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Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. The pathogenetic mechanisms underlying CRC development appear to be complex and heterogeneous. Contributory agents and mechanisms in CRC include dietary factors, lifestyle factors, inherited and somatic mutations. Among the most significant dietary and lifestyle risk factors for CRC appear to be a diet rich in unsaturated fats and red meat, total energy intake, excessive alcohol consumption, and reduced physical activity. However, nonsteroidal anti-inflammatory drugs, estrogen, calcium, and perhaps some statins protect against CRC. Many other exposures have been studied for their effects on CRC risk, but some have yielded ambiguous results.
The pathogenesis of CRC varies according to genetic or epigenetic changes that are related to each other in varying degrees. They satisfy the multiple stages pattern theorized by Fearon and Vogelstein. Such genetic and epigenetic alterations are directly responsible for a specific event within the sequence which leads to CRC, through contributing to the “initiation” of neoplastic transformation of healthy epithelium and/or determining the “progression” towards more malignant stages of the illness. The different pathways are characterized by distinctive models of genetic instability, subsequent clinical manifestations, and pathological behavior characteristics. Chromosomal instability (CIN) and microsatellite instability (MSI) are two molecular pathways that have been described in the progression of colorectal cancer. 65-70% of sporadic cancers arise from the CIN pathway, which is defined by insertion, deletion, or rearrangement of entire chromosomal regions. Cancers that form through the CIN pathway often have mutations in APC or KRAS. MSI is characterized by a genetic or epigenetic defect in DNA repair, leading to loss of function of the MMR protein and mismatch mutations. It accounts for 15% of CRC cases (12% sporadic, 3% due to Lynch syndrome) and it is also a part of the serrated pathway. The serrated neoplasia pathway is characterized by serrated appearing precursor lesions, which are divided into hyperplastic polyps, sessile serrated adenomas, and traditional serrated adenomas. This pathway consists of gene methylation (CpG island methylation phenotype, CIMP), microsatellite instability (MSI), and BRAF mutations.
Recently, it has been established that other systems and pathways are involved in the pathogenesis of colorectal cancer, including abnormal DNA methylation, inflammation and, more recently the discovery that microRNA (miRNA) can actively contribute to the carcinogenic process. The findings that different molecular pathways are involved in colorectal cancer development have helped researchers build different models and understand how colorectal cancer initiates and progresses. Nevertheless, the application of molecular markers on large-scale populations is now conducive to understand the peculiar role of these alterations on disease behavior, prognosis and response to treatments. Interestingly, several molecular markers (PI3KCA and BRAF, to cite some) have been found to be predictors of colon cancer risk and mortality in relation to aspirin and anti-inflammatory drugs consumption. Inflammation is an important contributor to colorectal carcinogenesis and anti-inflammatory drugs have been extensively explored also as chemopreventive agents. The recent findings that long-term use of low-dose Aspirin is protective against colorectal cancer development, clearly shows that anti-inflammatory drugs could be effectively used to prevent colorectal cancer.
Creative Biogene, as a leading biotechnology company, can offer various colorectal cancer pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.