Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.
Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.
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DOI：
10.1371/journal.pone.0028077
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Rueda BR
中科院分区：
文献类型：
--
作者：
McCann CK;Growdon WB;Kulkarni-Datar K;Curley MD;Friel AM;Proctor JL;Sheikh H;Deyneko I;Ferguson JA;Vathipadiekal V;Birrer MJ;Borger DR;Mohapatra G;Zukerberg LR;Foster R;Macdougall JR;Rueda BR
最近的证据表明，Hedgehog(HH)信号的异常激活与髓母细胞瘤、基底细胞瘤、小细胞肺癌、胰腺癌、前列腺癌和卵巢癌的发病机制有关。这项研究旨在确定抑制这一途径是否可以抑制浆液性卵巢癌的生长。我们利用浆液性卵巢癌的体内临床前模型来表征HH途径抑制剂环丙胺和临床适用的衍生物IPI-926的抗肿瘤活性。原发的人浆液性卵巢肿瘤组织被用来在小鼠身上产生肿瘤异种移植瘤，随后用环多巴胺或IPI-926治疗。两种化合物均表现出显著的抗肿瘤活性。当IPI-926与紫杉醇和卡铂(T/C)联合使用时，未观察到协同作用，但停止T/C后继续使用IPI-926继续抑制肿瘤生长。RT-PCR分析HH途径活性以评估Gli1转录本水平的变化。单剂量IPI-926在24小时抑制小鼠间质Gli1转录水平，而人肿瘤内Gli1水平不变。然而，21天的慢性IPI-926治疗抑制了小鼠间质和人类肿瘤细胞中的HH信号。来自人类浆液性卵巢肿瘤的显微解剖间质的表达数据证实了Gli1转录本的存在，并且Gli1转录本水平升高与生存率恶化之间存在显着关联。IPI-926治疗抑制浆液性肿瘤生长，提示HH信号通路参与了卵巢癌的发病机制，并有望成为一种新的治疗靶点，特别是在维持状态下。
Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth. We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926. Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival. IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
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