Inflammatory pathways in the early steps of colorectal cancer development

Abstract

Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal.

Keywords: Myeloperoxidase, Colorectal carcinogenesis, Inflammation, Aberrant crypt foci, Autophagy, Hypoxia, Apoptosis

Core tip: This paper examines the most important inflammatory pathways involved in the very early steps of colorectal carcinogenesis. In particular, it emphasizes the role played by cells of the immune system and key proteins, like cyclooxygenases, resistins, hypoxia-inducible factor 1, nuclear factor E2-related factor 2, and sirtuins, in fostering changes in mechanisms, like cell proliferation, DNA damage, apoptosis and autophagy, anaerobial metabolism and tissue remodeling, considered central for colorectal cancer development.