Ahmed Mansoor, Sottnik Joseph L, Dancik Garrett M, Sahu Divya, Hansel Donna E, Theodorescu Dan, Schwartz Martin A
Department of Internal Medicine (Cardiology), Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520, USA.
Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
Cancer Cell. 2016 Sep 12;30(3):432-443. doi: 10.1016/j.ccell.2016.08.002. Epub 2016 Sep 1.
RhoGDI2 specifically suppresses bladder cancer metastasis but not primary tumor growth, which involves tumor-associated macrophages. We report that macrophage-secreted osteopontin binds to CD44s on the tumor cells and promotes invasion and clonal growth. These effects are RhoGDI2-sensitive and require CD44s binding to the Rac GEF TIAM1. Osteopontin expression correlates with tumor aggressiveness and poor clinical outcome in patients. Inhibiting this pathway potently blocked lung and lymph node metastasis; however, primary tumors and established metastasis were less sensitive. Osteopontin-CD44s-TIAM1 promotes clonal growth in vitro but not at high cell density. These data identify osteopontin-CD44-TIAM1-Rac1 axis as a RhoGDI2-sensitive pathway and potential therapeutic target in bladder cancer metastasis. They also elucidate the mechanism behind RhoGDI2 specificity for metastasis over established tumors.
RhoGDI2特异性抑制膀胱癌转移，但不影响原发性肿瘤生长，这一过程涉及肿瘤相关巨噬细胞。我们报道巨噬细胞分泌的骨桥蛋白与肿瘤细胞上的CD44s结合，促进侵袭和克隆生长。这些效应对RhoGDI2敏感，且需要CD44s与Rac鸟苷酸交换因子TIAM1结合。骨桥蛋白表达与患者肿瘤侵袭性及不良临床预后相关。抑制该信号通路可有效阻断肺和淋巴结转移；然而，原发性肿瘤和已形成的转移灶对此敏感性较低。骨桥蛋白-CD44s-TIAM1在体外可促进克隆生长，但在高细胞密度下则不然。这些数据确定骨桥蛋白-CD44-TIAM1-Rac1轴是一条对RhoGDI2敏感的信号通路，也是膀胱癌转移的潜在治疗靶点。它们还阐明了RhoGDI2对已形成肿瘤转移具有特异性的背后机制。
