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

Tumor-associated vascular endothelial cells (TECs) can regulate tumor cell aggressiveness. However, the “core” mechanism by which TECs confer cancer stem cell-like features is unknown. In this paper, Dr. Shahin Rafii’s group in Weill Cornell Medical College showed that by exposing indolent non-aggressive tumors to an activated vascular niche, they can be coverted into producing cancer stem cells. The research team used in vivo murine and human tumor models to identify the checkpoint role of TEC-expressed IGF binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 restrains expansion and engraftment of tumor propagating cells expressing insulin-like growth factor 1-receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R+ TPCs to express FGF4 inducing a feed-forward FGFR1-ETS2 angiocrine cascade that obviates IGFBP7 checkpoint. Thus, loss of checkpoint-molecule IGFBP7 and upregulation of IGF1 in TECs converts naive tumor cells to chemoresistant tumor propagating cells and facilitates their engraftment and progression, performing as "cancer stem cell-enabling" vascular niche.

Zhongwei Cao, Joseph M Scandura, Giorgio G. Inghirami, Koji Shido, Bi-Sen Ding, Shahin Rafii. Molecular checkpoint decisions made by subverted vascular niche transform indolent tumors into chemoresistant cancer stem cells. Cancer Cell. 31:1-17 (2017).