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 invasion and metastasis in CRC. Importantly, significant increases in c-MET expression between tumour stages T1 and T2 infer that alterations in c-MET levels may contribute to the acquisition of an invasive phenotype in early stage CRC.
Method
In order to model CRC tumour cell invasion and metastasis, we have generated invasive subpopulations from CRC cells which have acquired a mesenchymal, migratory phenotype, and are resistant to therapy. We aim to assess the role of c-MET in acquisition of this phenotype, and the putative role of stromal fibroblast derived HGF secretion in this context by modelling in vivo tissue architecture using co-culture methods.
Results
Preliminary characterisation has revealed that c-MET-JAK1/2-STAT3 signalling is activated in invasive sublines lines, and blockade of this pathway abrogates migration in in vitro parental and invasive CRC sublines. Co-culture of CRC cells with HGF expressing colon-derived fibroblasts leads to activation of this pathway, thus implicating a putative role for the microenvironment in mediating this pathway. The prognostic roles of c-MET and HGF are currently being assessed using a CRC tissue microarray (TMA) derived from patients with early stage CRC.
Conclusion
The identification of key pathways driving drug resistance and metastasis has a huge potential to change treatment strategies in CRC. We intend to further investigate the role of c-MET-JAK1/2-STAT3 signalling in regulation of metastasis and drug resistance in CRC cell line in vitro models, and to explore the effect of stromal fibroblast derived factors in this context using co-culture methods. Characterisation of such novel mechanisms may provide a preclinical rationale for therapeutic c-MET inhibition in early stage CRC
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 invasion and metastasis in CRC. Importantly, significant increases in c-MET expression between tumour stages T1 and T2 infer that alterations in c-MET levels may contribute to the acquisition of an invasive phenotype in early stage CRC.
Method
In order to model CRC tumour cell invasion and metastasis, we have generated invasive subpopulations from CRC cells which have acquired a mesenchymal, migratory phenotype, and are resistant to therapy. We aim to assess the role of c-MET in acquisition of this phenotype, and the putative role of stromal fibroblast derived HGF secretion in this context by modelling in vivo tissue architecture using co-culture methods.
Results
Preliminary characterisation has revealed that c-MET-JAK1/2-STAT3 signalling is activated in invasive sublines lines, and blockade of this pathway abrogates migration in in vitro parental and invasive CRC sublines. Co-culture of CRC cells with HGF expressing colon-derived fibroblasts leads to activation of this pathway, thus implicating a putative role for the microenvironment in mediating this pathway. The prognostic roles of c-MET and HGF are currently being assessed using a CRC tissue microarray (TMA) derived from patients with early stage CRC.
Conclusion
The identification of key pathways driving drug resistance and metastasis has a huge potential to change treatment strategies in CRC. We intend to further investigate the role of c-MET-JAK1/2-STAT3 signalling in regulation of metastasis and drug resistance in CRC cell line in vitro models, and to explore the effect of stromal fibroblast derived factors in this context using co-culture methods. Characterisation of such novel mechanisms may provide a preclinical rationale for therapeutic c-MET inhibition in early stage CRC
| Original language | English |
|---|---|
| Title of host publication | The role of the c-MET-JAK1/2-STAT3 signalling axis in invasion and drug resistance in early stage colorectal cancer |
| Publisher | National Cancer Research Institute |
| Publication status | Published - Nov 2013 |
