Ahmed Ahmed Ashour, Mills Anthony D, Ibrahim Ashraf E K, Temple Jillian, Blenkiron Cherie, Vias Maria, Massie Charlie E, Iyer N Gopalakrishna, McGeoch Adam, Crawford Robin, Nicke Barbara, Downward Julian, Swanton Charles, Bell Stephen D, Earl Helena M, Laskey Ronald A, Caldas Carlos, Brenton James D
Functional Genomics of Drug Resistance Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Cancer Cell. 2007 Dec;12(6):514-27. doi: 10.1016/j.ccr.2007.11.014.
The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.
细胞外基质（ECM）可通过AKT介导的凋亡抑制来诱导化疗耐药。在此，我们表明ECM蛋白TGFBI（转化生长因子β诱导蛋白）的缺失足以诱导卵巢癌细胞对紫杉醇产生特异性耐药以及有丝分裂纺锤体异常。用重组TGFBI蛋白处理的紫杉醇耐药细胞通过FAK和Rho依赖的微管稳定作用显示出整合素依赖的紫杉醇敏感性恢复。一项前瞻性临床试验中紫杉醇治疗的卵巢癌的TGFBI免疫组化染色显示，紫杉醇诱导的细胞毒性形态学变化局限于TGFBI强表达区域。这些数据表明，ECM可通过调节微管稳定性来介导紫杉烷敏感性。
