Cytokine Gene Polymorphisms in Colorectal Cancer

Colorectal cancer is the second-leading cause of cancer-related deaths in Europe and the United States (Parkin DM, 2001). Although the primary therapy of CRC is surgical, the elucidation of different novel prognostic markers may prove to serve as future therapeutic options and contribute to the overall understanding of this cancer entity, as well as to improver disease outcome. Inflammation has been known to be a key factor of development and progression of cancer, and this is particularly notable in colorectal. At the cellular level, the colonic epithelium is exposed to a range of toxic and pathogenic challenges, including the balance between intestinal microflora. In turn, a shift can result in a change in immune response, leading to the induction of inflammation. Interactions between tumor and immune cells at the site of inflammation either enhance or inhibit cancer progression. The epidemiological data available are very impressive and show a clear association between chronic inflammatory conditions and subsequent malignant transformation in the inflamed tissue (Macarthur et al., 2004). New evidence suggests that up to 25% of all cancers are due to chronic infection or other types of chronic inflammation (Hussain SP, et al., 2007). Inflammation is mediated by an array of cytokines, which are synthesized by activated immune cells and exert their biological activities upon binding to specific receptors and activate the NF-κB transcription factor signal pathway in the epithelial cells. The ubiquitous transcription factor family NF-κB is a central regulator of the transcriptional activation of a number of genes involved in cell adhesion, immune and proinflammatory responses, apoptosis, differentiation, and growth. Induction of these genes in intestinal epithelial cells by activated NF-κB profoundly influences mucosal inflammation and repair (Jobin and Sartor, 2000). There is strong evidence to suggest that cytokines are involved in the control of cancer development and also promote tumorigenesis, invasion, propagation, and metastasis of tumors, and that they may be relevant for gastrointestinal tumors. More recently, the molecular mechanism whereby the inflammation regulates the antitumor immune responses has been elucidated. In many tumors, signal transducers and activator of transcription (STAT)3 are activated, and thereby antitumor immune surveillance is suppressed (H. Yu and R. Jove, 2004). In general the genes that encode cytokines involved in regulation of inflammatory conditions are genetically polymorphic and different genotypes are responsible for level of protein expression.