Dysbiotic stress increases the sensitivity of the tumor vasculature to radiotherapy and c-Met inhibitors

Angiogenesis. 2021 Aug;24(3):597-611. doi: 10.1007/s10456-021-09771-z. Epub 2021 Feb 24.

Abstract

Antibiotic-induced microbial imbalance, or dysbiosis, has systemic and long-lasting effects on the host and response to cancer therapies. However, the effects on tumor endothelial cells are largely unknown. Therefore, the goal of the current study was to generate matched B16-F10 melanoma associated endothelial cell lines isolated from mice with and without antibiotic-induced dysbiosis. After validating endothelial cell markers on a genomic and proteomic level, functional angiogenesis assays (i.e., migration and tube formation) also confirmed their vasculature origin. Subsequently, we found that tumor endothelial cells derived from dysbiotic mice (TEC-Dys) were more sensitive to ionizing radiotherapy in the range of clinically-relevant hypofractionated doses, as compared to tumor endothelial cells derived from orthobiotic mice (TEC-Ortho). In order to identify tumor vasculature-associated drug targets during dysbiosis, we used tandem mass tag mass spectroscopy and focused on the statistically significant cellular membrane proteins overexpressed in TEC-Dys. By these criteria c-Met was the most differentially expressed protein, which was validated histologically by comparing tumors with or without dysbiosis. Moreover, in vitro, c-Met inhibitors Foretinib, Crizotinib and Cabozantinib were significantly more effective against TEC-Dys than TEC-Ortho. In vivo, Foretinib inhibited tumor growth to a greater extent during dysbiosis as compared to orthobiotic conditions. Thus, we surmise that tumor response in dysbiotic patients may be greatly improved by targeting dysbiosis-induced pathways, such as c-Met, distinct from the many targets suppressed due to dysbiosis.

Keywords: Dysbiosis; Endothelial cells; Foretinib; Hypofractionated radiation; Tandem mass tag mass spectroscopy; Tumor microenvironment; c-MET inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dysbiosis* / enzymology
  • Dysbiosis* / microbiology
  • Endothelial Cells / enzymology*
  • Melanoma, Experimental* / blood supply
  • Melanoma, Experimental* / enzymology
  • Melanoma, Experimental* / microbiology
  • Melanoma, Experimental* / therapy
  • Mice
  • Neovascularization, Pathologic* / enzymology
  • Neovascularization, Pathologic* / microbiology
  • Neovascularization, Pathologic* / therapy
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met* / metabolism
  • Radiotherapy

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-met