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: Aberrant crypt foci; Apoptosis; Autophagy; Colorectal carcinogenesis; Hypoxia; Inflammation; Myeloperoxidase.

Figure 1

Inflammatory cells and proteins in the early phases of colorectal carcinogenesis. A: Inflammation and necrosis lead to monocytes recruitment and macrophages M1 polarization, with establishment of an inflammatory microenvironment and cytokines release [tumor necrosis factor α (TNFα), interleukin (IL)-12, IL-23]. Stromal, epithelial, and endothelial cells express lipooxygenases (5-LOX, 12-LOX), and cyclooxygenases 2 (COX2) proteins, with formation of inflammatory mediators leukotrienes and prostaglandins (i.e., LTB4, PGE2) that drive neutrophils recruitment. Neutrophils, at the site of injury, amplify inflammation through myeloperoxydase (MPO), reactive oxygen species (ROS) and matrix metalloproteinases (MMP); B: If the inflammatory stimulus is switched-off the stromal and epithelial cells expressing 15-LOX drive the formation of pro-resolving mediators lipoxins (LXA4 and LXB4). These lipids block the neutrophils migration and stimulate the phagocytosis of apoptotic neutrophils by macrophages M1. The clearance of neutrophils sustain the switch to M2-phenotype, with secretion of anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGFβ); C: If the stimulus is not resolved, the stromal and epithelial cells amplify the inflammatory signals (through IL-1, IL-8, 5-LOX and 12-LOX). In this way neutrophils apoptosis is inhibited, with continuous tissue and DNA damage by MPO, ROS and MMPs. The macrophages M1 support the inflammatory environment and the phagocyte afflux (IL-23 and IL-17), while M2 macrophages cause tissue remodeling.

Figure 2

Oxidative microenvironment in the inflammatory milieu of colorectal mucosa. Inflammation leads to an oxidative microenvironment with consequent modification of cell metabolism. The major players of these changes is hypoxia inducible factor 1 (HIF1), nuclear factor erythroid 2-related factor 2 (Nrf2), and sirtuins (SIRT). HIF1 activation supports the metabolic switch to anaerobial metabolism [fructose-1,6 bisphosphate aldolase (ALD); phosphoglycerate kinase (PGK); enolase 1 (ENO1); lactate dehydrogenase (LDH)]. Nrf2 is involved in the antioxidant defences of epithelial cells [NAD(P)H dehydrogenase (NQO1); glutathione S-transferase (GST); heme oxygenase-1 (HO-1)], while sirtuins affect apoptosis and anti-inflammatory genes.

Figure 3

Inflammation and remodelling of colorectal mucosa. Macrophages and neutrophils cause tissue damage and DNA damage by reactive oxygen species (ROS) formation. Inflammatory cytokines stimulate crypt stem cells proliferation driven by Wingless and Hedgehog. Defects in apoptosis and autophagy systems cause accumulation and proliferation of transformed cells. Indeed, inflammatory cells cause extracellular matrix (ECM) modifications, substaining disassembly of normal tissue architecture, angiogenesis and tumor invasion. CAF: Carcinoma associated fibroblasts; TAMs: Tumor-associated macrophages; MMP: Matrix metalloproteinases.