Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells.
Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells.
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DOI：
10.1016/j.ccell.2016.11.010
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发表时间：
2017-01-09
期刊：
影响因子：
50.3
通讯作者：
Rafii S
中科院分区：
文献类型：
--
作者：
Cao Z;Scandura JM;Inghirami GG;Shido K;Ding BS;Rafii S
肿瘤相关内皮细胞(TECs)调节肿瘤细胞的侵袭性。然而，TECs赋予惰性肿瘤干细胞样活性的“核心”机制尚不清楚。在此，我们使用活体小鼠和人肿瘤模型来确定TEC表达的胰岛素生长因子(IGF)结合蛋白-7(IGFBP7/血管调节蛋白)的肿瘤抑制检查点作用。在肿瘤发生过程中，IGFBP7阻断IGF1，抑制表达IGF1受体(IGF1R)的肿瘤干细胞(TSCs)的扩增和植入。然而，化疗触发TECs抑制IGFBP7，从而刺激IGF1R+TSCs表达FGF4，诱导前馈FGFR1-ETS2血管分泌级联反应，从而绕过TEC IGFBP7。因此，IGFBP7的缺失和IGF1的上调激活了TECs中的FGF4-FGFR1-ETS2通路，将原始肿瘤细胞转化为化疗耐药的TSCs，从而促进了它们的植入和进展。
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 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 engraftment 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 feed-forward 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 engraftment and progression.