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/þchr3/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 ¼ 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 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. Clin Cancer Res; 20(1); 164-75. Ó2013 AACR.

Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells

“…Therefore, we hypothesized that AXL signaling may be directly upregulated in an apoptotic environment through PS exposure. This would potentially explain previous observations of AXL-mediated, chemotherapy-induced migration and invasion [25]. …”

“…provide indications of this phenomenon, having reported that matched patient metastatic lesions exhibit higher AXL levels compared to those in the primary tumor [11]. In addition, it has been demonstrated that chemotherapy-induced migration and invasion of colorectal cancer cells is regulated by AXL [25]. …”

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

“…These data collectively challenge the general assumption that tumors classified as mesenchymal, or in the CMS4 subgroup, have undergone widespread EMT, resulting in lower levels of epithelial-associated traits in the tumor cell compartment, when actually these tumors have a higher component of stromal (particularly fibroblast) infiltration. Although IHC-based analysis of colorectal cancer tumors has shown that neoplastic epithelial cells expressing stem-like properties have a poor prognosis (15)(16)(17), our findings emphasize that the CMS4 subgroup represents tumors with higher transcription levels of mesenchymal-associated genes, which can be attributed to their overall stromal-rich, and in particular fibroblast, architecture.…”

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

“…Axl is a factor of poor prognosis when implicated in cancer development (27,31). Therefore, its overexpression is related to high level of recurrence (32) Taken together, all these data validate Axl as a therapeutic target to treat several cancers, and many research scientists are developing strategies to inhibit this RTK.…”