Inflammation and Colon Cancer

subject: Inlammatory factors in colorectal Ca Inflammatory pathways in the early steps of colorectal cancer development arginase/ Macrophages Francesco Mariani, Paola Sena, and Luca Roncucci
object_opposite: Inflammatory pathways in the early steps of colorectal cancer developmentColorectal 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 Francesco Mariani, Paola Sena, and Luca Roncucci
misc: Macrophages (Mfs) represent 10%-20% of all mononuclear cells found in the intestinal lamina propria making the intestine the largest reservoir of Mfs in humans. Type I macrophages (M1) (classical activated) as cells able to produce large amounts of proinflammatory cytokines, are implicated in the mechanism of killing pathogens and tumor cells by secreting agents such as tumor necrosis factor α (TNF-α), interleukin (IL)-12, reactive nitrogen (iNOS), and oxygen intermediates (ROS). In contrast, Type II macrophages (M2) (alternative activated), generated by various signals which include IL-4, IL-13, IL-10, and glucocorticoid hormones, moderate the inflammatory response, eliminate cell wastes, promote angiogenesis and tissue remodeling, and release cytokines, including IL-10[1-4]. Macrophages in tumors, usually termed tumor-associated macrophages (TAMs), play important roles in determining the clinical outcome, and often express the M2 phenotype. M1 macrophages are often abundant in chronic inflammatory sites, and where tumors are initiated and start to develop. Moreover, it is possible that the macrophages switch to an M2-like phenotype as the tumor begins to invade, vascularize, and develop [5,6]. IL-23 is produced by macrophages within a few hours after the activation. This, in turn, triggers rapid IL-17 responses from tissue-resident macrophages. IL-17 promotes the production of IL-1, IL-6, IL-8, CXC ligand 1 and TNF-α in stromal, epithelial and endothelial cells, and also in a subset of monocytes. Together, these proinflammatory cytokines rapidly recruit neutrophils to the site of infection. Neutrophils normally traffic to peripheral tissues, where they are phagocytosed by Mfs after transmigration and apoptosis. Apoptotic cell phagocytosis might downregulate IL-23 secretion and then curb IL-17 and granulocyte colony stimulating factor (G-CSF) production and eventually granulopoiesis. If this processes were interrupted, tissue Mfs would continue to express IL-23. This could drive IL-17 expression and increase neutrophils retrieval in peripheral tissues[7-9]. The production of arginase has been associated with M2 type macrophages. The switch from (nitric oxide) NO production to induction of arginase in these “alternatively activated” cells up-regulates polyamine and proline biosynthesis, that can stimulate cell replication, collagen deposition, and tissue repair[10,11]. Some in vivo evidences indicate that an exacerbated local M1 macrophage-like inflammation favors oxidative microenvironment, while M2 macrophage-like inflammation sustains progressive tumor growth[12-14]
author_year: Francesco Mariani/ Paola Sena/ Luca Roncucci /2014
journal_volume_page: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123361/ World J Gastroenterol/ Aug 7/ 20(29)/ 9716–9731

Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G7-17.

Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.

Itzkowitz SH¹, Yio X.

 

Abstract

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.