Critical role of TGF-beta for tumor angiogenic switch

血管生成是肿瘤进展所必需的，许多研究表明，抗血管生成剂包括抗血管内皮生长因子抗体可以减少肿瘤的生长。血管生成平衡向促血管生成状态的转变，被称为“血管生成开关”，是癌症进展的标志。血管内皮生长因子被认为是最有效的肿瘤血管生成介质之一。然而，血管内皮生长因子并不是一种血管生成因子，因为血管内皮生长因子不仅在癌组织中大量表达，而且在癌前病变及其起源组织中也有大量表达。最近，我们发现非内皮间充质细胞(NEMCs；成纤维细胞和血管平滑肌细胞)中的血小板衍生生长因子-AA(PDGF-AA)/p70S6K信号转导通路在治疗和肿瘤血管生成中是必不可少的。血管内皮细胞和肿瘤细胞通过PDGF-AA/p70S6K途径的自分泌系统调节和维持内源性血管内皮生长因子的表达。血小板衍生生长因子-AA/血管内皮生长因子α…因此，更多的XIs可能是一种普遍存在的增强血管生成信号的自分泌系统，而PDGF-AA及其相关通路可能比VEGF及其通路更有效地成为肿瘤血管生成治疗的靶点。另一方面，转化生长因子-β(TGF-β)是一种多功能多肽，调节包括细胞生长和血管生成在内的多项功能。转化生长因子-β的生长抑制特性引起了人们对其作为肿瘤抑制因子作用的广泛关注。然而，现在有越来越多的证据表明，随着肿瘤的进展，转化生长因子-β的作用从肿瘤抑制者转变为肿瘤促进者。鉴于转化生长因子-β在肿瘤进展中的重要作用，因此转化生长因子-β信号转导为肿瘤治疗提供了一个有吸引力的靶点。有趣的是，我们最近的独立研究显示，转化生长因子-β抑制了PDGF-AA/p70S6K途径上调的血管内皮生长因子的表达(未公布的数据)，提示转化生长因子-β可能是血管生成开关的关键调节因子。重要的是，这一假说暗示了如下几种可能性：1)转化生长因子-β是雷帕霉素选择性敏感性的一个有吸引力的分子标记物，即通过降低雷帕霉素靶标的活性而抑制p70S6K；2)抗转化生长因子-β和抗PDGF-AA/p70S6K信号通路的联合治疗可能成为肿瘤抗血管生成治疗的有效靶点。更多地了解血管生成开关的病理生理学和机制将使我们能够在不久的将来开发出临床适用的策略。较少

Angiogenesis is required for tumor progression, as supported by a number of studies showing a reduction in tumor growth by antiangiogenic agent, including anti-VEGF (vascular endothelial growth factor) antibody. A shift of the angiogenic balance to the proangiogenic state, temrmed the 'angiogenic switch', is a hallmark of cancer progression. VEGF has been recognized as one of the most potent mediators of tumor angiogenesis. However, VEGF is not an angiogenic factor, because VEGF is abundantly expressed in not only cancers but also precancerous lesions and their originating tissue. Recently, we showed that platelet-derived growth factor-AA (PDGF-AA)/p70S6K signal transduction pathways in nonendothelial mesenchymal cells (NEMCs ; fibroblasts and vascular smooth muscle cells) was essential for therapeutic and tumor angiogenesis. The endogenous expression of VEGF is regulated and maintained by NEMCs and tumor cells via the autocrine system of the PDGF-AA/p70S6K pathways. The PDGF-AA/VEGF a … More xis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of angiogenic therapy for cancers than VEGF and its pathways.On the other hand, transforming growth factor-beta (TGF-beta) is multifunctional polypeptides that regulate several functions, including cell growth and angiogenesis. The growth-inhibiting properties of TGF-beta have gained much attention into its role as a tumor suppressor. There is, however, now increasing evidence that TGF-beta switches roles, from tumor suppressor to tumor promoter, as the tumor progresses. Given the integral role of TGF-beta in the tumor progression, it follows that TGF-beta signaling offers an attractive target for cancer therapy. Interestingly, our recent independent study revealed that TGF-β inhibits VEGF expression upregulated by PDGF-AA/p70S6K pathways (unpublishied data), suggesting that TGF-beta may be a key regulator of angiogenic switch. Importantly, this hypothesis implies several possibilities as follows ; 1) TGF-beta is an attractive molecular marker for selective sensitivity to rapamycin, that is a specific inhibitor of p70S6K via reducing the activity of target of rapamycin ; 2) A combination therapy of anti-TGF-beta and anti-PDGF-AA/p70S6K signaling may be efficient target of antiangiogenic therapy for cancers. More understanding of pathophysiology and mechanism of angiogenic switch will allow us to develop clinically applicable strategies in the near future. Less