Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

Abstract

Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from decades of research, it seems clear that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. Highthroughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer. Introduction: Colorectal cancer is the 3 rd commonest cancer and the 2 nd leading cause of cancer-related deaths in the Western world (1). The outlook for disease incidence rates is bleak, reports predict up to a 60% rise in the global burden of CRC in developing countries by 2030 (2). Innovations in disease management are critical. Serine-20, may be less effective at mediating p53-dependent antitumor effects in these specific colorectal cancer patients. To our knowledge, such an investigation has not been reported as yet. Voltage-gated ion (sodium) channel expression in colorectal cancer: The bioelectricity of cancer cells generally differs from normal cells in several different respects [147]. In particular, increasing evidence suggest that a variety of ion channels, including voltage-gated ion channels, play a significant, dynamic role in the pathophysiology of cancer, including CRC [148]. Virtually all types of ion channel are involved, contributing to different components / stages of the cancer process. These include voltage-gated Na + , K +, Ca 2+ and Clchannels, ligand-gated ion channels and 'transient receptor potential' (Trp) channels [148]. Thus, cancer may even be regarded as a 'channelopathy' [148]. Here we focus on ion channels involved in metastasis since this is the main cause of death from cancer including CRC. In this regard, it is that has received the most attention [149]. According to the "Celex Hypothesis", acquisition of metastatic potential in cancer cells involves upregulation of functional voltage-gated Na + channels (VGSCs) activity and concomitant downregulation of outward currents, driven at least in part by voltage-gated K + channels (VGPCs) [150]. Overall, the possible electrical 'excitability' could form the basis of aggressive cancer cell behavior [150]. Membrane and protease genes Wnt signaling MAPK signaling Calcium signaling Membrane remodelling or secretion SCN5A Tumor cell invasion

Capicua suppresses colorectal cancer progression via repression of ETV4 expression

“…Alterations in several essential developmental signaling pathways including WNT, NOTCH, and Sonic hedgehog (SHH) are known to be associated with CRC progression [49] Among these, oncogenic mutations in the WNT pathway genes are prevalent in CRC. Mutations inactivating APC are found in 70-80% of CRCs, and these are believed to initiate malignant transformation of the colorectal epithelial cells [7,49]. However, the majority of APC mutant colon epithelial tumors are benign and never progress to CRC, suggesting that other genetic alterations are required for the development of WNT signaling-mutant colon epithelia into CRC.…”

LncRNA & Wnt signaling in colorectal cancer

“…Monoclonal antibodies targeted against epidermal growth factor receptor ( EFGR ) and vascular endothelial growth factor ( VEGF ) have gleaned some success. However, poor prognosis in advanced CRC has greatly hampered their effective use [ 3 ]. High-throughput technologies, e.g.…”

EZH2 regulates sFRP4 expression without affecting the methylation of sFRP4 promoter DNA in colorectal cancer cell lines

“…The Wnt signaling pathway regulates a number of biological processes, ranging from cell fate decision, cell differentiation, embryonic development and carcinogenesis (2). Abnormal activation of the Wnt signaling pathway has been identified in numerous types of solid tumors, particularly in colorectal cancer (CRC) (3), and dysregulation of the Wnt signaling pathway has been found in 90% of CRC case (4,5). Activation of the Wnt signaling pathway by both genetic and epigenetic mechanisms is important for both the initiation and progression of CRC.…”