Bardella Chiara, Dettori Daniela, Olivero Martina, Coltella Nadia, Mazzone Massimiliano, Di Renzo Maria Flavia
Laboratory of Cancer Genetics and Division of Molecular Oncology of the Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Turin, Italy.
Clin Cancer Res. 2007 Apr 1;13(7):2191-8. doi: 10.1158/1078-0432.CCR-06-1915.
Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance. We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics.
Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses.
In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own.
These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.
晚期卵巢癌最初对铂类药物和紫杉烷类的联合化疗有反应，但在大多数情况下会产生耐药性。我们最近发现，在体外，肝细胞生长因子（HGF）可增强顺铂（CDDP）和紫杉醇处理的人卵巢癌细胞系的死亡。本研究探讨体内HGF是否使卵巢癌细胞对这些化疗药物更敏感。
使用携带HGF转基因的慢病毒载体，转导SK-OV-3和NIH:OVCAR-3卵巢癌细胞系，以获得稳定的自分泌和旁分泌HGF受体激活。在体外，我们检测了未分选的分泌HGF的大量细胞群体的生长、迁移、侵袭以及对CDDP和紫杉醇的反应。在体内，我们测试了药物对免疫缺陷小鼠中野生型细胞和分泌HGF的细胞形成的皮下肿瘤的细胞毒性作用。荷瘤小鼠接受CDDP（腹腔注射）和紫杉醇（静脉注射）治疗，采用不同的给药方案和剂量联合使用。
在体外，分泌HGF的细胞未显示增殖率和存活率改变，但对单独或联合使用的CDDP和紫杉醇触发的死亡高度敏感。在体内，我们发现了一个治疗窗口，其中自分泌/旁分泌HGF使肿瘤对低剂量药物敏感，而这些药物单独使用时无效。
这些数据提供了概念验证，即HGF的体内基因治疗可能使卵巢癌细胞对传统化疗敏感。
