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Dissecting Oncogenic RTK Pathways in Colorectal Cancer Initiation and Progression

  • Stephen McManus
  • Walid Chababi
  • Dominique Arsenault
  • Claire M. Dubois
  • Caroline Saucier
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1765)

Abstract

Colorectal cancer (CRC) is a progressive disorder associated with an accumulation of multiple heterogeneous genetic alterations in intestinal epithelial cells (IEC). However, when these cells undergo neoplastic transformation and become cancerous and metastatic, they invariably acquire hallmarks conferring them the ability to hyperproliferate, escape growth-inhibitory and death-inducing cues, and promote angiogenesis as well as epithelial-to-mesenchymal transformation (EMT), fostering their invasive dissemination from primary tumor into distant tissues. Compelling clinical and experimental evidence suggest that aberrant engagement of cell surface growth factor receptor tyrosine kinase (RTK) signaling, like that of the hepatocyte growth factor (HGF)/MET receptor, underlies CRC metastatic progression by promoting these cancer hallmarks. To date, though, the use of RTK-targeting agents has been viewed as a promising approach for the treatment of metastatic CRC, clinical success has been modest.

Our vision is that the prospect of designing RTK-based, improved and innovative CRC therapies and prognostic markers likely rests on a comprehensive understanding of the biological processes and underlying regulatory molecular mechanisms by which deregulation of RTK signaling governs IEC’s neoplastic transformation and their transition from noninvasive to metastatic and malignant cells. Herein, we describe our scheme for defining the full scope of oncogenic MET-driven cancer biological processes, in cellulo and in vivo, as well as the individual contribution of MET-binding effectors in a nontransformed IEC model, the IEC-6 cell line.

Key words

Receptor tyrosine kinase Hepatocyte growth factor (HGF) MET receptor Intestinal epithelial cells GRB2 SHC EMT Angiogenesis Tumorigenesis Metastasis 

Notes

Acknowledgments

This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR, MOP-106476) awarded to CS.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Stephen McManus
    • 1
  • Walid Chababi
    • 1
  • Dominique Arsenault
    • 2
    • 3
  • Claire M. Dubois
    • 2
    • 3
  • Caroline Saucier
    • 1
  1. 1.Department of Anatomy and Cell Biology, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada
  2. 2.Department of Pediatrics, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada
  3. 3.Department of Immunology Division, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada

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