Figure 3.

(A) The molecular pathogenesis of CRC. There are two broad classifications of CRC based on differences in the sequence of mutations leading to the cancer as well as their histological presentation. Sporadic CRC (SCRC) (top) develops from dysplasia of 1 or 2 discrete foci of the colon. The primary event in the formation of early adenomas is the loss of APC protein function. The APC protein is a negative regulator of beta-catenin that helps to control how often a cell divides and is the product of the tumor suppressor gene APC. Early adenoma is also accompanied by expression of the mucin-associated carbohydrate antigen, sialyl-Tn [36], miRNA dysregulation dysregulation and progression to an intermediate stage of adenoma that is characterized by activation of the oncogenic k-ras gene and COX-2. COX-2 induction leads to production of the pro-inflammatory prostaglandin PGE₂ which in turn binds to EP1-4 leading to several important pathways (shown in the figure) that promote CRC progression from early to intermediate adenoma stages [37]. The intermediate adenoma stage is also characterized by SRC overexpression and subsequent promotion of CRC cell proliferation and survival [38]. The loss of the tumor suppressor genes DCC and DPC4 often occur in the progression from intermediate to late adenoma [39]. The advancement to CRC from late adenoma is characterized by loss of p53 as the final mutation event. Colitis-associated CRC (CCRC) first presents as dysplastic lesions that are polyploidy, flat, localized or multifocal and which are the product of chronic inflammation. Rather than distinct polyps (adenomas) there is instead a large spreading region that often indicates removal of the entire colon and rectum [40]. There are some major differences in the timing and sequence of mutations from those seen for SCRC. Rather than adenoma stages there are instead varying degrees of epithelial dysplasia in the staging of the disease. Abbreviations: sporadic CRC (SCRC), colitis-associated CRC (CCRC), adenomatous polyposis coli (APC), microsatellite instability (MSI), Kirsten rat sarcoma viral oncogene homolog (k-ras), cyclooxygenase-2 (COX-2), prostaglandin E₂ (PGE2), dependence receptor in colorectal cancer (DCC), deleted in pancreatic cancer-4 (DPC4), proto-oncogene tyrosine protein-kinase Src 5 (SRC). (B) CRC differences in left vs. right-sided colon. The molecular features of left-sided (distal) colon cancers are different from right-sided (proximal) colon cancers. Based on the different gene expressions in CRC, four consensus molecular subtypes (CMS, 1-4) have been identified; MSI immune (CMS1), canonical (CMS2), metabolic (CMS3), and mesenchymal (CMS4). The left-sided cancers have better prognosis because they are less resistant to chemotherapy (CMS2, 4). Sidedness is particularly relevant during metastasis and is predictive of drug response [34].