Molecular Network of Colorectal Cancer and Current Therapeutic Options

Abstract

Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field.

Keywords: biomarkers; cellular signaling; colorectal cancer; epigenetic changes; microenvironment modulation.

Figure 1

The three major molecular pathways of colorectal cancer. The conventional chromosomal instability (CIN) pathway, initiated by APC mutation, then followed by mutations in KRAS, PIK3CA and SMAD4, loss of heterozygosity of p53 mutation was observed in most CRC cases. CRC progress and development via this pathway is often associated with no or low levels of the CpG island methylation pathway (CIMP- ), high levels of CIN (CIW⁺⁺⁺), and microsatellite stability (MSS). Approximately one third CRC cases is regulated through the serrated pathway, which can be subdivided into CIMP^low MSS tumors with KRAS mutations, BRAF mutant CIMP^high MSS tumors or BRAF mutant CIMP^high microsatellite instability (MSI) tumors. Serrated pathway is commonly associated with silencing of 0-6-methylguanine-DNA methyltransferase (MGMT), cyclin-dependent kinase inhibitor 2A (CDKN2A) or MLHl. MSI pathway is a third important pathway of CRC caused by dysfunction of DNA mismatch repair genes, encoding Mutl homolog (MLH) or MutS homolog (MSH) proteins.