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

Publication date: Available online 15 December 2016
Source:Cancer Cell
Author(s): Zhongwei Cao, Joseph M. Scandura, Giorgio G. Inghirami, Koji Shido, Bi-Sen Ding, Shahin Rafii
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.

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Teaser

Cao et al. show that IGFBP7 expressed by tumor-associated endothelial cells (TECs) suppresses IGF1R signaling and the stem cell-like property of tumor cells. Tumor-derived FGF4 activates an FGFR1-ETS2 axis in TECs that upregulates IGF1 and downregulates IGFBP7, facilitating IGF1R⁺ tumor stem-like cell expansion.


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