Interleukin-6--a key regulator of colorectal cancer development

Abstract

Growing evidence proposes an important role for pro-inflammatory cytokines during tumor development. Several experimental and clinical studies have linked the pleiotropic cytokine interleukin-6 (IL-6) to the pathogenesis of sporadic and inflammation-associated colorectal cancer (CRC). Increased IL-6 expression has been related to advanced stage of disease and decreased survival in CRC patients. According to experimental studies, these effects are mediated through IL-6 trans-signaling promoting tumor cell proliferation and inhibiting apoptosis through gp130 activation on tumor cells with subsequent signaling through Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). During recent years, several therapeutics targeting the IL-6/STAT3 pathway have been developed and pose a promising strategy for the treatment of CRC. This review discusses the molecular mechanisms and possible therapeutic targets involved in IL-6 signaling in CRC.

Keywords: IL-6; colorectal cancer; interleukin-6.

Figure 1

IL-6 signaling in colorectal cancer. IL-6 secreted by cells of the innate or adaptive immune system binds to soluble IL‑6R (sIL‑6R). The complex of IL‑6 and sIL‑6R interacts with gp130 on tumor cells through trans‑signaling and induces subsequent activation of Janus kinases (JAKs) and phosphorylation of signal transducer and activator transcription 3 (STAT3). A homodimer of phosphorylated STAT3 then translocates to the nucleus and induces the transcription of several target genes promoting proliferation, cell growth and the inhibition of apoptosis.