Cancer Research UK and University of Manchester Dept. Translational Angiogenesis, Paterson Institute, Withington, Manchester, UK.
Cancer Biol Ther. 2010 Sep 1;10(5):495-504. doi: 10.4161/cbt.10.5.12585. Epub 2010 Sep 4.
Fibroblast Growth Factors (FGFs) have been implicated in malignant transformation, tumor mitogenesis, angiogenesis and chemoresistance. The aim of this study was to determine which FGFs and FGFRs play functional roles in epithelial ovarian cancer. Restriction enzyme analysis of mRNA revealed that transformation was associated with a switch in FGFR2 and FGFR3, from the IIIc to the IIIb isoform. There was widespread expression of FGFs, including FGF7, in all tissues but, FGF3 and FGF19 were expressed by malignant cell lines and cancer tissue but were not present in normal tissue. Using FGFR-specific shRNAi we demonstrated that reductions in FGFR2 inhibited proliferation of ovarian cancer cell lines in vitro (>50%, p < 0.006) and reduced cisplatin IC(50) (>60%, p < 0.0001). Cell cycle analysis revealed increased cisplatin sensitivity was associated with increased G(2)/M arrest and increased apoptosis. FGFR2 shRNAi reduced growth rates of ovarian tumor xenografts by 20% (p < 0.006) and when combined with cisplatin caused a 40% reduction in proliferation rates (p < 0.007). In contrast, RNAi-induced reductions in FGFR1 increased SKOV3 cell numbers, with associated changes in cell cycle but had no effect on ES2 cells. However, the cisplatin IC(50) was reduced (>50%, p < 0.0001) by FGFR1 shRNAi in both cell lines and there was increased apoptosis (46-50%) compared with control cells (35%) (p < 0.004). Together our data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. However, data on the inhibition of FGFR1 suggest that broad spectrum FGFR inhibitors may have unexpected effects on proliferation.
成纤维细胞生长因子（FGFs）已被牵连到恶性转化、肿瘤有丝分裂、血管生成和化疗耐药中。本研究旨在确定哪些 FGFs 和 FGFRs 在卵巢上皮性癌中发挥功能作用。mRNA 的限制性内切酶分析显示，转化与 FGFR2 和 FGFR3 从 IIIc 向 IIIb 同工型的转变有关。所有组织中都广泛表达 FGFs，包括 FGF7，但 FGF3 和 FGF19 仅在恶性细胞系和癌症组织中表达，而不存在于正常组织中。使用 FGFR 特异性 shRNAi，我们证明 FGFR2 的减少抑制了卵巢癌细胞系在体外的增殖（>50%，p < 0.006），并降低了顺铂的 IC50（>60%，p < 0.0001）。细胞周期分析显示，增加的顺铂敏感性与增加的 G2/M 期阻滞和增加的细胞凋亡有关。FGFR2 shRNAi 使卵巢肿瘤异种移植物的生长速度降低了 20%（p < 0.006），与顺铂联合使用时导致增殖速度降低了 40%（p < 0.007）。相比之下，RNAi 诱导的 FGFR1 减少使 SKOV3 细胞数量增加，伴随细胞周期的变化，但对 ES2 细胞没有影响。然而，FGFR1 shRNAi 在两种细胞系中均降低了顺铂的 IC50（>50%，p < 0.0001），并且与对照细胞（35%）相比，凋亡增加（46-50%）（p < 0.004）。总之，我们的数据表明，将 FGFR2 抑制剂与含铂细胞毒性药物联合用于治疗上皮性卵巢癌可能会增加抗肿瘤活性。然而，关于 FGFR1 抑制的数据表明，广谱 FGFR 抑制剂可能对增殖产生意想不到的影响。
