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Article Dans Une Revue Cancers Année : 2020

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Résumé

Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer. 1. Colorectal Cancer Colorectal cancer (CRC) is a heterogeneous disease influenced by specific genetic, epigenetic, and environmental factors [1]. It is one of the leading causes of malignancy-related death worldwide because of its recurrent and invasive nature [2]. The current clinical management of localized tumours involves their surgical removal and adjuvant chemotherapy; however, tumour recurrence and metastatic spread are observed in about 25-40% of patients, resulting in poor prognosis with a 5-year survival rate of 10% [2]. CRC aggressiveness is associated with the epithelial tumour cell's capacity to promote dissemination and tumour reactivation, through mechanisms that have not been fully elucidated yet [3]. Comprehensive genomic analyses of CRC heterogeneity allowed the classifying of tumours into different molecular subtypes: ultramutated, microsatellite instability-high/hypermutated (MSI), and microsatellite stable (MSS) [4]. Moreover, early-stage CRCs can be grouped into four consensus molecular subtypes (CMS) in function of the driving gene alteration: MSI+ tumours with strong immune infiltration (CMS1), Wnt/beta-catenin proliferative tumours (CMS2) and KRAS mutated and metabolic-deregulated tumours with strong immune exclusion (CMS3), and "mesenchymal" tumours with stromal and innate immune infiltration (CMS4) [5,6]. More recently, sequencing of metastatic CRC samples identified few genetic differences between primary tumours and metastases, but some alterations in the p53 pathway. Specifically, Wnt/beta-catenin signalling alterations were detected in most metastatic samples, suggesting that this oncogenic pathway has an obligate role in metastatic progression [7]. These findings are consistent with the model of CRC progression
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Dates et versions

hal-02989641 , version 1 (17-11-2020)

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Audrey Sirvent, Rudy Mevizou, Dana Naim, Marie Lafitte, Serge Roche. Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis. Cancers, 2020, 12 (8), pp.2014. ⟨10.3390/cancers12082014⟩. ⟨hal-02989641⟩
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