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Title: AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer
Authors: Dunne, P.D.
McArt, D.G.
Blayney, J.K.
Kalimutho, M.
Greer, S.
Wang, T. 
Srivastava, S. 
Ong, C.W. 
Arthur, K.
Loughrey, M.
Redmond, K.
Longley, D.B.
Salto-Tellez, M.
Johnston, P.G.
Van Schaeybroeck, S.
Issue Date: 1-Jan-2014
Citation: Dunne, P.D., McArt, D.G., Blayney, J.K., Kalimutho, M., Greer, S., Wang, T., Srivastava, S., Ong, C.W., Arthur, K., Loughrey, M., Redmond, K., Longley, D.B., Salto-Tellez, M., Johnston, P.G., Van Schaeybroeck, S. (2014-01-01). AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer. Clinical Cancer Research 20 (1) : 164-175. ScholarBank@NUS Repository.
Abstract: Purpose: Despite the use of 5-fluorouracil (5-FU)-based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse. Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression. Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-tomesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU-induced migration and invasion. Significantly, high AXL mRNAand protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues. Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF-targeted therapies have failed. Clin Cancer Res; 20(1); 164-75. © 2013 AACR.
Source Title: Clinical Cancer Research
ISSN: 10780432
DOI: 10.1158/1078-0432.CCR-13-1354
Appears in Collections:Staff Publications

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