Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells

Cancer Cell. 2017 Jan 9;31(1):110-126. doi: 10.1016/j.ccell.2016.11.010. Epub 2016 Dec 15.


Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and aggresiveness of tumor stem-like cells (TSCs) expressing IGF1 receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R+ TSCs to express FGF4, inducing a feedforward FGFR1-ETS2 angiocrine cascade that obviates TEC IGFBP7. Thus, loss of IGFBP7 and upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and converts naive tumor cells to chemoresistant TSCs, thereby facilitating their invasiveness and progression.

Keywords: ETS2; IGFBP7/angiomodullin; angiocrine factors; cancer stem cells; chemoresistance; insulin growth factor-1; tumor aggressiveness; tumor endothelial cell; tumor microenvironment; vascular niche.

Publication types

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm
  • Endothelial Cells / physiology
  • Fibroblast Growth Factor 4 / physiology
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / physiology*
  • Insulin-Like Growth Factor I / physiology
  • Mice
  • Neoplastic Stem Cells / drug effects*
  • Proto-Oncogene Protein c-ets-2 / physiology
  • Receptor, IGF Type 1 / physiology


  • ETS2 protein, human
  • FGF4 protein, human
  • Fibroblast Growth Factor 4
  • Insulin-Like Growth Factor Binding Proteins
  • Proto-Oncogene Protein c-ets-2
  • insulin-like growth factor binding protein-related protein 1
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1