Cao Zhongwei, Scandura Joseph M, Inghirami Giorgio G, Shido Koji, Ding Bi-Sen, Rafii Shahin
Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Birth Defects and Related Diseases of Women and Children, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
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.
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，我们利用体内小鼠和人类肿瘤模型来确定TECs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并抑制表达IGF1受体（IGF1R）的肿瘤干细胞样细胞（TSCs）的扩增和侵袭性。然而，化疗会触发TECs抑制IGFBP7，这会刺激IGF1R TSCs表达FGF4，诱导一个前馈FGFR1-ETS2血管分泌级联反应，从而消除TEC IGFBP7。因此，IGFBP7的缺失和IGF1的上调激活了TECs中的FGF4-FGFR1-ETS2通路，并将幼稚肿瘤细胞转化为化疗耐药的TSCs，从而促进它们的侵袭和进展。
