Inflammatory Mediators and Colorectal Cancer Progression

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  • DuBois Raymond N.
    Department of Biochemistry and Molecular Biology, The Medical University of South Carolina, USA

Abstract

<p>Although epidemiologic and experimental observations support the hypothesis that chronic inflammation and diet are risk factors for colorectal cancer, the precise mechanisms by which these factors contribute to the development of cancer are poorly understood. Evidence for the link between inflammation and cancer comes from epidemiologic and clinical studies showing that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the relative risk for developing colorectal cancer (CRC) by 40-50%. NSAIDs exert some of their anti-inflammatory and anti-tumor effects by targeting cyclooxygenase enzymes (COX-1 and COX-2). Metabolism of arachidonic acid, a major ingredient in animal fats, by cyclooxygenase enzymes provides one mechanism for the contribution of dietary fats and chronic inflammation to carcinogenesis. COX-2-derived prostaglandin E2 (PGE2) is a pro-inflammatory mediator that promotes tumor progression, metastatic spread, cell motility and modulates the immune cells within the tumor microenvironment. </p><p>Considering the importance of PGE2 signaling in inflammation and colorectal carcinogenesis, the aim of our work is to determine how PGE2 modulates the tumor microenvironment in order to promote tumor progression. We have found that PGE2 regulates a number of genes involved in many of the basic hallmarks of cancer some of which are context specific. Via its effect on cancer stem cells (CSCs), it can increase the numbers of CSCs and their metastatic spread to the liver. Via its effects on CXCL1 and other CXCR2 ligands it modulates the number of myeloid derived suppressor cells in the tumor microenvironment. PGE2 can also modulate the &quot;pre-metastatic&quot; niche prior to cancer cell metastasis. All of these issues will be discussed along with unpublished data that has been recently acquired by the laboratory.</p>

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