S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma

Cancer Res. 2019 Nov 15;79(22):5758-5768. doi: 10.1158/0008-5472.CAN-19-1366. Epub 2019 Oct 4.

Abstract

Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC. SIGNIFICANCE: These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Annexin A2 / metabolism*
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line
  • Cell Line, Tumor
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • S100 Proteins / metabolism*
  • Signal Transduction / physiology

Substances

  • Annexin A2
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • S100 Proteins
  • S100 calcium binding protein A10
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase