Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives

Table 2 Cytokines implicated in tumorigenesis in the colon

Cytokines	The mechanism	Potential target of therapy?	Ref.
TNF-α	Triggers systemic inflammation and is one of the cytokines that make up the acute phase reaction in IBD and other chronic inflammatory diseases TNF-α regulates the induction MACC1 via the NF-κB subunit p65 and the transcription factor c-Jun in CRC cells	Yes: Anti TNF used to control inflammation in IBD; hence may reduce incidence of CRC but this is debatable	Pache et al[119], Kobelt et al[120]
IL-6 family	In the chronic phase of inflammation, IL-6 is able to activate almost all the cells of the body: trans-signalling-Increased formations of IL-6-sIL-6R complexes interact with gp130 on the membrane of CD4+T-cells and leads to an increased expression and nuclear translocation of STAT3, which causes the induction of anti-apoptotic genes, e.g., Bcl-xl. This leads to resistance of lamina propria T-cells to apoptosis. T-cell expansion contributes to chronic intestinal inflammation	No: Anti IL-6 antibodies not successfully used in IBD. Unlikely to be useful in reducing risk of IBD-CRC	Atreya and Neurath[121], Allocca et al[122], Coskun et al[123], Danese et al[124]
IL-11	IL-11 belongs to the IL-6 family of cytokines. IL-11 has pro-tumorigenic activities such as proliferation, self-renewal, invasion and angiogenesis	No: No evidence to suggest it could be used as therapeutic agent. Could be useful as a diagnostic and prognostic biomarker	Murakami et al[125], Johnstone et al[126], Ren et al[127], Unver and McAllister[128], Pastor et al[129], Putoczki et al[130]
IL-17	IL-7 is a cytokine that helps the long-term survival of Th17 cells and innate lymphoid cells that express the transcription factor RORγt. It is suspected to be important for maintaining populations of T cells that induce and induce mucosal inflammation in IBD. IL-7 also maintains NKT cells that produce IL-17, using the PI3K/AKT/mTOR pathway	No: Anti-IL-17 medications are associated with IBD exacerbation	Hohenberger et al[131], Moschen et al[132]
IL-21	IL21 plays a dual role: IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development. Reduced numbers of circulating CD19 (+) B cells, including IgM (+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. IL-21 Overproduction: IL-21 plays an important role in sustaining tissue-damaging immune responses	Yes: Could be used as a potential new therapeutic target in CD but unclear if it will influence IBD-CRC	Di Fusco et al[133], Salzer et al[134]
IL-23	IL-23R signalling affects disease susceptibility increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients	Yes: Currently in clinical trials for CD but too early to comment on effect on IBD-CRC	Moschen et al[132], Neurath[135]

NKT: Natural killer cells; MACC1: MET transcriptional regulator; UC: Ulcerative colitis; IBD-CRC: Inflammatory bowel disease-related colorectal cancer; AKT/PKB: Protein kinase B; IL: Interleukins; TNF-α: Tumor necrosis factor-α; RORγ: DNA-binding transcription factor; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-kinases; gp130: Glycoprotein 130; Bcl-xl: B-cell lymphoma-extra large; c-Jun: c-Jun proto-oncogene; p65: Nuclear factor NF-kappa-B p65 subunit.