Mechanisms of Immune Signaling in Colitis-Associated Cancer

Abstract

The inflammatory bowel diseases ulcerative colitis and Crohn's disease are associated with an increased risk for the development of colorectal cancer. During recent years, several immune signaling pathways have been linked to colitis-associated cancer (CAC), largely owing to the availability of suitable preclinical models. Among these, chronic intestinal inflammation has been shown to support tumor initiation through oxidative stress-induced mutations. A proinflammatory microenvironment that develops, possibly as a result of defective intestinal barrier function and host-microbial interactions, enables tumor promotion. Several molecular pathways such as tumor necrosis factor/nuclear factor-κB or interleukin 6/signal transducer and activator of transcription 3 signaling have been identified as important contributors to CAC development and could be promising therapeutic targets for the prevention and treatment of CAC.

Keywords: AOM-DSS, azoxymethane–dextran sulfate sodium; APC, adenomatous polyposis coli; CAC, colitis-associated cancer; CD, Crohn’s disease; CRC, colorectal cancer; Colorectal Cancer; Crohn's Disease; Cytokines; DDR, DNA damage response; IBD, inflammatory bowel disease; IKK, IκB kinase; IL, interleukin; IL6R, interleukin 6 receptor; Inflammatory Bowel Disease; Interleukin-6; LPS, lipopolysaccharide; Myd88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor-κB; NLR, NOD- and leucine-rich repeat–containing protein; NLRP, nucleotide-binding oligomerization domain- and leucine-rich repeat–containing protein family, pyrin domain-containing; NOD, nucleotide-binding oligomerization domain; RONS, reactive oxygen and nitrogen species; STAT3, signal transducer and activator of transcription 3; TLR, Toll-like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; Th17, T-helper 17; Tumor Necrosis Factor Alpha; UC, ulcerative colitis; Ulcerative Colitis; gp, glycoprotein.

Figure 1

TNFα-dependent activation of NF-κB in CAC. TNF, a major proinflammatory cytokine involved in the pathogenesis of IBD, contributes to CAC development through the activation of NF-κB in myeloid and intestinal epithelial cells. Although TNFR1 activation in myeloid cells leads to the release of additional proinflammatory cytokines that contribute to tumor growth, TNFR2 activation in epithelial cells promotes cell survival as well as the activation of myosin light chain kinase (MLCK), which supports epithelial barrier loss through direct effects on tight junctions (TJ). After TNFR2 activation, the MLCK promoter can be regulated via NF-κB or activator protein 1. IEC, intestinal epithelial cell.

Figure 2

IL6- and IL11-dependent STAT3 activation promotes tumor proliferation and survival. IL6 and IL11 released from immune cells such as macrophages and effector T cells bind to their specific receptors and induce STAT3 activation via gp130. Phosphorylated STAT3 promotes survival and proliferation of intestinal epithelial cells via direct effects on cell-cycle regulators (CC) and down-regulation of p53. Furthermore, activated STAT3 promotes sustained NF-κB activity. IL11R, IL11 receptor; sIL6R, soluble IL6 receptor. IEC, intestinal epithelial cell.

Figure 3

Microbiota and innate immune mechanisms regulate a proinflammatory microenvironment promoting tumor growth. Possibly as the result of a defective intestinal barrier, microbial products activate innate immune cells or intestinal epithelial cells (IECs), perhaps via TLRs, which then create a proinflammatory microenvironment with subsequent activation of Th17 cells characterized by the transcription factor RAR-related orphan receptor γT (RORγt). Proinflammatory cytokines released by activated innate immune cells, intestinal epithelial cells, or Th17 cells contribute to tumor cell proliferation and survival.