Endoglin regulates cancer-stromal cell interactions in prostate tumors.
Endoglin regulates cancer-stromal cell interactions in prostate tumors.
复制标题
DOI：
10.1158/0008-5472.can-10-2665
复制
发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Vary CP
中科院分区：
文献类型：
--
作者：
Romero D;O'Neill C;Terzic A;Contois L;Young K;Conley BA;Bergan RC;Brooks PC;Vary CP
内皮糖蛋白是转化生长因子-β（TGF-β）的辅助受体，其与前列腺癌细胞的脱离、迁移和侵袭有关。然而，endoglin对前列腺肿瘤发生的病理生理学意义尚未完全确定。在这项研究中，我们解决了这个问题，通过研究内皮依赖性前列腺癌的进展，在TRAMP小鼠模型中，内皮糖蛋白基因删除。在该模型中，内皮糖蛋白是单倍不足的，使得其等位基因缺失略微增加肿瘤发生的频率，但产生比TRAMP对照肿瘤更小、血管化更少和转移性更少的肿瘤。最引人注目的是，TRAMP：eng+/−肿瘤缺乏TRAMP前列腺肿瘤特征性的癌相关成纤维细胞（CAF）的明显浸润。在人原代前列腺源性基质成纤维细胞（PrSC）中的研究证实，抑制内皮糖蛋白表达可降低细胞增殖、募集内皮细胞的能力以及响应肿瘤细胞条件培养基的迁移能力。我们发现分泌的胰岛素样生长因子结合蛋白（IGFBP）的水平增加的条件培养基中内皮素缺乏的PrSC，和内皮素依赖性调节IGFBP-4分泌是至关重要的基质细胞条件培养基刺激前列腺肿瘤细胞的生长。总之，我们的结果牢固地确立了内皮糖蛋白在前列腺癌进展中的病理生理学参与，并且它们显示了内皮糖蛋白如何在肿瘤微环境中支持肿瘤浸润CAF的活力以促进新血管形成和生长。
Endoglin is an accessory receptor for transforming growth factor-β (TGF-β) that has been implicated in prostate cancer cell detachment, migration and invasiveness. However, the pathophysiological significance of endoglin to prostate tumorigenesis has yet to be fully established. In this study we addressed this question by investigation of endoglin-dependent prostate cancer progression in a TRAMP mouse model where endoglin was genetically deleted. In this model, endoglin was haploinsufficient such that its allelic deletion slightly increased the frequency of tumorigenesis, yet produced smaller, less vascularized, and less metastatic tumors than TRAMP control tumors. Most strikingly, TRAMP:eng+/− tumors lacked the pronounced infiltration of carcinoma-associated fibroblasts (CAFs) that characterize TRAMP prostate tumors. Studies in human primary prostate-derived stromal fibroblasts (PrSC) confirmed that suppressing endoglin expression decreased cell proliferation, the ability to recruit endothelial cells, and the ability to migrate in response to tumor cell-conditioned medium. We found increased levels of secreted insulin-like growth factor binding proteins (IGFBPs) in the conditioned media from endoglin-deficient PrSCs, and that endoglin-dependent regulation of IGFBP-4 secretion was crucial for stromal cell-conditioned media to stimulate prostate tumor cell growth. Together, our results firmly establish the pathophysiological involvement of endoglin in prostate cancer progression, and they show how endoglin acts to support the viability of tumor infiltrating CAFs in the tumor microenvironment to promote neovascularization and growth.