Critical role of TGF-beta for tumor angiogenic switch

TGF-β 对肿瘤血管生成开关的关键作用

• 批准号: 21791243
• 负责人: FUJII Takaaki
• 金额: $ 2.75万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21791243/
• 关键词: 腫瘍血管新生; TGF-β; VEGF; FGF-2; angiogenic switch; PDGF-AA; p70S6K; 血管新生; シグナル伝達; angioenic switch; rapamycin

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

血管生成是肿瘤进展所必需的，正如许多研究所支持的，这些研究显示抗血管生成剂（包括抗VEGF（血管内皮生长因子）抗体）可减少肿瘤生长。血管生成平衡向促血管生成状态的转变，称为“血管生成开关”，是癌症进展的标志。VEGF被认为是肿瘤血管生成最有效的介质之一。然而，VEGF不是血管生成因子，因为VEGF不仅在癌症中而且在癌前病变及其起源组织中大量表达。最近，我们发现，血小板衍生生长因子-AA（PDGF-AA）/p70 S6 K信号转导通路在非内皮间充质细胞（NEMCs ;成纤维细胞和血管平滑肌细胞）是必不可少的治疗和肿瘤血管生成。NEMC和肿瘤细胞通过PDGF-AA/p70 S6 K通路的自分泌系统调节和维持VEGF的内源性表达。PDGF-AA/VEGF a ...更多信息 因此，xis可能是一个普遍存在的增强血管生成信号的自分泌系统，而PDGF-AA及其相关通路可能是比VEGF及其通路更有效的肿瘤血管生成治疗靶点。TGF-β的生长抑制特性已经引起了人们对其作为肿瘤抑制剂的作用的广泛关注。然而，现在有越来越多的证据表明，随着肿瘤的进展，TGF-β的角色从肿瘤抑制因子转变为肿瘤促进因子。鉴于TGF-β在肿瘤进展中的不可或缺的作用，因此TGF-β信号传导为癌症治疗提供了有吸引力的靶标。有趣的是，我们最近的独立研究显示，TGF-β抑制由PDGF-AA/p70 S6 K途径上调的VEGF表达（未公开的数据），表明TGF-β可能是血管生成开关的关键调节因子。重要的是，这一假设暗示了以下几种可能性：1）TGF-β是对雷帕霉素选择性敏感性的有吸引力的分子标记物，其是通过降低雷帕霉素靶点的活性的p70 S6 K的特异性抑制剂; 2）抗TGF-β和抗PDGF-AA/p70 S6 K信号传导的组合疗法可能是癌症抗血管生成疗法的有效靶点。对血管生成开关的病理生理学和机制的进一步了解将有助于我们在不久的将来开发出临床适用的策略。少

项目成果

Thickness of Subcutaneous Fat as a Strong Risk Factor for Wound Infections in Elective Colorectal Surgery: Impact of Prediction Using Preoperative CT

• DOI: 10.1159/000297521
• 发表时间: 2010-01-01
• 期刊: DIGESTIVE SURGERY
• 影响因子: 2.7
• 作者: Fujii, Takaaki;Tsutsumi, Soichi;Kuwano, Hiroyuki
• 通讯作者: Kuwano, Hiroyuki

VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B

• DOI: 10.1152/ajpheart.00015.2009
• 发表时间: 2009-11-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Onimaru, Mitsuho;Yonemitsu, Yoshikazu;Sueishi, Katsuo
• 通讯作者: Sueishi, Katsuo

MCF-7に対するRapamycinのVEGF発現抑制による直接的抗腫瘍効果

雷帕霉素通过抑制 VEGF 表达对 MCF-7 产生直接抗肿瘤作用

• 发表时间: 2010
• 作者: Hideaki Tahara;Marimo Sato;Magdalena Thurin;Ena Wang;Lisa H Butterfield;Mary L Disis;Bernard A Fox;Peter P Lee;Jon M Wigginton;Stefan Ambs;Yasunori Akutsu;Damien Chaussabel;Yuichiro Doki;Yoshihiko Hirohashi;Kohzoh Imai;James Jacobson;Masah;藤井孝明
• 通讯作者: 藤井孝明

An Autocrine Linkage Between Matrix Metalloproteinase-14 and Tie-2 Via Ectodomain Shedding Modulates Angiopoietin-1-Dependent Function in Endothelial Cells

• DOI: 10.1161/atvbaha.109.201111
• 发表时间: 2010-04-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Onimaru, Mitsuho;Yonemitsu, Yoshikazu;Sueishi, Katsuo
• 通讯作者: Sueishi, Katsuo

血管新生過程におけるShh、FGF-2によるAngiopoietin-1、angiopoietin-2発現制御機構の検討

血管生成过程中Shh和FGF-2对Angiopoietin-1和Angiopoietin-2表达的调节机制研究

• 发表时间: 2009
• 作者: 藤井孝明;et al
• 通讯作者: et al