Abstract
Background
Despite the use of 5-FU-based adjuvant treatments, a large proportion of high risk stage II/III colorectal cancer (CRC) patients will relapse. Thus, novel therapeutic strategies are needed for early stage CRC. Residual micrometastatic disease from the primary tumour is a major cause of patient relapse.
Method
In order to model CRC tumour cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53null) CRC cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins which underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumours from patients with early stage CRC (N=336) were examined for AXL expression.
Results
Invasive CRC cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability and an attenuation of EGFR/HER2 autocrine signalling. Receptor tyrosine kinase arrays showed significant increases in AXL levels in all invasive sub-lines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion and targeting AXL using pharmacologic inhibition or RNAi approaches, suppressed basal and 5-FU-induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early stage CRC tissues (N=336).
Conclusion
We have identified AXL as poor prognostic marker and important mediator of cell migration/invasiveness in CRC. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in CRC, in particular in the adjuvant disease where EGFR/VEGF-targeted therapies have failed.
Despite the use of 5-FU-based adjuvant treatments, a large proportion of high risk stage II/III colorectal cancer (CRC) patients will relapse. Thus, novel therapeutic strategies are needed for early stage CRC. Residual micrometastatic disease from the primary tumour is a major cause of patient relapse.
Method
In order to model CRC tumour cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53null) CRC cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins which underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumours from patients with early stage CRC (N=336) were examined for AXL expression.
Results
Invasive CRC cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability and an attenuation of EGFR/HER2 autocrine signalling. Receptor tyrosine kinase arrays showed significant increases in AXL levels in all invasive sub-lines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion and targeting AXL using pharmacologic inhibition or RNAi approaches, suppressed basal and 5-FU-induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early stage CRC tissues (N=336).
Conclusion
We have identified AXL as poor prognostic marker and important mediator of cell migration/invasiveness in CRC. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in CRC, in particular in the adjuvant disease where EGFR/VEGF-targeted therapies have failed.
| Original language | English |
|---|---|
| Title of host publication | AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early stage colon cancer |
| Publisher | National Cancer Research Institute |
| Publication status | Published - Nov 2013 |
