Colorectal Cancer
Colorectal cancer (CRC) is the most common gastrointestinal cancer. It is the second most common cancer in men and third most common in women by incidence. It represents the fourth most common cause of cancer mortality in both sexes worldwide [1]. It is m
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Introduction to Colorectal Cancer Colorectal cancer (CRC) is the most common gastrointestinal cancer. It is the second most common cancer in men and third most common in women by incidence. It represents the fourth most common cause of cancer mortality in both sexes worldwide [1]. It is mainly a disease of the western civilization with almost 60 % of the cases recorded in the developed countries. Nearly 90 % of CRCs are sporadic and caused by a complex interplay between genetic, host, and (most importantly) dietary factors. A “western” diet rich in red and processed meat and animal fat and of low fiber content is a well-recognized risk factor [2]. Recent research has further highlighted the key role of microbiota in mediating the dietary risk of colon cancer [3]. In addition, other environmental factors such as alcohol and smoking, inflammatory bowel disease, and obesity increase the CRC risk [4].
K. Vipperla Division of General Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, 933W MUH, Pittsburgh, PA 15213, USA e-mail: [email protected] S.J. O’Keefe (*) Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, 200 Lothrop Street, PUH Mezzanine Level – C Wing, Pittsburgh, PA 15213, USA e-mail: [email protected]
Pathophysiology of Colorectal Cancer CRC results from a stepwise accumulation of genetic defects and clonal proliferation of mutated colonic epithelial cells in an adenomacarcinoma transformation sequence of normal colonic mucosa, a protuberant growth known as polyp or adenoma (Fig. 1), and ultimately adenocarcinoma [5]. Mutations of the adenomatous polyposis colon (APC) tumor suppressor gene are the most common (~80 %) genetic defects observed in sporadic CRC. The nonmutated protein product of the APC gene prevents the accumulation of β-catenin protein, its nuclear translocation, and inappropriate activation of gene transcription via the canonical Wnt pathway that promotes cell proliferation [6]. A plethora of carcinogens, e.g., present in tobacco smoke, reach the colonic mucosal epithelium and cause genetic mutations. Poor folate intake among heavy alcoholics and interference of its absorption by alcohol can result in genetic defects from impaired folatemediated DNA synthesis, DNA methylation, and repair processes [7]. The proliferative influence of high levels of insulin-like growth factors (IGF-1 and IGF-2) on colonocytes during hyperinsulinemia and inflammation is believed to contribute to a higher CRC risk in obesity (see chapter “Metabolic syndrome”) [8]. There is also a convincing evidence of a positive association between consumption of red and processed meat and CRC, whereas
E. Lammert, M. Zeeb (eds.), Metabolism of Human Diseases, DOI 10.1007/978-3-7091-0715-7_24, © Springer-Verlag Wien 2014
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Other environmental toxins Host factors: Alcohol Smoking Obesity
Polyp
Proteolytic fermentation
Protein Red meat Processed meat
BCFA, Indoles, Phenols, Amines NOC, PAH, HCA, Heme, Iron
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