Laboratory of Novel Therapeutic Targets, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain.
Exp Cell Res. 2010 Feb 15;316(4):554-67. doi: 10.1016/j.yexcr.2009.11.020. Epub 2009 Dec 16.
Vascular endothelial growth factor (VEGF) is overexpressed during the transition from prostate intraepithelial neoplasia (PIN) to invasive carcinoma. We have mimicked such a process in vitro using the PIN-like C3(1)/Tag-derived Pr-111 cell line, which expresses low levels of VEGF and exhibits very low tumorigenicity in vivo. Elevated expression of VEGF164 in Pr-111 cells led to a significant increase in tumorigenicity, invasiveness, proliferation rates and angiogenesis. Moreover, VEGF164 induced strong changes in cell morphology and cell transcriptome through an autocrine mechanism, with changes in TGF-beta1- and cytoskeleton-related pathways, among others. Further analysis of VEGF-overexpressing Pr-111 cells or following exogenous addition of recombinant VEGF shows acquisition of epithelial-mesenchymal transition (EMT) features, with an increased expression of mesenchymal markers, such as N-cadherin, Snail1, Snail2 (Slug) and vimentin, and a decrease in E-cadherin. Administration of VEGF led to changes in TGF-beta1 signaling, including reduction of Smad7 (TGF-beta inhibitory Smad), increase in TGF-betaR-II, and translocation of phospho-Smad3 to the nucleus. Our results suggest that increased expression of VEGF in malignant cells during the transition from PIN to invasive carcinoma leads to EMT through an autocrine loop, which would promote tumor cell invasion and motility. Therapeutic blockade of VEGF/TGF-beta1 in PIN lesions might impair not only tumor angiogenesis, but also the early dissemination of malignant cells outside the epithelial layer.
血管内皮生长因子（VEGF）在前列腺上皮内瘤变（PIN）向浸润性癌的转变过程中过度表达。我们在体外使用类似于 PIN 的 C3(1)/Tag 衍生的 Pr-111 细胞系模拟了这样的过程，该细胞系表达低水平的 VEGF，体内致瘤性非常低。Pr-111 细胞中 VEGF164 的高表达导致致瘤性、侵袭性、增殖率和血管生成显著增加。此外，VEGF164 通过自分泌机制导致细胞形态和细胞转录组发生强烈变化，改变 TGF-β1 和细胞骨架相关途径等。进一步分析过表达 VEGF 的 Pr-111 细胞或外源添加重组 VEGF 后，发现获得了上皮间质转化（EMT）特征，间充质标志物如 N-钙粘蛋白、Snail1、Snail2（Slug）和波形蛋白表达增加，E-钙粘蛋白表达减少。VEGF 的给药导致 TGF-β1 信号的改变，包括 Smad7（TGF-β 抑制性 Smad）减少、TGF-βR-II 增加以及磷酸化 Smad3 向核内易位。我们的结果表明，在从 PIN 到浸润性癌的转变过程中，恶性细胞中 VEGF 的表达增加会通过自分泌环导致 EMT，从而促进肿瘤细胞侵袭和迁移。在 PIN 病变中阻断 VEGF/TGF-β1 的治疗可能不仅会损害肿瘤血管生成，还会损害恶性细胞在上皮层外的早期扩散。
