Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma

Cheong A. Bae, In Hye Ham, Hye Jeong Oh, Dagyeong Lee, Jongsu Woo, Sang Yong Son, Jung Hwan Yoon, James B. Lorens, Rolf A. Brekken, Tae Min Kim, Sang Uk Han, Won Sang Park, Hoon Hur

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Abstract

Background: The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. Methods: We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. Results: The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). Conclusions: We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

Original languageEnglish (US)
JournalGastric Cancer
DOIs
StateAccepted/In press - 2020

Keywords

  • AXL
  • Cancer-associated fibroblasts
  • GAS6
  • Gastric cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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    Bae, C. A., Ham, I. H., Oh, H. J., Lee, D., Woo, J., Son, S. Y., Yoon, J. H., Lorens, J. B., Brekken, R. A., Kim, T. M., Han, S. U., Park, W. S., & Hur, H. (Accepted/In press). Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma. Gastric Cancer. https://doi.org/10.1007/s10120-020-01066-4