The Role of Proinflammatory Pathways in the Pathogenesis of Colitis-Associated Colorectal Cancer

Abstract

Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). The risk factors of CRC in IBD patients include long disease duration, extensive colitis, severe histological inflammation, and coexistence with primary sclerosing cholangitis (PSC). Several molecular pathways that contribute to sporadic CRC are also involved in the pathogenesis of colitis-associated CRC. It is well established that long-standing chronic inflammation is a key predisposing factor of CRC in IBD. Proinflammatory pathways, including nuclear factor kappa B (NF-κB), IL-6/STAT3, cyclooxygenase-2 (COX-2)/PGE₂, and IL-23/Th17, promote tumorigenesis by inducing the production of inflammatory mediators, upregulating the expression of antiapoptotic genes, and stimulating cell proliferation as well as angiogenesis. Better understanding of the underlying mechanisms may provide some promising targets for prevention and therapy. This review aims to elucidate the role of these signaling pathways in the pathogenesis of colitis-associated CRC using evidence-based approaches.

Figure 1

NF-κB pathway functions as the molecular link between inflammation and tumorigenesis. NF-κB pathway can be activated by proinflammatory cytokines (TNF-α and IL-1), bacterial components (such as LPS), viruses, and DNA-damaging agents. Activation of NF-κB pathway induces expression of proinflammatory cytokines (such as TNF-α, IL-1, and IL-6), chemokines (IL-8), and enzymes (COX-2) that contribute to inflammation-related tissue damages and are associated with tumor initiation. Antiapoptotic factors GADD45β, BFL1, and BCL-X_L ensure tumor cell survival and proliferation. In addition, VEGF, COX-2, and IL-8 promote angiogenesis and play an important role in tumor progression. MMP-9 contributes to tumor progression through facilitating metastasis.

Figure 2

The role of COX-2/PGE₂ pathway in colitis-associated CRC. The COX enzymes catalyze the biosynthesis of PGG₂ and PGH₂ from arachidonic acid. PGH₂ is subsequently metabolized to TXA₂, PGI₂, PGE₂, PGD₂, and PGF_2α by PG synthases. COX-2-derived PGE₂ acts via specific receptor EP1-4 and plays an important role in tumor development and progression through inducing expression of antiapoptotic proteins (such as BCL-2), proangiogenic chemokines (such as CXCL1), and MMP. In addition, PGE₂ mediates the activation of PPARδ through PI3K/Akt signaling. PPARδ contributes to tumorigenesis by ensuring tumor cell survival and proliferation. Activation of PPARδ can further enhance the production of COX-2-derived PGE₂.