Translational approaches to addressing complex genetic pathways in colorectal cancer

Abstract

Colorectal cancer (CRC) is among the most prevalent cancers worldwide and represents a major public health challenge in the developed world. From the perspective of translational investigation, scientists have enormous opportunity to elucidate the molecular genetic mechanisms contributing to CRC pathogenesis since the majority of cancers arise from adenomatous precursor lesions. The process of adenoma growth and transformation is accompanied by cumulative mutations in dominant genetic pathways that confer a growth advantage. While this developmental process permits interrogation of informative pathways prior to the development of cancer, only a minority of adenomas progress to CRC. Accordingly, a major challenge for clinical translational investigators is to identify the molecular signatures that indicate increased likelihood for adenoma progression. By corollary, these molecular signatures include mutations in high penetrance alleles, including the Adenomatous Polyposis Coli (APC) gene as well as other alleles in the Wnt/β-catenin signaling pathway that specify increased genetic susceptibility to CRC. Interactions between these high penetrance alleles and other modifier genes as well as with environmental factors are of particular importance in understanding the complex network of events leading to CRC. This brief review will highlight three areas where important questions concerning genetic and environmental risk factors have fueled translational investigation into possible pathways leading to CRC.There have been substantial advances in the last two decades in our understanding of the molecular pathways that lead to colorectal cancer (CRC), the results of research that demonstrated the role of mutational activation of oncogenes coupled with loss of function of tumor suppressor genes in a model that advanced the concept of finite, but cumulative mutational events (summarized in (1)). These studies in preclinical, animal models as well as cell-based models, clinical observational and randomized studies in humans have led to a more complete understanding of the role of both environmental and genetic factors in CRC pathogenesis.One tangible result of this expanded scientific foundation is an emerging consensus that familial or inherited factors play an increasingly relevant role in our approach to patients with CRC(2). Examples of dominant genetic pathways include those governed by Adenomatous Polyposis Coli (APC) tumor suppressor gene, and also the microsatellite instability pathway 4 To whom communication should be directed

Overexpression of Twist in colorectal adenocarcinoma

“…10 Like the majority of cancers in other organs, there are conditions associated with risk of tumor development. 10 Like the majority of cancers in other organs, there are conditions associated with risk of tumor development.…”

“…CRA is the third most common malignancy worldwide. 10 Like the majority of cancers in other organs, there are conditions associated with risk of tumor development. Its pathogenesis characterized by clinical and histopathological changes known as 'adenomacarcinoma sequence', as well as de novo pathways.…”

Use of multiple biomarkers for the localization and characterization of colon cancer stem cells by indirect immunocytochemistry

“…However, the underlying mechanisms for the involvement of LGR5 in carcinogenesis are poorly understood. It is generally accepted that the WNT/β-catenin pathway plays a critical role in CRC tumorigenesis (19). Since Korinek et al (20) first reported the complete depletion of stem cells in the small intestine after the mutation of β-catenin and the Tcf4 interaction partner in mice, several studies have subsequently shown evidence of the important role of WNT signaling in stem cell maintenance and development (4,(21)(22)(23)(24)).…”

Altered gene expression and miRNA expression associated with cancerous IEC-6 cell transformed by MNNG

“…Substantial advances in our understanding during the past decades have led to a complete understanding of the role of both environmental and genetic factors in colorectal cancer pathogenesis. It has been well demonstrated that the its development and progress are associated with deregulation of many genes, as well as mutational activation of oncogenes and loss of function of tumor suppressor genes [ 22 ]. And its tumorigenesis is also a process of multistage of hit.…”