| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Research Abstract |
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
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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
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