The Role of the c-MET/HGF Signalling Axis as a Critical Regulator of Invasion and Migration in Colorectal Cancer

Conor Bradley, Philip Dunne, Keara Redmond, Darragh McArt, Ken Arthur, Stephen McQuaid, Jaine Blayney, Manuel Salto-Tellez, Patrick Johnston, Sandra Van Schaeybroeck

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Background
The c-MET proto-oncogene is frequently overexpressed (50-60%), amplified (5-10%), and mutated (5%) in colorectal cancer (CRC). Hepatocyte growth factor (HGF)-induced c-MET activation has been linked with enhanced proliferation, migration, survival and invasion, and has been suggested as a possible prognostic biomarker for CRC.

Method
To model CRC tumour cell invasion, we have generated invasive CRC subpopulations using Boyden Invasion chambers. Invasive cell lines were characterised for protein expression/activity by Western blotting, and analysed for migratory and invasive potential using the xCELLigence System. To model the CRC microenvironment, we have utilised a range of co-culture techniques with CRC cell lines and colon fibroblasts. c-MET expression in FFPE tissues was measured using IHC in a tissue microarray (TMA) derived from early stage CRC patients.

Results
HCT116 and LoVo invasive subpopulations showed a mesenchymal, migratory/invasive phenotype, and showed increased expression of the EMT marker SNAIL, CD44, and loss of E-Cadherin. In addition, increased expression/activation of c-MET was observed in these sublines. Inhibition of c-MET using RNAi abrogated both basal and HGF-induced migration/invasion in CRC cell lines. Co-culture of CRC cells with HGF expressing colon-derived fibroblasts leads to activation of c-MET, increasing the migratory/invasive capacity of the cancer cells. Significant increased expression levels of c-MET were also found in a CRC TMA compared to matched normal tissues. We are currently investigating the role of the tumour microenvironment in regulating migration/invasion and resistance to targeted therapy in CRC.

Conclusion
The identification of key pathways driving metastasis has a huge potential to change treatment strategies in CRC. We intend to further investigate the role of c-MET in regulation of migration and invasion in CRC in vitro and in vivo models. Characterisation of such novel mechanisms may provide a preclinical rationale for therapeutic c-MET inhibition in early stage CRC, specifically in patient subpopulations which display enhanced c-MET expression and activation.
Original languageEnglish
Title of host publicationThe Role of the c-MET/HGF Signalling Axis as a Critical Regulator of Invasion and Migration in Colorectal Cancer
PublisherNational Cancer Research Institute
Publication statusPublished - Nov 2014

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