Colorectal cancer molecular biology moves into clinical practice

ArticleinGut 60(1):116-29 · October 2010with24 Reads
DOI: 10.1136/gut.2009.206250 · Source: PubMed
Abstract
The promise of personalised medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the recent advances in testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers) and the prediction of treatment responses (predictive markers) are examined.
    • "Wnt/ β-catenin signalling is a key driver of CRCs [6, 16, 47–54], with activating mutations being present in over 70% of patients, and is therefore an attractive therapeutic target [16, 55]. While the importance of canonical Wnt/β-catenin signalling for CRC oncogenesis and progression has long been recognised [16, 50], and Wnt pathway activation is nearly a universal feature of all CRCs [55], there is currently no clinical use for APC or β-catenin mutations for early cancer detection or treatment selection as proven Wnt directed clinical therapies are lacking [4, 27, 55]. There is an unmet clinical need for novel therapies in each of these three cancer entities, with the targeting of the Wnt pathway representing a potentially useful strategy. "
    [Show abstract] [Hide abstract] ABSTRACT: Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
    Full-text · Article · Nov 2016
    • "CRC has one of the highest incidences and mortality rates of all cancers worldwide [1][2][3][4][5] 30]. The formation of CRC is a multistep process that may be induced by the accumulation of genetic or epigenetic alterations [31, 32]. These alterations tend to occur in chromosomal fragile regions, which can provide a strategy to discover cancer susceptibility genes [33, 34]. "
    [Show abstract] [Hide abstract] ABSTRACT: The human TESTIN (TES) gene has been identified as a candidate tumor suppressor based on its location at a common fragile site - a region where loss of heterozygosity has been detected in numerous types of tumors. To investigate its role in colorectal cancer (CRC), we examined TES protein levels in CRC tissue samples and cell lines. We observed that TES was markedly reduced in both CRC tissue and cell lines. Additionally, overexpression of TES significantly inhibited cell proliferation, migration, and invasion, while increasing cell apoptosis in colon cancer cells. By contrast, shRNA-mediated TES knockdown elicited the opposite effects. TES inhibited the progression of CRC by up-regulating pro-apoptotic proteins, down-regulating anti-apoptotic proteins, and simultaneously activating p38 mitogen-activated protein kinase (MAPK) signaling pathways. Collectively, these data indicate that TES functions as a necessary suppressor of CRC progression by activating p38-MAPK signaling pathways. This suggests that TES may have a potential application in CRC diagnosis and targeted gene therapy.
    Article · Jun 2016
    Huili LiHuili LiKun HuangKun HuangLu GaoLu Gao+1more author...[...]
    • "More recently, the chemo-preventive ability of a cocoa rich-diet on colon inflammation and pre-neoplastic lesions has been studied in male Wistar rats using the AOM-induced colon cancer model [44]. Administration of the colon-specific carcinogen AOM to rodents evokes the growth of aberrant crypt foci, which are pre-neoplastic lesions in the colon that may progress into cancer [68]. Feeding animals with a 12% cocoa-enriched diet for eight weeks suppressed intestinal inflammation induced by AOM through the inhibition of NF-κB signaling and the down-regulation of the expression of pro-inflammatory enzymes COX-2 and iNOS [44]. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic inflammation has been identified as a necessary step to mediate atherosclerosis and cardiovascular disease and as a relevant stage in the onset and progression of several types of cancer. Considerable attention has recently been focused on the identification of dietary bioactive compounds with anti-inflammatory activities as an alternative natural source for prevention of inflammation-associated diseases. The remarkable capacity of cocoa flavanols as antioxidants, as well as to modulate signaling pathways involved in cellular processes, such as inflammation, metabolism and proliferation, has encouraged research on this type of polyphenols as useful bioactive compounds for nutritional prevention of cardiovascular disease and cancer. Data from numerous studies suggest that cocoa and cocoa-derived flavanols can effectively modify the inflammatory process, and thus potentially provide a benefit to individuals with elevated risk factors for atherosclerosis/cardiovascular pathology and cancer. The present overview will focus on the most recent findings about the effects of cocoa, its main constituents and cocoa derivatives on selected biomarkers of the inflammatory process in cell culture, animal models and human cohorts.
    Full-text · Article · Apr 2016
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