, structure, and function[J]. Cytokine Growth Factor Rev. 2005; 16:215–220

[17] Roy NM, Sagerstrom GG. An early Fgf signal required for gene expression in the zebrafish hindbrain primordium[J]. Brain Res Dev Brain Res. 2004; 148(1): 27-42

[18] Katoh Y, Katoh M. Comparative genomics on FGF7, FGF10, FGF22, orthologs, and identification of fgf25[J]. Int J Mol Med. 2005; 16(4): 767-70

[19] Schlessinger J. Cell signaling by receptor tyrosine kinases[J]. Cell. 2000, 103:211–25

[20] Nguyen T, Mège RM. N-Cadherin and Fibroblast Growth Factor Receptors crosstalk in the control of developmental and cancer cell migrations[J]. Eur J Cell Biol. 2016, 95(11):415-426

[21] Feng S, Zhou L, et al. Fibroblast growth factor receptors: multifactorial-contributors to tumor initiation and progression[J]. Histol Histopathol. 2015, 30(1):13-31

[22] Haugsten EM, Wiedlocha A, et al. Roles of fibroblast growth factor receptors in carcinogenesis[J]. Mol Cancer Res. 2010, 8(11):1439-52

[23] Sanak M. Molecular genetics of congenital skeletal dysplasias related to mutations of fibroblast growth factor receptors[J]. Med Wieku Rozwoj. 1999, 3(1):67-82

[24] Wang S, Ding Z. Fibroblast growth factor receptors in breast cancer[J]. Tumour Biol. 2017, 39(5):1010428317698370

[25] Morales-Barrera R, Suárez C, et al. Targeting fibroblast growth factor receptors and immune checkpoint inhibitors for the treatment of advanced bladder cancer: New direction and New Hope[J]. Cancer Treat Rev. 2016, 50:208-216

[26] Inokuchi M, Fujimori Y, et al Therapeutic targeting of fibroblast growth factor receptors in gastric cancer[J]. Gastroenterol Res Pract. 2015, 2015:796380

[27] Sonpavde G, Willey CD, et al. Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma[J]. Expert Opin Investig Drugs. 2014, 23(3):305-15

[28] Kelleher FC, O’Sullivan H, et al. Fibroblast growth factor receptors, developmental corruption and malignant disease[J]. Carcinogenesis. 2013, 34(10):2198-205

[29] Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases[J]. Cell. 2010, 141:1117–1134

[30] Potter JD. Colorectal cancer: molecules and populations[J]. J Natl. Cancer Inst. 1999, 91:916–932

[31] Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression[J]. Nat Rev Cancer 2010, 10:415-424

[32] Huakang Tu, Thomas U. Ahearn, et al. Transforming Growth Factors and Receptor as Potential Modifiable Pre-Neoplastic Biomarkers of Risk for Colorectal Neoplasms[J]. MOLECULAR CARCINOGENESIS. 2015, 54:821-830

[33] Bellone G, Gramigni C, et al. Abnormal expression of Endoglin and its receptor complex (TGF-beta1 and TGF-beta receptor II) as early angiogenic switch indicator in premalignant lesions of the colon mucosa[J]. Int J Oncol. 2010, 37:1153–1165

[34] Hawinkels LJ, Verspaget HW, et al. Active TGF-beta1 correlates with myofibroblasts and malignancy in the colorectal adenoma-carcinoma sequence[J]. Cancer Sci. 2009, 100:663–670

[35] Li Y, Zhu G, et al. Simultaneous stimulation with tumor necrosis factor-α and transforming growth factor-β1 induces epithelial-mesenchymal transition in colon cancer cells via the NF-κB pathway[J]. Oncol Lett. 2018, 15(5):6873-6880

[36] Badawy AA, El-Hindawi A, et al. Impact of epidermal growth factor receptor and transforming growth factor-α on hepatitis C virus-induced hepatocarcinogenesis[J]. APMIS. 2015, 123(10):823-31

[37] Walker F, Abramowitz L, et al. Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus[J]. Human Pathology. 2009, 40 (11): 1517–27

[38] Midgley AC, Rogers M, et al. Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts[J]. The Journal of Biological Chemistry[J]. 2013, 288 (21): 14824–38

[39] Holmes K, Roberts OL, et al. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition[J]. Cell Signal. 2007, 19 (10): 2003–2012

[40] Zygmunt T, Gay CM, et al. Semaphorin-PlexinD1 Signaling Limits Angiogenic Potential via the VEGF Decoy Receptor sFlt1[J]. Dev Cell. 2011, 21 (2): 301–314

Leukemia is a malignant clonal disease of hematopoietic stem cells. Leukemia cells in the clone will stop at different stages of cell development due to uncontrolled proliferation, differentiation failure, and obstructed apoptosis. In bone marrow and other hematopoietic tissues, leukemia cells proliferate and accumulate in large numbers, and infiltrate other tissues and organs, causing normal hematopoietic function to be inhibited. As the figure 1 shows, normal blood contains red blood cells (RBCs), white blood cells (WBCs), and platelets. Leukemia cells outnumber normal cells in leukemia.

Figure 1. a diagram of components of normal blood and leukemia

Generally speaking, leukemia refers to cancers of the WBCs. WBCs play a vital role in protecting body from invasion by bacteria, viruses, and fungi. In leukemia, the WBCs have an abnormal unlike normal WBCs. They divide too quickly and eventually crowd out normal cells. Most of WBCs are produced in the bone marrow, but certain types of WBCs are also made in the lymph nodes, spleen, and thymus gland.

In fact, there are many types of leukemia in clinic. Based on different speed of disease development, leukemia is divided into two types, including acute leukemia and chronic leukemia. In acute leukemia, leukemia cells multiply rapidly and the disease progresses quickly. In chronic leukemia, the disease progresses slowly and early symptoms may be very mild.

Most often, leukemia is a cancer of the white blood cells, but some leukemias start in other blood cell types. According to different cell types, leukemia is classified into two types. One is myelogenous leukemia developing from the myeloid cell line. Another is lymphocytic leukemia developing from the lymphoid cell line.

Hence, there are four major types of leukemia in clinic. As the following table shows, acute myelogenous leukemia is the most common form of leukemia. The five-year survival rate of chronic lymphocytic leukemia is the highest. Most childhood leukemias are acute lymphocytic leukemia (ALL). Most of the remaining cases are acute myeloid leukemia (AML). Chronic leukemias are rare in children.

In addition to these four main types of leukemia, there also are various subtypes of leukemia. Subtypes of lymphocytic leukemia include hairy cell, Waldenstrom’s macroglobulinemia, prolymphocytic, and lymphoma cell leukemia.

What causes leukemia? This question is frequently asked by patients and parents alike. As mentioned previously, blood has three types of cells, involving red blood cells, white blood cells, and platelets. White blood cells fight infection, red blood cells carry oxygen, and platelets help blood clot. Every day, your bone marrow produces billions of new blood cells, and most of them are red cells. When you have leukemia, your body produces more white cells than it needs.

These leukemia cells can’t fight infection as well as white blood cells do. And because there are so many of them, they start to affect the function of your organs. Over time, you may not have enough red blood cells to carry oxygen, enough platelets to clot your blood, and enough normal white blood cells to fight infection.

Generally, leukemia develops when the DNA of some blood cells (mainly white cells) mutates or damages, disabling their ability to guide the action of cells. Certain abnormalities cause the cell to grow and divide more rapidly and to continue living when normal cells would die. Over time, these mutated cells replace the healthy blood cells and crowd out healthy blood cells in the bone marrow, leading to fewer healthy white blood cells, red blood cells and platelets, causing the signs and symptoms of leukemia.

Different types of leukemia can cause different problems. You might not notice any signs in the early stages. Although the signs and symptoms aren’t enough to diagnose the disease, they can be clues for you and your doctor so that you can find the problem as soon as possible. When you do have symptoms, they may include:

Poor blood clotting: This can cause a person to bruise or bleed easily and heal slowly.

Red spots on the skin: These red spots, also called petechiae develop when immature white blood cells crowd out platelets, which are crucial for blood clotting.

Frequent infections: The white blood cells are crucial for fighting infection. If white blood cells don’t function correctly, a person may develop frequent infections.

Anemia: As fewer effective red blood cells become available, a person may become anemic. This means that they do not have enough hemoglobin in their blood.

Additionally, the symptoms of leukemia also include weakness or fatigue, fever or chills, pain in your bones or joints, weight loss, night sweats, shortness of breath and swollen lymph nodes or organs like your spleen. Leukemia can also cause symptoms in organs that have been infiltrated by the cancer cells. For example, if the cancer spreads to the central nervous system, it can cause headaches, nausea and vomiting, confusion, loss of muscle control, and seizures. Furthermore, leukemia can also spread to other parts of your body, including: the lungs, gastrointestinal tract, heart and kidneys.

What causes leukemia? This question is frequently asked by patients and parents alike ^[1]. Currently, scientists don’t understand the exact causes of leukemia. It seems to develop from a combination of genetic and environmental factors. Most subtypes of childhood leukemia have their initial genetic mutation before birth ^[2] and only a fraction of these preleukemic clones will progress to the development of leukemia.

You can’t prevent leukemia, but certain things (called risk factors) may trigger it. A risk factor is anything that affects your chance of getting a disease. But having one or more risk factors does not mean that you will get the disease. However, it’s still important to know about the risk factors for leukemia because there may be things you can do that might lower your risk of getting it. The risks of leukemia include:

• Exposure to high levels of radiation or chemotherapy: This could include having received radiation therapy or chemotherapy for a previous cancer, although this is a more significant risk factor for some types than others.
• Certain viruses: The human T-lymphotropic virus (HTLV-1) has links to leukemia.
• Exposure to benzene: This is a solvent that manufacturers use in some cleaning chemicals and hair dyes.
• Have a family history of leukemia: Having siblings with leukemia can lead to a low but significant risk of leukemia. If a person has an identical twin with leukemia, they have a 1 in 5 chance of having the cancer themselves.
• Have a genetic disorder like Down syndrome: Children with Down syndrome have a third copy of chromosome 21. This increases their risk of acute myeloid or acute lymphocytic leukemia to 2–3%, which is higher than in children without this syndrome.
• Smoking, which increases your risk of developing acute myeloid leukemia (AML).
• Immune suppression: Childhood leukemia may develop because of the deliberate suppression of the immune system. This might occur after an organ transplant when a child takes medications to prevent their body from rejecting the organ.

Leukemia may be suspected if you have concerning symptoms. Your doctor will begin with

Blood tests: a complete physical examination, but leukemia can’t be fully diagnosed by a physical exam. So doctors will further to use blood tests, biopsies, and imaging tests to make a diagnosis.

Blood tests: A complete blood count is usually used to determine the numbers of RBCs, WBCs, and platelets in the blood.

Biopsies: Tissue biopsies can be obtained from the bone marrow or lymph nodes to look for evidence of leukemia. The type of leukemia and its growth rate can be identified by these small samples. Moreover, biopsies of other organs, like the liver and spleen, can suggest if the cancer has spread.

Once leukemia is diagnosed, it’ll be staged. Staging helps your doctor determine your outlook. And a number of other tests can be used to assess the progression of the disease, including flow cytometry (determining their growth rate), liver function tests (whether leukemia cells are affecting or invading the liver), lumbar puncture (whether the cancer has spread to the central nervous system) and Imaging tests (such as X-rays, ultrasounds, and CT scans, help doctors look for any damage to other organs that’s caused by the leukemia).

The treatment of Leukemia usually depends on the type of the cancer a person has, their age, and their overall state of health. Some types of leukemia grow slowly and don’t need immediate treatment. However, if treatment starts early, the chance of a person achieving remission is higher. Types of treatment for leukemia usually involves one or more of the following:

Watchful waiting: A doctor may not actively treat slower growing leukemias, such as chronic lymphocytic leukemia (CLL).

Chemotherapy, a primary treatment for AML, uses drugs to target and kill leukemia cells through a drip or a needle. According to different types of leukemia, you may take a single drug or a combination of different drugs. However, besides killing cancer cells, they can also damage noncancerous cells and cause severe side effects, including hair loss, weight loss, and nausea.

Radiation therapy uses high-energy radiation to destroy bone marrow tissue before a transplant. Radiation can be applied to a specific area or to your entire body.

Stem cell transplantation replaces diseased bone marrow with healthy bone marrow to create noncancerous blood cells, either your own or from a donor. This procedure is also called a bone marrow transplant. Before transplantation, your doctor will destroy the existing bone marrow with chemotherapy, radiation therapy, or both.

Immune therapy uses treatments that help your immune system recognize and attack cancer cells ^[3].

Targeted therapy uses tyrosine kinase inhibitors that target cancer cells without affecting other cells, reducing the risk of side effects. For example, imatinib (Gleevec) is a targeted drug that’s commonly used against CML.

[1] Gary Dahl and Joseph Wiemels. What Causes Leukemia [J]? Pediatr Blood Cancer. 2015, 62:1123–1124.

[2] Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia [J]. Nat Rev Cancer. 2003, 3:639–649.

[3] Evan M. Hersh, Jordan U. Gutterman, and Giora M. Immunotherapy of leukemia [J]. Medical Clinics of North America. 1976.

Endometrial cancer, sometimes also called uterine cancer, starts in the layer of cells that form the lining (endometrium) of the uterus (Figure 1). Most uterine cancers start as endometrial cancer. Other types of cancer can form in the uterus, including uterine sarcoma, but all of them are much less common than endometrial cancer. Endometrial cancer affects mainly post-menopausal women. The mean age of women diagnosed with endometrial cancer is 61 years, with most cases diagnosed in women between the ages of 50 and 60 years ^{[1] [2]}. It’s uncommon in women under the age of 45.

Figure 1. a diagram of endometrial cancer

According to the National Cancer Institute, approximately 3 in 100 women will be diagnosed with endometrial cancer at some point in their lives. More than 80 percent of people with endometrial cancer survive for five years or longer after receiving the diagnosis.

Endometrial cancer commonly has been classified into two types. Type I commonly is estrogen-related and accounts for about 80% of endometrial cancers. It usually occurs in younger, obese, or perimenopausal women. These tumors are usually low-grade and mainly secondary to endometrial hyperplasia. The degree of malignancy is not high, and it is closely related to estrogen exposure without progesterone resistance. The risk factors for type I endometrial cancer are relatively clear, including exposure to more endogenous estrogen or exogenous estrogen. These tumors may show microsatellite instability and mutations in PTEN, PIK3CA, K-ras, and CTNNBI ^[3].

Type II is relatively rare. It was originally called non-estrogen-dependent. It occurs in an older cohort of women than type I, and is mainly high-grade serous cell carcinoma and clear cell carcinoma. These tumors may exhibit p53 mutations in approximately 10–30% of cases. Type II disease represents up to 10% of cases. The epidemiologic profile of women with type II disease is not certain. In this article, we focus on the type I endometrial cancer.

Unlike most other cancers in the U.S, endometrial cancer is rising in both incidence and associated mortality ^[4]. The patient with endometrial cancer usually has some symptoms as follows:

• Vaginal bleeding: A small number of early endometrial cancers may have no symptoms and are difficult to detect clinically. But 90% of the main symptoms of endometrial cancer are various vaginal bleeding, including after menopause and between periods. Among of them, Postmenopausal vaginal bleeding is the main symptom of endometrial cancer patients, and more than 90% of postmenopausal patients see a doctor with vaginal bleeding symptoms.
• Menstrual disorders: About 20% of endometrial cancer patients are perimenopausal women, and only 5%-10% of young women under 40 years old. Patients may present with changes in the length or heaviness of menstrual periods.
• Abnormal vaginal discharge: a small amount of serous or bloody discharge can be seen in the early stage. In the late stage, local infection and necrosis occurred due to the increase in tumor volume, and foul-smelling pus and blood-like fluid was discharged.
• Pain: It is mostly low abdominal pain and discomfort, which can be caused by empyema or effusion in the uterus. In the late stage, the disease spreads to the parauterine tissue ligaments or compresses nerves and organs, and lower limbs or lumbosacral pain may also occur.
• Others: The enlarged uterus in the lower abdomen can be palpable in advanced patients, and systemic failure such as anemia, weight loss, fever, and cachexia can occur.

Endometrial cancer is most often diagnosed after a woman see a doctor. The doctor will ask about the woman’s symptoms, risk factors, and medical history. Moreover, the doctor will also do a pelvic exam and a physical exam. Procedures used to diagnose endometrial cancer usually include:

• Examining the pelvis. During a pelvic exam, your doctor carefully inspects the outer portion of your genitals, and then inserts two fingers of one hand into your vagina and simultaneously presses the other hand on your abdomen to feel your uterus and ovaries. Additionally, He or she also inserts a device called a speculum into your vagina. The speculum opens your vagina so that your doctor can view your vagina and cervix for abnormalities.
• Using sound waves to take pictures of the inside of the body. A transducer or probe gives off sound waves and picks up the echoes as they bounce off the organs. A computer translates the echoes into pictures. Your doctor may recommend a transvaginal ultrasound to look at the thickness and texture of the endometrium and help rule out other conditions.

To find out exactly what kind of endometrial change is present, the doctor usually does the following procedures.

• Using a scope to examine your endometrium. During a hysteroscopy, your doctor inserts a very thin, flexible, lighted tube via your vagina and cervix into your uterus.
• Removing a sample of tissue for testing. To get a sample of cells from inside your uterus, you’ll likely undergo an endometrial biopsy. This involves removing tissue from your uterine lining for laboratory analysis.
• Dilation and curettage (D&C). If biopsy sample doesn’t provide enough tissue or if the biopsy results are unclear, a D&C must be done. During D&C, tissue is scraped from the lining of your uterus and examined under a microscope for cancer cells.

Over time, endometrial cancer can potentially spread from the uterus to other parts of the body. Once you have been diagnosed as endometrial cancer, doctor works to determine the stage of your cancer. Tests used to determine your cancer’s stage may include a chest X-ray, a computerized tomography (CT) scan, positron emission tomography (PET) scan and blood tests (including complete blood count and CA-125 blood test). The final determination of your cancer’s stage may not be made until after you undergo surgery. Generally, the cancer is classified into five stages based on how much it has grown or spread:

A risk factor is anything that increases your chance of getting a disease. Different cancers have different risk factors. Some risk factors, such as smoking or sun exposure, can be changed. But, others, like a person’s age or family history, can’t be changed. The epidemiology of endometrial cancer includes women with genotypic and phenotypic risk, including:

• Obesity – raises oestrogen levels. Obesity is one of the most important risk factors for this disease, and as rates of obesity have risen, rates of endometrial cancer have also increased. Obesity and conditions associated with metabolic syndrome, including diabetes and polycystic ovary syndrome, are risk factors for the development of endometrial cancer ^{[5] [6] [7]}. In the U.S, 57% of all endometrial cancers are attributable to obesity.
• Reproductive, menstrual, and medical risk comorbidities can increase or decrease the risk of a woman having development of endometrial cancer ^[8]. Continuous estrogen stimulation, albeit it exogenous or endogenous, like taking estrogen after menopause, birth control pills, or tamoxifen, can alter the normal endometrial cycle.
• Using an intrauterine device (IUD) for birth control seem to have a lower risk of getting endometrial cancer. Information about this protective effect is limited to IUDs that do not contain hormones.
• Age. The risk of endometrial cancer increases as a woman gets older.
• Family history. Endometrial cancer tends to run in some families with the history of endometrial, colorectal, or breast cancer.

The stage of endometrial cancer is the most important factor in choosing treatment. In another word, Treatment depends upon the stage. Generally speaking, surgery is the first treatment for almost all women diagnosed as endometrial cancer. The operation includes removing the uterus, fallopian tubes, and ovaries. Lymph nodes from the pelvis and around the aorta may also be removed and tested for cancer spread. And pelvic washings may be done, too. The tissues removed at surgery are tested to see how far the cancer has spread (the stage, please see the section 5). Depending on the stage of the cancer, other treatments, such as radiation and/or chemotherapy may be recommended.

For some women who still want to be able to get pregnant, surgery may be put off for a time and other treatments tried instead. If a woman isn’t well enough to have surgery, other treatments, like radiation, will be used.

[1] Sorosky JI. Endometrial cancer [J]. Obstet Gynecol. 2008, 111: 436–47.

[2] Joel I. Sorosky. Endometrial cancer [J]. OBSTETRICS & GYNECOLOGY. 2012, 120 (2): 383-397.

[3] Prat J, Gallardo A, Cuatrecasas M, et al. Endometrial carcinoma: pathology and genetics [J]. Pathology. 2007, 39: 1–7.

[4] Henley SJ, Ward EM, Scott S, et al. Annual report to the nation on the status of cancer. I. National cancer statistics [J]. Cancer. 2020, 126: 2225-49.

[5] Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body fatness and cancer — viewpoint of the IARC Working Group [J]. N Engl J Med. 2016, 375: 794-8.

[6] Saed L, Varse F, Baradaran HR, et al. The effect of diabetes on the risk of endometrial cancer: an updated a systematic review and meta-analysis [J]. BMC Cancer. 2019, 19: 527.

[7] Karen H. Lu, and Russell R. Broaddus. Endometrial Cancer [J]. N Engl J Med. 2020, 383: 2053-64.

[8] Brinton LA, Berman ML, Mortel R, et al. Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study [J]. Am J Obstet Gynecol 1992, 167: 1317–25.

Bladder cancer refers to a malignant tumor that occurs on the cells of bladder. The bladder is a hollow muscular organ in your lower abdomen that stores urine (Figure 1). Bladder cancer most often begins in the cells (also called urothelial cells) that line the inside of your bladder. It is the most common malignant tumor of the urinary system and one of the ten most common tumors throughout the body. Its incidence is second only to prostate cancer in the West. Bladder cancer can occur at any age, even in children. The incidence rate increases with age, with a high incidence age of 50 to 70 years.

Figure 1. Male urinary system

In 2004, the pathological types of bladder cancer in the histological classification of urinary system tumors in the WHO “Urinary System and Male Reproductive Organ Tumor Pathology and Genetics” include bladder urothelial carcinoma, bladder squamous cell carcinoma, bladder adenocarcinoma, and other rare (including bladder clear cell carcinoma, bladder small cell carcinoma and bladder carcinoid). The most common one is bladder urothelial cancer, which accounts for more than 90% of the total number of bladder cancer patients. The commonly referred to as bladder cancer refers to bladder urothelial cancer (formerly called bladder transitional cell carcinoma).

No matter what’s your age, it’s good to know the possible symptoms of bladder cancer. Although they aren’t enough to diagnose the disease, they can be clues for you and your doctor so that you can find the problem as soon as possible. Treatment works best early on, when a tumor is small and hasn’t spread. These symptoms are important to see your doctor so they can take a closer look at your health and take action. Bladder cancer symptoms may include blood in urine (hematuria), frequent urination, painful urination and back pain.

Among of them, blood in urine is the main symptom of bladder cancer. About 90% of patients with bladder cancer have hematuria in the initial clinical manifestations, usually painless, intermittent, gross hematuria, and sometimes microscopic hematuria. Hematuria may only occur once or last for 1 day to several days, and can be relieved or stopped by itself. It often gives the patient with the hematuria the illusion of healing after taking the medicine.

Before learning the stages of bladder cancer, we need to know the structure of bladder. The bladder consists of three layers of tissue (Figure 2). The innermost layer of the bladder (called mucosa or urothelium), which comes in contact with the urine stored inside the bladder. The middle layer is a thin lining (known as the “lamina propria”) and forms the boundary between the inner “mucosa” and the outer muscular layer. This layer has a network of blood vessels and nerves and is an important landmark of the staging of bladder cancer. The outer layer of the bladder (the “muscularis”) comprises of the “detrusor” muscle. This is the thickest layer of the bladder wall.

Figure 2. Types and stages of bladder cancer.

*This figure is derived from the publication on Nat Rev Dis Primers. ^[2]

As the Figure 2 shows, bladder cancer generally originates from the urothelium of the bladder and is referred to as urothelial carcinoma, which is the most common type of bladder cancer. Papillary tumors that are limited to mucosa or have invaded the lamina propria are classified as Ta and T1, respectively. Carcinoma in situ (Tis) is a flat, poorly differentiated tumor confined to mucosa. Stage 2 is that tumors have invaded the muscle layer either superficially (T2a) or deeply (T2b). T3 tumors have invaded beyond the muscularis propria into perivesical fat (T3a invasion is microscopic, T3b is macroscopic). T4a tumours have invaded the prostate, uterus, vagina and/or bowel, whereas T4b tumours have invaded the pelvic or abdominal walls ^[3].

Current studies have shown that bladder cancer, like many other cancers, is due to a variety of carcinogenic factors acting on normal cells for a long time, leading to the activation of proto-oncogenes, and failure to repair damaged DNA in time during the replication and transcription process, affecting the cell cycle and causing unlimited replication and proliferation of cancer cells.

In terms of mechanisms of bladder cancer, metabolism of bladder cancer represents a key issue for cancer research ^[4]. Several metabolic altered pathways are involved in bladder tumorigenesis. In this section, we list the main metabolic pathways involved in the pathogenesis of bladder cancer.

Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. And the high glycolytic flux usually depends on the overexpression of glycolysis-related genes, including SRC-3, GLUT1, GLUT3, LDHA, LDHB, HK1, HK2, PKM, and HIF-1a, leading to an overproduction of pyruvate, alanine and lactate.

Concurrently, bladder cancer metabolism also displays an increased expression of genes G6PD and FASN, and companies with a decrease of AMPK and Krebs cycle activities. G6PD is favored in the pentose phosphate pathway, and FASN is favored in the fatty-acid synthesis. Moreover, the PTEN/PI3K/AKT/mTOR pathway, as central regulator of aerobic glycolysis, is hyper-activated in bladder cancer, contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway also plays a robust role in bladder cancer development.

The etiology of bladder cancer is currently unclear. There are both internal factors and external environmental factors. The two more clear risk factors for disease are smoking and occupational exposure to aromatic amine chemicals.

Smoking is currently the most certain risk factor for bladder cancer. 30% to 50% of bladder cancer is caused by smoking. Comparing to people without smoking, smoking can increase the risk of bladder cancer by 2 to 6 times. With the prolongation of smoking, the incidence of bladder cancer also significantly increased.

Another important disease risk factor is related to a series of occupations or occupational exposure. It has been confirmed that aniline, diaminobiphenyl, 2-naphthylamine, and 1-naphthylamine are all carcinogens of bladder cancer. People with long-term exposure to these chemicals are more likely to develop bladder cancer. Patients with bladder cancer caused by occupational factors account for 25% of the total number of bladder cancer patients. Industries related to bladder cancer include aluminum products, coal tar, asphalt, dyes, rubber, and coal gasification.

In addition, according to a report issued by the International Agency for Research on Cancer (IARC) on October 17, 2013, air pollution is also one of the human carcinogens, and its carcinogenic risk is classified as the first category. The report pointed out that there is sufficient evidence that air pollution not only has a causal relationship with lung cancer, but also increases the risk of bladder cancer. So far, haze is also one of the clear carcinogenic factors.

Urothelial carcinoma of the bladder is divided into non-muscle invasive urothelial carcinoma and muscle invasive urothelial carcinoma. Patients with non-muscular invasive urothelial carcinoma usually use transurethral resection of the bladder tumor, followed by bladder perfusion to prevent recurrence.

Patients with muscular invasive urothelial carcinoma, bladder squamous cell carcinoma, and adenocarcinoma are mostly treated with total cystectomy, and some patients can be treated with partial cystectomy. Patients with muscular invasive urothelial carcinoma can also be treated with neoadjuvant chemotherapy and surgery first. Metastatic bladder cancer is dominated by chemotherapy. Commonly used chemotherapy regimens include M-VAP (methotrexate + vinblastine + adriamycin + cisplatin), GC (gemcitabine + cisplatin) and MVP (methotrexate + The vinblastine + cisplatin) regimen, the effective rate of chemotherapy is 40% to 65%.

Bladder cancer has the characteristics of multifocality and implantation, so the recurrence rate after surgery is high. Therefore, after bladder cancer surgery, adjuvant treatment is usually needed. So, what treatments are needed after bladder cancer surgery?

As mentioned previously, patients with non-muscular invasive urothelial carcinoma will be treated with bladder perfusion therapy. Bladder perfusion therapy is to inject anticancer drugs into the bladder to kill tumor cells remaining after surgery. There are two main types of drugs for bladder perfusion therapy, one is chemotherapeutics and the other is immunotherapy, and chemotherapy drugs are currently more commonly used. The chemotherapeutics used for bladder cancer include birubicin, epirubicin, adriamycin and mitomycin. For most bladder cancers, bladder infusion chemotherapy can significantly reduce the risk of tumor recurrence after surgery.

In addition to bladder perfusion therapy, regular cystoscopy is also very important. In low-risk patients, there was no recurrence after the cystoscopy was rechecked 3 months after the operation. The next cystoscopy can be checked 1 year after the operation. Then once a year for 5 years. But, high-risk patients need to review the cystoscopy every 3 months for 2 years after the operation, and every 6 months from the 3rd year, and once a year after the 5th year.

Although there’s no guaranteed way to prevent bladder cancer, you can take the following steps to help reduce your risk.

Increase drinking water: Researchers from Harvard University in the United States conducted a 10 year follow-up study on nearly 50,000 American men between the ages of 40 and 75, and found that men who drink 6 large glasses of plain water a day have a lower risk of bladder cancer than those who drink only 1 cup. It may be that the liquid will excrete carcinogens from the body before they can affect the bladder. Thereby reducing the chance of attaching to the bladder wall. Note that, in order to minimize the intake of the chemical components in the water, the water must be boiled.

Quit smoking and alcohol: Studies have shown that cigarettes contain nicotine, tar, tobacco-specific nitrosamines and other toxic carcinogens. People who smoke a lot have a higher concentration of carcinogens in the urine. If the daily smoking index reaches 600 (number of cigarettes smoked per day × number of years of smoking), it has reached the risk of bladder cancer. Therefore, early quitting smoking and drinking can minimize the risk of bladder cancer.

Adhere to scientific eating habits and eat more fresh vegetables and fruits: Eat as little meat as possible, because meat can produce substances similar to aniline and benzidine during the process of metabolism in the body. An investigation found that workers exposed to chemical raw materials such as aniline and benzidine suffer more from bladder cancer.

Cervical cancer is a type of cancer that occurs in the cells of the cervix-the lower part of the uterus that connects to the vagina (Figure 1). It is the most common gynecological malignancy. This cancer can affect the deeper tissues of their cervix and may spread to other parts of their body, often the lungs, liver, bladder, vagina, and rectum.

Figure 1. a diagram of cervical cancer

Cervical cancer is mainly divided into two types, including squamous cell carcinoma and adenocarcinoma. Among of them, squamous cell carcinoma begins in the thin, flat cells (squamous cells) lining the outer part of the cervix, which projects into the vagina. It is the main type of cervical cancers. Adenocarcinoma begins in the column-shaped glandular cells that line the cervical canal. Actually, less commonly, cervical cancer have features of both squamous cell carcinomas and adenocarcinomas. This type of cervical cancer is also called adenosquamous carcinomas or mixed carcinomas.

Generally, cervical cancer begins when healthy cells in the cervix develop changes or mutations in their DNA. The mutations tell the cells to grow and multiply out of control, and they don’t die. And the accumulating abnormal cells form a tumor. Cancer cells invade nearby tissues and can break off from a tumor to metastasize elsewhere in the body.

Currently, accumulating evidence has revealed that most cervical cancer are caused by the sexually transmitted human papillomavirus (HPV), which is a group of about 100 related virus. Some of them cause a type of growth called papillomas, which are more commonly known as warts. In addition to HPV infection, there are also several other things that can increase your risk of cervical cancer, including having HIV (the virus that causes AIDS), smoking, taking birth control pills for a long time (five or more years), having given birth to three or more children and having several sexual partners. So what is HPV? And how does HPV infection cause cervical cancer?

HPV encompass more than 120 different types that may infect human skin and mucosa. HPV is a relatively small, non-enveloped virus, 55 nm in diameter. The HPV gene consists of a single molecule of double-stranded, circular DNA containing approximately 7,900 bp associated with histones. All open reading frame (ORF) protein-coding sequences are restricted to one strand. The gene is functionally divided into three regions. The first is a noncoding upstream regulatory region of 400 to 1,000 bp, which has been referred to as the noncoding region, the long control region (LCR), or the upper regulatory region. The second is an early region, consisting of ORFs E1, E2, E4, E5, E6, and E7, which are involved in viral replication and oncogenesis. The third is a late region, which encodes the L1 and L2 structural proteins for the viral capsid (Figure 2) ^{[3] [4]}.

Figure 2. Schematic representation of the circular HPV DNA gene

*This figure is derived from the publication on Clin. Microbiol. ^[4]

Among of these HPVs, Only 13–15 are found in cervical cancers and other malignancies and are called ‘high risk’ HPV (HPV-HR) ^[5]. HPV 16 is the most important HPV-HR-type, and HPV 18 is the second. HPV 16 and 18 are associated with two thirds of all cervical cancers. HPV-HR differs from other HPV types by oncogenic properties of two proteins E6 and E7 that may interfere with cell regulation and differentiation. In fact, uterine cervix infected with HPV is very common, especially in women in their early 20s. Most infections will clear spontaneously and only a minority will finally persist for many years and decades.

As mentioned before, being infected with a cancer-causing strain of HPV doesn’t mean you’ll get cervical cancer. As the figure 3 shows, your immune system eliminates the vast majority of HPV infections and prevents the virus from doing serious harm within two years. But sometimes, the virus survives for years (generally 10-30 years). The virus can lead to the conversion of normal cells on the surface of the cervix into cancerous cells.

Figure 3. How HPV damages cells

*This figure is derived from The Nobel Committee for Physiology or Medicine 2008 illustration: Annika Rohl

Regarding of pathogenesis of oncogenic HPV, as HPVs encode only 8 to 10 proteins, they must employ host cell factors to regulate viral transcription and replication. The replication of HPV begins with host cell factors which interact with the LCR region of the HPV gene and begin transcription of the viral E6 and E7 genes. The proteins encoded by E6 and E7 gene deregulate the host cell growth cycle via binding and inactivating tumor suppressor proteins, cell cyclins, and cyclin-dependent kinases (Fig. 2) ^[6]. The function of the proteins encoded by E6 and E7 gene during a productive HPV infection is to bind to cellular p53 and pRB proteins, disrupt their functions, and alter cell cycle regulatory pathways, leading to cellular transformation.

Figure 4. Pathogenesis of oncogenic HPV

*This figure is derived from the publication on Clin. Microbiol. ^[4]

In terms of diagnosis, doctors usually use many tests to find, or diagnose, cancer. Here, we describe the most common examination and tests for cervical cancer diagnosis. If you are suspected with cervical cancer, your doctor may do a colposcopy to check the cervix for abnormal cells. During the colposcopic examination, your doctor will take a sample of cervical cells for laboratory testing. There are two ways to obtain tissue. One is using punch biopsy, which involves using a sharp tool to pinch off small samples of cervical tissue. Another is using endocervical curettage, which uses a small, spoon-shaped instrument (curet) or a thin brush to scrape a tissue sample from the cervix.

If the biopsy indicates that cervical cancer is really present, the doctor will recommend the woman to a gynecologic oncologist, which is a doctor who specializes in treating cervical cancer. The specialist may suggest additional tests to see whether the cancer has spread beyond the cervix, such as pelvic examination under anesthesia, X-ray, computed tomography (CT or CAT) scan, magnetic resonance imaging (MRI) and positron emission tomography (PET) or PET-CT scan.

Treatment for cervical cancer depends on the kind of cervical cancer and how far it has spread. Treatments include surgery, chemotherapy, radiation therapy and a combination of the three.

First, surgery is the typical treatment in the early-stage cervical cancer. According to different size of your cancer, its stage and whether you would like to consider becoming pregnant in the future, there are three options of surgery, including cutting away the cancer only, removing the cervix and hysterectomy.

Second, chemotherapy is a drug treatment that uses special medicines to shrink or kill the cancer. The drugs can be pills you take or medicines given through your veins, or sometimes both. For locally advanced cervical cancer, low doses of chemotherapy are often combined with radiation therapy, since chemotherapy may enhance the effects of the radiation. Higher doses of chemotherapy might be recommended to help control symptoms of very advanced cancer.

Third, Radiation therapy uses high-energy rays to kill the cancer. Radiation therapy is often combined with chemotherapy as the primary treatment for locally advanced cervical cancers. It can also be used after surgery if there’s an increased risk that the cancer will come back.

Actually, cervical cancer is one of the few cancers that’s almost totally preventable. It comes down to avoiding HPV, which is sexually transmitted. As mentioned before, HPV is the primary cause of cervical cancer. But it doesn’t always cause the disease. Many people have HPV and don’t develop cervical cancer.

If you’re sexually active, you will be informed to have Pap or HPV tests, which can find abnormal cells in your cervix before the cancer starts. In addition, there’s also an HPV vaccine that you might want to get. It targets some of the strains of HPV that are the riskiest. And HPV vaccine is usually the most common way to prevent yourself from cervical cancer.

Regarding to HPV vaccine, there are three kind of HPV vaccine now, including 2-valent, 4-valent and 9-valent HPV vaccine. The 2-valent vaccine, suitable for women aged 9-45, has a protective effect on two high-risk types (HPV-16 and HPV-18). The 4-valent HPV vaccine is suitable for women aged 20-45. Two low-risk types HPV-6 and HPV-11 are added to the bivalent HPV vaccine, which can prevent the four types of HPV6, 11, 16, 18 infections. The 9-valent HPV vaccine, suitable for women aged 16-26, is a non-infectious recombinant vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is an upgraded version of the 4-valent vaccine. The WHO pointed out: From the perspective of public health, there is no significant difference in the immunogenicity of the 2-valent, 4-valent, and 9-valent vaccines in terms of effectiveness in preventing HPV-related types 16 and 18.

[1] Campos NG, Sharma M, Clark A, et al. The health and economic impact of scaling cervical cancer prevention in 50 low- and lower-middle-income countries [J]. Int J Gynaecol Obstet. 2017;138 (suppl 1): 47-56.

[2] Carla J. Chibwesha, Jeffrey S. A. Cervical Cancer as a Global Concern Contributions of the Dual Epidemics of HPV and HIV [J]. JAMA. 2019, 332 (16):1558-1560.

[3] Apt, D., R. M. Watts, G. Suske, et al. High Sp1/Sp3 ratios in epithelial cells during epithelial differentiation and cellular transcription correlate with the activation of the HPV-16 promoter [J]. Virology. 1996, 224:281–291.

[4] Eileen M. Burd. Human Papillomavirus and Cervical Cancer [J]. Clin. Microbiol. Rev. 2003, 16(1):1.

[5] KARL ULRICH PETRY. HPV and cervical cancer [J]. Scandinavian Journal of Clinical & Laboratory Investigation. 2014, 74(Suppl 244): 59–62.

[6] Syrja¨nen, S. M., and K. J. Syrja¨nen. New concepts on the role of human papillomavirus in cell cycle regulation [J]. Ann. Med. 1999, 31:175–187.

According to the origin of tumor cells, ovarian cancer can be divided into three types: epithelial tumor, stromal tumor and germ cell tumor.

There are almost no symptoms in the early stage of ovarian cancer, and even if there are symptoms, it is not specific. It’s difficult to diagnosis it in the early stage of ovarian cancer. When receiving treatment, 60% to 70% of patients are in advanced stages.

This seriously affects the survival of patients with ovarian cancer. Therefore, ovarian cancer is also known as the “silent killer”.

Symptoms in the early stages of ovarian cancer are often vague and can easily be attributed to other causes. So if these symptoms appear, you should be alert to whether it is related to ovarian cancer.

Early signs of ovarian cancer include bloating, abdominal and/or pelvic pain, fatigue and shortness of breath ^[2], lower body pain, lower abdominal pain, back pain, indigestion or heartburn, rapid satiety when eating, frequent and urgent urination, painful intercourse, and changing bowel habits, such as constipation. As ovarian cancer progresses, it can also cause nausea, weight loss and loss of appetite.

If these symptoms occur frequently, you need to see a doctor as soon as possible.

The cause of ovarian cancer is unclear. However, genetic factors, reproductive factors, environmental factors and lifestyle factors may all play a role.

The typical symptoms of ovarian cancer are not obvious in the early stage, and there is still no proper screening method, which leads to its high mortality rate, making it the third most malignant tumor in the female reproductive system. Finding effective methods for early diagnosis and improving the specificity of diagnosis are the focus of ovarian cancer diagnostic research.

The following tests are used to diagnose ovarian cancer:

Blood test: Tumor marker CA125 and human epididymis protein 4 (HE4) are the most valuable tumor markers in ovarian epithelial cancer.

However, CA125 level is also increased in some non-ovarian cancer diseases, such as breast cancer, lung cancer, endometrial cancer and some benign ovarian tumors ^[9]. This indicates that serum CA125 has poor sensitivity and specificity in the diagnosis of ovarian cancer, and the false positive rate is high. Therefore, in the diagnosis of ovarian cancer, the detection of CA125 level has certain limitations. The combination of human epididymis protein 4 and CA125 can provide a higher diagnostic rate for ovarian cancer. HE4 is a glycoprotein expressed in epithelial carcinoma of ovary, which is specific for the diagnosis of ovarian cancer. Ferraro et al. ^[10] found that human epididymis protein 4 was more advantageous than CA125.

In addition to these two tumor markers, there are several other markers:

Carcinoembryonic antigen (CEA);

Alpha fetoprotein (AFP);

Carbohydrate antigen 199 (CA199)

Many new tumor markers are still being studied, such as serum macrophage colony-stimulating factor (M-CSF) and lysophosphatidic acid (LPA). The positive rate in serum of LPA ovarian cancer patients was high ^[11].

Ultrasonography: Ultrasonography is the first choice for ovarian cancer screening to determine the benign and malignant tumors. At present, transvaginal ultrasound, transabdominal ultrasound are widely used.

Laparoscopy: a laparoscope (a thin observation tube with a camera at the end) is inserted into the patient through a small incision in the lower abdomen.

Colonoscopy: If the patient has symptoms of rectal bleeding or constipation, the doctor may ask for a colonoscopy of the large intestine (colon).

CT Scan: CT scan is used to detect ovarian lesions, which can clearly show the location, size and relationship of the tumor to adjacent organs and tissues. It is also used for tumor location, characterization, and staging.

Magnetic Resonance Imaging: MRI provides fine pelvic anatomy , which plays an important role in the detection of ovarian diseases.

Genomics and Proteomics Assays: most of these techniques are currently in the laboratory. In addition, the doctor will also perform a vaginal examination to confirm whether the uterus or ovary is abnormal. It is also necessary to inquire about the patient’s history and family history. For women with confirmed ovarian cancer, doctors need to determine the stage and grade.

Treatments for ovarian cancer include surgery, chemotherapy, surgery and chemotherapy, and sometimes radiotherapy. The type of treatment depends on the type, stage and grade of ovarian cancer, as well as the patient’s overall health. At present, cytoreductive surgery and platinum-based chemotherapy are the gold standard for the treatment of ovarian cancer.

[1] Gubbels J A, Claussen N, Kapur A K, et al. The detection, treatment, and biology of epithelial ovarian cancer [J]. Journal of Ovarian Research, 2010, 3(1): 8.

[2] Goff B A, Mandel L, Muntz H G, et al. Ovarian carcinoma diagnosis [J]. Cancer, 2015, 89(10): 2068-2075.

[3] Zhang S, Royer R, Li S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer [J]. Gynecologic Oncology, 2011, 121(2): 353-357.

[4] Pennington K P, Swisher E M. Hereditary ovarian cancer: Beyond the usual suspects [J]. Gynecologic Oncology, 2012, 124(2): 347-353.

[5] Norquist B M, Harrell M I, Brady M F, et al. Inherited Mutations in Women With Ovarian Carcinoma [J]. Jama Oncol, 2015, 2(4): 482-490.

[6] Moorman P G, Havrilesky L J, Gierisch J M, et al. Oral Contraceptives and Risk of Ovarian Cancer and Breast Cancer Among High-Risk Women: A Systematic Review and Meta-Analysis [J]. Journal of Clinical Oncology, 2013, 31(33): 4188-4198.

[7] Ellen L?kkegaard, Susanne KrügerKjaer, Ellen L?kkegaard. Hormone therapy and ovarian cancer [J]. Lancet, 2015, 386(9998): 298.

[8] Keum N N, Greenwood D C, Lee D H, et al. Adult Weight Gain and Adiposity-Related Cancers: A Dose-Response Meta-Analysis of Prospective Observational Studies [J]. JNCI Journal of the National Cancer Institute, 2015, 107(3).

[9] Moss E L, Hollingworth J, Reynolds T M. The role of CA125 in clinical practice [J]. Journal of Clinical Pathology, 2005, 58(3): 308-312.

[10] Ferraro S, Braga F, Lanzoni M, et al. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review [J]. Journal of Clinical Pathology, 2013, 66(4): 273-281.

[11] Jacobs I. Discussion: Ovarian Cancer Screening [J]. Gynecologic Oncology, 2003, 88(1-supp-S): 0-0.

[12] King M C. Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 [J]. Science, 2003, 302(5645): 643-646.

[13] Kaye S B, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer [J]. Journal of Clinical Oncology, 2012, 30(4): 372-379.

[14] Ledermann J A, El-Khouly F. PARP inhibitors in ovarian cancer: Clinical evidence for informed treatment decisions [J]. British Journal of Cancer, 2015, 113: S10-S16.

[15] Jones P, Wilcoxen K, Rowley M, et al. Niraparib: A Poly (ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination [J]. Journal of Medicinal Chemistry, 2015, 58(8): 3302-3314.

[16] Gianpiero D L, Croce C M. The Role of microRNAs in the Tumorigenesis of Ovarian Cancer [J]. Frontiers in Oncology, 2013, 3.

[17] Song J X, Li F Q, Cao W L, et al. Anti-Sp17 monoclonal antibody-doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma [J]. Targeted Oncology, 2013, 9(3): 263-272.

Breast Cancer Pathway Map

Breast cancer is the leading cause of cancer death among women worldwide. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, or a red scaly patch of skin. Risk factors for developing breast cancer include being female, obesity, lack of physical exercise, drinking alcohol, hormone replacement therapy during menopause, ionizing radiation, early age at first menstruation, having children late or not at all, older age, and family history. About 5–10% of cases are due to genes inherited from a person’s parents, including BRCA1 and BRCA2 among others.
As the following figure shows, we summarize the breast cancer pathway and aim to help us in the research of breast cancer, including causes identification and the development of strategies for prevention, diagnosis, treatments and cure. Cusabio has a sound platform for the development of ELISA kit, mature antigen-antibody research and development system. Now we offer 178 ELISA kits in high specificity, high sensitivity, high stability and different species for your breast cancer research. Some of our products has cited by publications, such as HER2, HES1, WNT10B, and so on. We also have other products such as gene, protein and antibody for breast cancer research. If you are in need of other products such as gene, protein and antibody for breast cancer research, please feel free to contact us.

Breast cancer is a cancer that develops in the tissues of breasts. Symptoms of breast cancer usually include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. Among them, the first sign of breast cancer often is a breast lump or an abnormal mammogram in breast. Breast cancer starts when cells in the breast begin to grow out of control. These cells usually form a tumor that can often be seen on an x-ray or felt as a lump. If the cells can invade surrounding tissues or spread to distant areas of the body, the tumor is malignant. Breast cancer occurs almost entirely in women, but men can get breast cancer, too. In the recent decades years, breast cancer prevalence and mortality are still on the rise, meanwhile, the studies of breast cancer is hot in Clinical research and basic research. In this review, we summarize breast cancer-related signaling pathways and hotspot therapeutic targets, and hope that can give your research a hand.

Asia and sub-Saharan Africa are the areas with the highest incidence of HCC and are also high-risk areas of HBV infection. HBV and aflatoxin together influence the occurrence of HCC in Africa. It is estimated that aflatoxin B1 is a cofactor in 60% of liver cancer cases in Sudan.

In North America, Europe, and Japan, hepatitis C is the leading cause of liver cancer.

The situation in some countries is as follows:

The liver is the largest internal organ in the human body. It is of great significance to human health. It has several important features:

• Storage and Decomposition of Substances. Some nutrients must be altered in the liver. It also breaks down alcohol, drugs and toxic waste in the blood.
• Production of Coagulation Factors. When you’re injured, it produces most of the coagulation factors that prevent you from bleeding too much.
• It secretes bile into the intestines and helps absorb nutrients (especially fat).

Hepatocellular carcinoma is the most common type of liver cancer in adults. It is usually diagnosed in people aged 50 or older.

The etiology of liver diseases is diverse, including chronic viral infection of hepatitis b or hepatitis c virus, alcohol toxicity, autoimmune and cholestasis liver diseases, and metabolic factors ^[3].

In the early stages of hepatocellular carcinoma, there may be no symptoms. As cancer progresses, the following symptoms may occur:

A lump or pain on the right side of the abdomen.

Abdominal swelling or effusion.

Loss of appetite.

Unexplained weight loss.

Nausea and vomiting.

Weakness or extreme fatigue.

Yellowing of the skin and eyes (jaundice).

Fever.

Abnormal bruises or bleeding.

Abdominal vein dilatation.

Early diagnosis of hepatocellular carcinoma is of great value for the treatment and prognosis of patients with hepatocellular carcinoma.

Targeted prevention according to risk factors for hepatocellular carcinoma.

Treatment depends on the extent of cancer progression.

The most commonly used liver cancer comprehensive staging tool in the world is the Barcelona Clinical Liver Cancer (BCLC) system.

• (BCLC A): Patients with single tumours or up to three nodules that are 3 cm or smaller and preserved liver function are classified as having very early or early-stage hepatocellular carcinoma. The treatments available to patients at this stage are surgical resection, liver transplantation or local ablation.
• (BCLC B): In the mid-term, patients with compensatory cirrhosis have no tumor-related symptoms or vascular invasion. Transarterial chemoembolization (TACE) can be considered.
• (BCLC C): In advanced stages, the patient’s symptoms at this stage are characterized by tumors or invasive tumors (extra-hepatic spread or vascular invasion), or both. This stage can be treated with the multi-kinase inhibitor sorafenib.
• (BCLC D): At the end of the period, there are serious cancer-related symptoms or severe liver damage, or both, and are not suitable for transplantation. Symptomatic treatment is recommended at this stage.

7.4 Targeted therapy

Targeted therapy is a method that uses drugs or other substances to specifically recognize and attack specific cancer cells without harming normal cells.

Hepatocellular carcinoma is associated with abnormal activation of multiple cellular signaling pathways ^[20], which leads to the complexity of its etiology. The current therapeutic targets for hepatocellular carcinoma include:

Figure 3 The targets involved in hepatocellular carcinoma

Cell membrane receptors: such as tyrosine kinase receptor, vascular endothelial growth factor receptor.

Growth factors: Wnt/beta-catenin, Ras /Raf /MEK /ERK and PI3K /Akt /mTOR.

Cell cycle regulatory proteins: p53, p16 /INK4, cyclin /CDK complex.

Unfortunately, currently there are so few clinically effective HCC targeted therapies that multiple kinase inhibitors are the only HCC therapy drugs approved by FDA.

Sorafenib

Sorafenib is currently approved as a first-line systemic therapy for unresectable liver cancer ^[21]. It is a multi-kinase inhibitor and is the only advanced HCC-targeted drug currently marketed in the United States and the European Union.

Sorafenib inhibits kinases such as RAF kinase, VEGFR-2, VEGFR-3, PDGFR-β, KIT and FLT-3. It can also directly inhibit tumor growth through the RAF / MEK / ERK signaling pathway; it also inhibits tumor cell growth indirectly by inhibiting VEGFR and PDGFR.

7.5 Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill or prevent cancer cells from growing.

7.6 New therapy

Studies on microflora and HCC have found that in the mouse model of liver cancer induced in the laboratory, intestinal microorganisms influence the development of tumors and induce the occurrence of tumors ^[22].One study found that a specific probiotics (inulin type fructan) can reduce the proliferation of hepatocellular carcinoma cells in mice by stimulating the production of short-chain fatty acid propionate ^[23].

 

Even after liver cancer treatment is completed, you still need some tests, such as alphafetoprotein (AFP) level, liver function test (LFTs) and so on.

Patients after liver transplantation need to take medication to prevent rejection.

[1] Jemal A, Bray F, Center M M, et al. Global cancer statistics [J]. Ca Cancer J Clin, 2011, 61(2): 69-90.

[2] Hemming A W, Berumen J, Mekeel K. Hepatitis B and Hepatocellular Carcinoma [J]. Gastroenterologist, 2016, 20(4): 703-720.

[3] Ibrahim G A, Khan S A, Toledano M B, et al. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis [J]. World Journal of Gastroenterology, 2008, 14(27): 4300-.

[4] Yang D, Hanna D L, Usher J, et al. Impact of sex on the survival of patients with hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results analysis [J]. Cancer, 2015, 120(23): 3707-3716.

[5] Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology [J]. Best Practice & Research Clinical Gastroenterology, 2014, 28(5): 753-770.

[6] Stanaway J D, Flaxman A D, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 [J]. The Lancet, 2016: 1081-1088.

[7] Hoshida Y, Fuchs B C, Bardeesy N, et al. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma [J]. Journal of Hepatology, 2014, 61(1): S79-S90.

[8] Bolondi L. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis [J]. Gut, 2001, 48(2): 251-259.

[9] Turati F, Galeone C, Rota M, et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies [J]. Annals of Oncology, 2014, 25(8): 1526-1535.

[10] Gan L, Liu Z, Sun C. Obesity linking to hepatocellular carcinoma: A global view [J]. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 2018, 1869(2): 97-102.

[11] Chen H P, Shieh J J, Chang C C, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies [J]. Gut, 2013, 62(4): 606-615.

[12] Chuang S C, Vecchia C L, Boffetta P. Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection [J]. Cancer Letters, 2009, 286(1): 0-14.

[13] Nault J C, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas [J]. Nature Genetics, 2015.

[14] Hayes C, Kazuaki C. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma [J]. International Journal of Molecular Sciences, 2016, 17(3): 280-.

[15] Lai C L, Yuen M F. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy [J]. Hepatology, 2013, 57(1): 399-408.

[16] Webster D P, Klenerman P, Dusheiko G M. Hepatitis C [J]. Lancet, 2015, 385(9973): 1124-1135.

[17] Clavien P A, Lesurtel M, Bossuyt P M, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report [J]. Lancet Oncology, 2012, 13(1): e11-e22.

[18] Lencioni R, Crocetti L. Local-Regional Treatment of Hepatocellular Carcinoma [J]. Radiology, 2012, 262(1): 43-58.

[19] Lin S M. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less [J]. Gut, 2005, 54(8): 1151-1156.

[20] Cervello M, Mccubrey J A, Cusimano A, et al. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon [J]. Oncotarget, 2012, 3(3).

The present situation is that most patients (approximately 80%) diagnosed with hepatocellular carcinoma are at advanced stage and cannot be surgically resected due to the absence of early HCC symptoms, coupled with a lack of awareness of screening and unclear definition of screening strategies ^{[1] [2]}. Sorafenib, a first-line systemic therapy for advanced HCC, is a multikinase inhibitor. As the first effective drug to target liver cancer, it significantly prolongs patient survival and progression time, but its overall survival benefit is limited ^[3]. The lack of effective treatment options is one of the main reasons for the high mortality of HCC patients, which highlights the need for new treatments.

Several major molecular signaling pathways involved in the pathogenesis of liver cancer:

[1] Bruix J, Sherman M. Management of hepatocellular carcinoma: An update [J]. Hepatology, 2011, 53(3): 1020-1022.

[2] X-P. Chen, F-Z. Qiu, Z-D. Wu, et al. Long-term outcome of resection of large hepatocellular carcinoma [J]. Br J Surg, 2010, 93(5): 600-606.

[3] Schwartz J D. Sorafenib in Advanced Hepatocellular Carcinoma [J]. N Engl J Med, 2008, 359(23): 378-390.

[4] Lian Z, Liu J, Wu M, et al. Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis [J]. Hepatology, 2007, 45: 1390–1399.

[5] Avila MA, Berasain C, Sangro B, et al. New therapies for hepatocellular carcinoma [J]. Oncogene, 2006, 25: 3866–3884.

[6] Bangoura G, Liu ZS, Qian Q, et al. Prognostic significance of HIF-2 alpha/EPAS1 expression in hepatocellular carcinoma [J]. World J Gastroenterol, 2007, 13: 3176–3182.

[7] Yamaguchi R, Yano H, Iemura A, et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma [J]. Hepatology, 1998, 28: 68–77.

[8] Wilhelm S M, Carter C, Tang L Y, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis [J]. Cancer Research, 2004, 64(19): 7099-7109.

[9] Bjornsti M A, Houghton P J. The TOR pathway: a target for cancer therapy [J]. Nature Reviews Cancer, 2004, 4(5): 335-48.

[10] Hu T H, Huang C C, Lin P R, et al. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma [J]. Cancer, 2010, 97(8): 1929-1940.

[11] Midorikawa Y, Ishikawa S, Iwanari H, et al. Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling [J]. International Journal of Cancer, 2003, 103(4): 455-465.

[12] Villanueva A, Chiang D Y, Newell P, et al. Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma [J]. Gastroenterology, 2008, 135(6): 1972-1983.e11.

[13] Lang S A, Moser C, Fichnterfeigl S, et al. Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice [J]. Hepatology, 2010, 49(2): 523-532.

[14] Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors [J]. ONCOGENE, 2006, 25(27): 3778-3786.

[15] Wang X Q, Luk J M, Leung P P, et al. Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma [J]. Clinical Cancer Research, 2005, 11(1): 483-489.

[16] Liu L X, Lee N P, Chan V W, et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma [J]. Hepatology, 2009, 50(5): 1453-63.

[17] Lucrecia Márquez-Rosado, María Cristina Trejo-Solís, Claudia María García-Cuéllar, et al. Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats [J]. Journal of Hepatology, 2005, 43(4): 0-660.

[18] Hu Z, Zhang Z, Doo E, et al. Hepatitis B Virus X Protein Is both a Substrate and a Potential Inhibitor of the Proteasome Complex [J]. Journal of Virology, 1999, 73(9): 7231-7240.

[19] Munakata T, Nakamura M, Liang Y, et al. Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase [J]. Proc Natl Acad Sci USA, 2005, 102(50): 18159-18164.

[20] Altaba A R I, Pilar Sánchez, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells [J]. Nature Reviews Cancer, 2002, 2(5): 361-72.

[21] Katoh Y, Katoh M. Hedgehog signaling pathway and gastric cancer [J]. Cancer Biology & Therapy, 2005, 4(10): 1050-1054.

[22] Velcheti V, Govindan R. Hedgehog Signaling Pathway and Lung Cancer [J]. Journal of Thoracic Oncology, 2007, 2(1): 7-10.

[23] Thiyagarajan S, Bhatia N, Reaganshaw S, et al. Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells [J]. Cancer Research, 2007, 67(22): 10642-10646.

[24] Capurro M I, Xu P, Shi W, et al. Glypican-3 Inhibits Hedgehog Signaling during Development by Competing with Patched for Hedgehog Binding [J]. Developmental Cell, 2008, 14(5): 0-711.

[25] Tian. Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells [J]. International Journal of Oncology, 2009, 34(3): 829-836.

Gastric cancer, also known as stomach cancer, begins when cancer cells form in the inner lining of your stomach. As the figure 1 shows, these cells can grow into a tumor. The disease usually grows slowly over many years.

Figure 1 Gastric cancer begins in the cells of your stomach

In general, cancer begins when an error (mutation) occurs in a cell’s DNA. The mutation causes the cell to grow and divide at a rapid rate and to continue living when a normal cell would die. The accumulating cancerous cells form a tumor that can invade nearby structures. And cancer cells can break off from the tumor to spread throughout the body.

In this section, we summarize six types of people who have gastric cancer with high-risk.

Figure 3 The Six High-risk Groups of Gastric Cancer

Generally, gastric cancer may not cause any signs or symptoms or it may cause only nonspecific symptoms in its early stages because the tumor is small. Also, the abdomen and stomach are large structures that are able to expand, so a tumor can grow without causing symptoms.

Once symptoms occur, the cancer has often reached an advanced stage and may have metastasized (tumor grows into surrounding tissues and organs), which is one of the main reasons for its relatively poor prognosis. See your doctor if you have the following signs and symptoms:

As mentioned before, gastric cancer is one of the world’s most common cancers. However, the pathogenesis mechanism of gastric cancer is still not completely clear. Here, we refer to the research data and pathway from KEGG and collect several gastric cancer related signaling pathways.

According to Lauren’s histological classification gastric cancer is divided into two distinct histological groups – the intestinal and diffuse types. Several genetic changes have been identified in intestinal-type GC.

As shown in figure 2, the intestinal metaplasia is characterized by mutations in p53 gene, reduced expression of retinoic acid receptor beta (RAR-beta) and hTERT expression. Gastric adenomas furthermore display mutations in the APC gene, reduced p27 expression and cyclin E amplification. In addition, amplification and overexpression of c-ErbB2, reduced TGF-beta receptor type I (TGFBRI) expression and complete loss of p27 expression are commonly observed in more advanced GC. The main molecular changes observed in diffuse-type GCs include loss of E-cadherin function by mutations in CDH1 and amplification of MET and FGFR2F.

Figure 2 The diagram of gastric cancer signaling pathway

As the figure 2 shows, pathways affected by gastric cancer normally regulate cell growth and differentiation including Wnt, cell cycle, PI3K/AKT and TGFβ signaling pathway ^{[1][2][3][4][5]}. Besides, the analysis of gastric cancer data have revealed a fact that gastric cancer affects 3 times as many men than women. This fact suggests a protective effect by estrogen and its signaling pathways.

In addition, a signaling pathway demonstrated via a large amount of studies plays a critical role in gastric cancer. It is hedgehog signaling pathway.

During progression from the inflamed stomach to gastric cancer, the epithelium goes through defined series of morphological transitions. Interestingly high Shh expression in the stomach is lost upon the development of intestinal metaplasia, suggesting that gastric epithelium-specific effects of the morphogen. Indeed Shh controls gastric epithelial cell maturation and differentiation in the adult stomach ^[6][7][8].

Gastric cancer has long been seen as one of the most difficult gastrointestinal malignancies to treat. According to different clinical stages, gastric cancer has different treatment methods. The specific methods are as follows:

Surgical treatment: for early gastric cancer, no distant metastasis and invasion of surrounding organs, surgery can be performed, after surgery with radiotherapy, chemotherapy, the majority of patients with good prognosis.

Actually, surgical resection is the only effective treatment for this cancer, although current surgical therapeutic strategies are far from optimal and most patients are diagnosed with late-stage disease when surgical intervention is of limited use.

Targeted therapy: for patients who have lost the opportunity for the first diagnosis, targeted drug therapy, some patients can obtain long-term tumor-bearing state.

General treatment: maintain a good attitude, courageously face the reality, and actively adjust the lifestyle and diet structure.

However, the prognosis, is still unsatisfactory, with an overall five-year survival rate of 24%. Hence, there is an urgent need for new therapeutic strategies.

[1] Melucci E, Casini B, et al. Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy [J]. J Transl Med. 2018, Feb, 16,1,22.

[2] Clements WM, Wang J, et al. beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer [J]. Cancer Res. 2002, Jun, 62, 12, 3503-6.

[3] Yin J, Ji Z, et al. Sh-MARCH8 Inhibits Tumorigenesis via PI3K Pathway in Gastric Cancer [J]. Cell Physiol Biochem. 2018, Aug, 49, 1, 306-321.

[4] Chen ZL, Qin L, et al. INHBA gene silencing inhibits gastric cancer cell migration and invasion by impeding activation of the TGF-β signaling pathway [J]. J Cell Physiol. 2019, Apr.

[5] Almasi S, Sterea AM, et al. TRPM2 ion channel promotes gastric cancer migration, invasion and tumor growth through the AKT signaling pathway [J]. Sci Rep. 2019, Mar, 9, 1, 4182.

[6] Merchant JL, Ding L. Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions [J]. Cell Mol Gastroenterol Hepatol. 2017, 3:201-10.

[7] Adamu Ishaku Akyala and Maikel P. Peppelenbosch. Gastric cancer and Hedgehog signaling pathway: emerging new paradigms [J]. Genes & Cancer. 2018, January, 9 (1-2).

[8] van den Brink GR, Hardwick JC, et al . Sonic hedgehog regulates gastric gland morphogenesis in man and mouse [J]. Gastroenterology. 2001, 121:317-28.

Lung cancer is a malignant tumor that begins in the lungs. Our lungs are two spongy organs in your chest that take in oxygen when you inhale and release carbon dioxide when you exhale. Clinically, lung cancer, also called primary bronchogenic carcinoma, is a type of cancer that originates in the bronchi and alveoli. As the figure 1 shows:

Figure 1. Lung cancer begins in the cells of your lungs

The clinical symptoms of lung cancer are very complex. Actually, lung cancer typically doesn’t cause signs and symptoms in its earliest stages. Signs and symptoms of lung cancer typically occur only when the disease is advanced.

Generally speaking, the symptoms of lung cancer include cough, blood in the sputum, chest pain, hoarseness, shortness of breath and fever.

Lung cancer can occur in any lung of both lungs, but the right lung is more than the left lung, the upper lobe is more than the lower lobe, the middle lobe is the least, and the upper lobe is the most.

Clinically, lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). And non-small cell lung cancer accounts for about 85% of lung cancer.

The proliferation and expansion of NSCLC and SCLC are completely different, and the treatment measures are different.

Although the pathogenesis mechanism of lung cancer is still not completely clear, we refer to the research data and pathway from KEGG and summarize several lung cancer related signaling pathways.

[1] De Marco C, Laudanna C, et al. Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer [J]. PLoS One.2017, 12(6).

[2] Fan J, Bao Y, et al. Mechanism of modulation through PI3K-AKT pathway about Nepeta cataria L.’s extract in non-small cell lung cancer [J]. Oncotarget. 2017, 8(19):31395-31405.

[3] Jin X, Luan H, et al. Netrin?1 interference potentiates epithelial?to?mesenchymal transition through the PI3K/AKT pathway under the hypoxic microenvironment conditions of non?small cell lung cancer [J]. Int J Oncol.2019, 54(4):1457-1465.

[4] Pikor LA, Lockwood WW, et al. YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway [J]. Cancer Res.2013, 73(24):7301-12.

[5] Sun Y, Cao L, et al. WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway [J]. Cell Death Dis. 2017, 8(4):e2743.

[6] Xing Y, Liu Y, et al. TNFAIP8 promotes the proliferation and cisplatin chemoresistance of non-small cell lung cancer through MDM2/p53 pathway [J]. Cell Commun Signal. 2018, 16(1):43.

[7] Okimoto RA, Lin L, et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer [J]. Proc Natl Acad Sci U S A. 2016, 113(47):13456-13461.

[8] Bhardwaj V, Mandal AKA. Next-Generation Sequencing Reveals the Role of Epigallocatechin-3-Gallate in Regulating Putative Novel and Known microRNAs Which Target the MAPK Pathway in Non-Small-Cell Lung Cancer A549 Cells [J]. Molecules. 2019, Jan, 24, 2.

[9] Wagner AH, Devarakonda S, et al. Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer [J]. Nat Commun. 2018, Sep 17;9(1):3787.

The thyroid gland is a butterfly-shaped gland located in front of the neck, under the throat, and above the clavicle. The thyroid gland is part of the endocrine system that controls heart rate, blood pressure, body temperature and metabolism by secreting hormones.

There are two main cell types in the thyroid gland: follicular cells and C cells.

Follicular cells use iodine in the blood to make thyroid hormones, which help regulate the body’s metabolism. The amount of thyroid hormone released by the thyroid gland is regulated by the pituitary gland at the bottom of the brain, which promotes the release of thyroid hormone by producing a substance called thyroid stimulating hormone (TSH).

C cells (also known as parafollicular cells) produce calcitonin, a hormone that helps control how the body uses calcium.

Thyroid cancer can be classified into four types according to the origin of cells and the rate of cancer cell division: papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer.

In the early stages, thyroid cancer usually shows no signs or symptoms.

As a thyroid tumor grows, it may produce the following symptoms:

Neck mass or node: This is the most common symptom of thyroid cancer. A hard, fixed mass with an uneven surface was found in the thyroid gland. The glands are less mobile up and down during swallowing.

Persistent hoarseness or changes in voice, and frequent coughs unrelated to a cold may occur.

Difficulty swallowing or breathing.

Swollen lymph nodes in the neck.

Pain in the ear, pillow, shoulder, etc. may occur in the late stage.

Risk factors for thyroid cancer include ionizing radiation, family history, gender, obesity, alcohol consumption, and smoking. Recent studies have also demonstrated the relationship between exposure to flame retardants and PTC ^[10].

First, the doctor needs to understand the basic condition of the patient and whether there are common clinical symptoms of thyroid tumor. For patients with a family history of medullary thyroid cancer, your doctor will test your blood for calcitonin and calcium levels. Elevated levels of calcitonin suggest cancer.

The main methods of diagnosis of thyroid tumors are as follows:

Cancer treatment strategies need to be developed according to the stage of the tumor.

[1] Kilfoy B, Zheng T, Holford T, et al. International patterns and trends in thyroid cancer incidence, 1973-2002 [J]. CANCER CAUSES & CONTROL, 2009, 20(5): 525-531.

[2] Arribas J, Castellvi J, Marcos R, et al. Expression of YY1 in Differentiated Thyroid Cancer [J]. Endocrine Pathology, 2015, 26(2): 111-118.

[3] Nagy R, Ringel M D. Genetic Predisposition for Nonmedullary Thyroid Cancer [J]. Hormones and Cancer, 2015, 6(1): 13-20.

[4] Nikiforov Y E, Nikiforova M N. Molecular genetics and diagnosis of thyroid cancer [J]. NATURE REVIEWS ENDOCRINOLOGY, 2011, 7(10): 569-580.

[5] Carneiro R M, Carneiro B A, Agulnik M, et al. Targeted therapies in advanced differentiated thyroid cancer [J]. Cancer Treatment Reviews, 2015, 41(8): S0305737215001243.

[6] Chiacchio S, Lorenzoni A, Boni G, et al. Anaplastic thyroid cancer: Prevalence, diagnosis and treatment [J]. Minerva endocrinologica, 2009, 33(4): 341-357.

[7] Xu B, Ghossein R. Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma [J]. Endocrine Pathology, 2016, 27(3): 205-212.

[8] Chiappetta G, Valentino T, Vitiello M, et al. PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration [J]. Oncotarget, 2014, 6(7): 5310-23.

[9] Hoang J K, Nguyen X V, Davies L. Overdiagnosis of Thyroid Cancer: Answers to Five Key Questions [J]. Academic Radiology, 2015, 22(8): 1024-1029.

[10] Hoffman K, Lorenzo A, Butt C M, et al. Exposure to flame retardant chemicals and occurrence and severity of papillary thyroid cancer: A case-control study [J]. Environment International, 2017, 107: 235-242.

[11] Lodish M B, Stratakis C A. RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer [J]. Expert Review of Anticancer Therapy, 2008, 8(4): 625-632.

[12] None. Integrated Genomic Characterization of Papillary Thyroid Carcinoma [J]. Cell, 2014, 159(3): 676-690.

[13] Raman P, Koenig R J. Pax-8–PPAR-γ fusion protein in thyroid carcinoma [J]. Nature Reviews Endocrinology, 2014, 10(10): 616-623.

[14] Biondi B, Filetti S, Schlumberger M. Thyroid-hormone therapy and thyroid cancer: a reassessment [J]. Nature Clinical Practice Endocrinology & Metabolism, 2005, 1(1): 32-40.

[15] Mazzaferri E L. Current Approaches to Primary Therapy for Papillary and Follicular Thyroid Cancer [J]. Journal of Clinical Endocrinology & Metabolism, 2001, 86(4): 1447-1463.

[16] Spitzweg C, Bible K C, Hofbauer L C, et al. Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets [J]. The Lancet Diabetes & Endocrinology, 2014, 2(10): 830-842.

[17] Cooper D S, Doherty G M, Haugen B R, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer [J] .Thyroid, 2009, 19: 1167-214.

[18] Haugen Bryan R, Alexander Erik K, Bible Keith C, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer [J] .Thyroid, 2016, 26: 1-133.

[19] Xing M. BRAF mutation in thyroid cancer[J]. Endocrine Related Cancer, 2005, 12(2): 245-262.