AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Philip D. Dunne, Darragh G. McArt, Jaine K. Blayney, Murugan Kalimutho, Samanda Greer, Tingting Wang, Supriya Srivastava, Chee Wee Ong, Ken Arthur, Maurice Loughrey, Keara Redmond, Daniel B. Longley, Manuel Salto-Tellez, Patrick G. Johnston, Sandra Van Schaeybroeck

Research output: Contribution to journalArticle

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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-to-mesenchymal 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 mRNA and 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.
Original languageEnglish
Pages (from-to)164-175
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number1
Early online date29 Oct 2013
DOIs
Publication statusPublished - 01 Jan 2014

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Colonic Neoplasms
Colorectal Neoplasms
Drug Therapy
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Fluorouracil
Autocrine Communication
Phenotype
Therapeutics
Recurrence
Epithelial-Mesenchymal Transition
RNA Interference
Cell Movement
Neoplasms
Proteins
Research Design
Biomarkers
Neoplasm Metastasis
Messenger RNA
Survival

Cite this

@article{993319f49a10462bbecf8a3c6c338646,
title = "AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer",
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-to-mesenchymal 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 mRNA and 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.",
author = "Dunne, {Philip D.} and McArt, {Darragh G.} and Blayney, {Jaine K.} and Murugan Kalimutho and Samanda Greer and Tingting Wang and Supriya Srivastava and Ong, {Chee Wee} and Ken Arthur and Maurice Loughrey and Keara Redmond and Longley, {Daniel B.} and Manuel Salto-Tellez and Johnston, {Patrick G.} and {Van Schaeybroeck}, Sandra",
year = "2014",
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language = "English",
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publisher = "American Association for Cancer Research Inc.",
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AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer. / Dunne, Philip D.; McArt, Darragh G.; Blayney, Jaine K.; Kalimutho, Murugan; Greer, Samanda; Wang, Tingting; Srivastava, Supriya; Ong, Chee Wee; Arthur, Ken; Loughrey, Maurice; Redmond, Keara; Longley, Daniel B.; Salto-Tellez, Manuel; Johnston, Patrick G.; Van Schaeybroeck, Sandra.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 164-175.

Research output: Contribution to journalArticle

TY - JOUR

T1 - AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

AU - Dunne, Philip D.

AU - McArt, Darragh G.

AU - Blayney, Jaine K.

AU - Kalimutho, Murugan

AU - Greer, Samanda

AU - Wang, Tingting

AU - Srivastava, Supriya

AU - Ong, Chee Wee

AU - Arthur, Ken

AU - Loughrey, Maurice

AU - Redmond, Keara

AU - Longley, Daniel B.

AU - Salto-Tellez, Manuel

AU - Johnston, Patrick G.

AU - Van Schaeybroeck, Sandra

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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-to-mesenchymal 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 mRNA and 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.

AB - 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-to-mesenchymal 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 mRNA and 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.

U2 - 10.1158/1078-0432.CCR-13-1354

DO - 10.1158/1078-0432.CCR-13-1354

M3 - Article

C2 - 24170546

VL - 20

SP - 164

EP - 175

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -