Cytokines, inflammation and colon cancer

Abstract

Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are at increased risk of developing colon cancer, confirming that chronic inflammation predisposes to development of tumors. Moreover, it appears that colon cancers that do not develop as a complication of inflammatory bowel disease are also driven by inflammation, because it has been shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the mortality from sporadic colon cancer and results in regression of adenomas in familial adenomatous polyposis (FAP) patients, who inherit a mutation in the Apc gene. Colorectal cancer therefore represents a paradigm for the link between inflammation and cancer. Inflammation is driven by soluble factors, cytokines and chemokines, which can be produced by tumor cells themselves or, more often, by the cells recruited to the tumor microenvironment. Inflammatory cytokines and chemokines promote growth of tumor cells, perturb their differentiation, and support the survival of cancer cells. Tumor cells become addicted to inflammatory stroma, suggesting that the tumor microenvironment represents an attractive target for preventive and therapeutic strategies. Proinflammatory cytokines, such as TNFα, IL-6 and IL-1β, or transcription factors that are required for signaling by these cytokines, including NF-κB and STATs, are indeed emerging as potential targets for anticancer therapy. TNFα antagonists are in phase I/II clinical trials and have been shown to be well tolerated in patients with solid tumors, and IL-1β antagonists that ameliorate several inflammatory disorders characterized by excessive IL-1β production, will likely follow. Therefore, development of drugs that normalize the tumor microenvironment or interrupt the crosstalk between the tumor and the tumor microenvironment is an important approach to the management of cancer.

Figure 1. NF-κB signaling

Binding of TNFα (or IL-1β) to their respective receptors triggers canonical NF-κB signaling. Signaling is initiated by activation of an IκB kinase (IKK) complex consisting of catalytic kinase subunits (IKKα and/or IKKβ) and the regulatory scaffold protein IKKγ. IKK-mediated phosphorylation results in proteasomal degradation of the IκB inhibitor enabling the active NFκB transcription factor subunits to translocate to the nucleus and induce target gene expression. One of the target genes is IκBα gene itself, which re-sequesters NFκB subunits and terminates transcriptional activity, unless a persistent activation signal is present. NF-κB is activated also through TLR signaling via Myd88 dependent pathway. Receptor induced association of MyD88 with the TIR domain allows the formation of a complex, including IRAK1 and TRAF6, resulting in activation of TAK1, which phosphorylates and activates IKKβ. TLR3 can also induce NFκB in a MyD88 independent manner (not shown).

Figure 2. Signaling pathway whereby tumor associated macrophages promote Wnt signaling in tumor cells

Peripheral blood monocytes (Mo) were cultured with control medium or with conditioned medium from HCT116 or Hke-3 colon cells for 48 hours. As shown here, soluble factor(s) from HCT116 and Hke-3 cells induced maturation of normal peripheral blood monocytes (Mo), demonstrated by phalloidin/DAPI staining, coupled to the release of IL-1β. IL-1β, through activation of NF-κB, induced phosphorylation of PDK1 and AKT, which inactivates GSK3β, leading to enhanced β–catenin/TCF4 transcriptional activity, and increased expression of Wnt target genes in tumor cells, including c-myc and c-jun (adapted from [65]).

Figure 3. STAT3 signaling

Binding of IL-6 to the receptor triggers receptor heterodimerization with the gp130. Subsequently, JAKs are activated by phosphorylation which results in the recruitment of STAT3 to the receptor. Phosphorylated STAT3 dimerize and translocate to the nucleus, bind DNA and regulate the expression of its target genes.