Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer
Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer
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DOI：
10.1002/path.4181
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发表时间：
2013-06-01
影响因子：
7.3
通讯作者：
Presta, Marco
中科院分区：
文献类型：
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作者：
Ronca, Roberto;Alessi, Patrizia;Presta, Marco
成纤维细胞生长因子(FGFs)通过刺激血管生成和肿瘤生长在前列腺癌中发挥自分泌/旁分泌功能。在这里，双氢睾酮(DHT)上调了小鼠前列腺癌TRAMP-C2细胞中FGF2和FGF8b的生成，激活了依赖于成纤维细胞生长因子的自分泌刺激环路。可溶性模式识别受体长五肽-3(PTX3)是一种天然的成纤维细胞生长因子拮抗剂，通过其N-末端结构域与FGF2和FGF8b结合。我们证明了重组PTX3蛋白和PTX3衍生的五肽Ac-ARPCA-NH2取消了小鼠TRAMP-C2细胞和人LNCaP前列腺癌细胞对DHT和FGFs的促有丝分裂反应。此外，PTX3抑制DHT激活的TRAMP-C2细胞在鸡胚绒毛尿囊膜(CAM)上的血管生成活性。因此，人PTX3过表达可抑制DHT或FGFs对hPTX3_TRAMP-C2细胞的促有丝分裂活性及其血管生成活性。此外，hPTX3_TRAMP-C2细胞在移植到同基因或免疫缺陷的雄性裸鼠身上时，其血管生成和肿瘤形成的潜力显著降低。当TRAMP-C2细胞仅过度表达成纤维细胞生长因子结合的N末端PTX3结构域时，也观察到类似的抑制作用。与PTX3在实验性前列腺癌中的抗肿瘤活性一致，对前列腺癌患者前列腺针刺活检的免疫组织化学分析表明，在正常腺体的基底细胞中大量表达的PTX3在高级别前列腺上皮内瘤变和浸润性肿瘤区中缺失。这些结果表明PTX3是一种有效的抗前列腺癌血管生成和抗肿瘤活性的成纤维细胞生长因子拮抗剂。版权所有(C)2013年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up-regulates FGF2 and FGF8b production in murine TRAMP-C2 prostate cancer cells, activating a FGF-dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin-3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N-terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3-derived pentapeptide Ac-ARPCA-NH2 abolish the mitogenic response of murine TRAMP-C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT-activated TRAMP-C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP-C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP-C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP-C2 cells overexpress only the FGF-binding N-terminal PTX3 domain. In keeping with the anti-tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high-grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti-angiogenic and anti-neoplastic activity in prostate cancer. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.