Cytokines in Colitis-Associated Cancer: Potential Drug Targets?

Abstract

In inflammatory bowel disease (IBD), such as UC and CD, the development of colorectal carcinoma can be initiated through chronic inflammation, depending on the duration and severity of the disease. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of colitis associated cancer (CAC). For instance, TNF-alpha has been recently shown to promote tumor development in experimental colitis. Due to its role in the pathogenesis of IBD, TNF-alpha blockade has become one of the cornerstones of IBD therapy. Thus, anti-TNF-alpha strategies could also provide effective anti-tumor therapies. TGF-beta has been shown to attenuate an anti-tumor immune-response through the induction of regulatory T cells in spontaneous and inflammation associated cancer. However, IL-6 signaling promotes tumor growth in experimental CAC, and this signaling is inhibited by TGF-beta. Members of the IL-12 family, such as IL-12, IL-23, and IL-27, have been implicated in pathogenesis of colitis and IL-23 seems to be involved in inflammation associated carcinogenesis. However, a role for those cytokines in CAC remains to be shown. Whereas the above-mentioned cytokines promote tumor growth, others provide an anti tumor effect. IL-10 deficient mice develop colitis and CAC a few weeks after birth. Besides its immunosuppressive properties, IL-10 also has anti angiogenic and both tumor promoting and -inhibiting properties, which could be responsible for these observations. Since most of the above mentioned cytokines are involved in both, inflammation and carcinogenesis, it is difficult to account their contribution to the individual steps during pathogenesis of CAC. However, as already shown in IBD, cytokines may also provide promising therapeutic targets in CAC.

The Role of Inflammation in Colon Cancer

“…It is reported that more than 20 % of IBD patients develop cancer and 50 % of these will die of colon cancer (Lakatos and Lakotos 2008). These patients are reported to have increased inflammatory infiltration and increased expression of inflammatory genes Waldner and Neurath 2008;Clevers 2004). A higher risk for colon cancer is observed in IBD patients who have a family history of CRC (Askling et al 2001).…”

Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation

“…Inflammatory cytokines play an extremely important role in the occurrence, development and prognosis of inflammation (Fichtner-Feigl et al, 2008;Waldner and Neurath, 2008). Thus, we sought to evaluate the effects of BBR on the production of inflammatory cytokines in TNBS-treated mice.…”

Knockdown of type I insulin-like growth factor receptor inhibits human colorectal cancer cell growth and downstream PI3K/Akt, WNT/β-catenin signal pathways

“…It has been reported that more than 20% of inflammatory bowel disease (IBD) patients develop cancer and 50% of them will die of colon cancer [24,25]. All of these patients are reported to have increased infiltration with various types of innate immune cells, such as neutrophils, mast cells, natural killer cells, dendritic cells, tumor-associated macrophages and increased expression of inflammatory factors [26,27]. Actually, there are several inflammatory factors are highly expressed in colon cancer progression, such as COX-2, 5-LOX and its receptors [28].…”