| Project/Area Number |
12219203
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
TAKETO Makoto Mark Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (70281714)
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| Co-Investigator(Kenkyū-buntansha) |
OSHIMA Masanobu Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (40324610)
AOKI Masahiro Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (60362464)
MIYOSHI Hiroyuki Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (30362479)
KITAMURA Takanori Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (10378622)
石川 智夫 京都大学, 医学研究科, 助手 (70322162)
高久 和明 京都大学, 医学研究科, 助手 (90313121)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥109,000,000 (Direct Cost: ¥109,000,000)
Fiscal Year 2004: ¥20,000,000 (Direct Cost: ¥20,000,000)
Fiscal Year 2003: ¥20,000,000 (Direct Cost: ¥20,000,000)
Fiscal Year 2002: ¥22,000,000 (Direct Cost: ¥22,000,000)
Fiscal Year 2001: ¥23,000,000 (Direct Cost: ¥23,000,000)
Fiscal Year 2000: ¥24,000,000 (Direct Cost: ¥24,000,000)
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| Keywords | APC / COX-2 / Prostaglandin / Stromal cells / Transgenic mouse / Cancer / Pathology / LKB 1 / Apc / マイクロアレイ / Lkb1 / Fhit / 線維芽細胞 / TGF-βシグナル / 大腸癌 / 肝癌 / ノックアウトマウス / 血管新生 / Smad2 / β-catenin / ポリープ / cPLA2 / PGE_2 / EP2 |
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| Research Abstract |
Epithelium-stroma interactions play essential roles in tumor growth and progression. We have obtained the following results during the funded period through analysis of various tumors in mouse models of human cancers.
We first showed increased expression of COX-2 and mPGES, important enzymes in PGE_2 synthesis, in fibroblasts of the polyps with diameters larger than 1 mm that developed in the Apc gene knockout mice. VEGF expression was also induced in the stroma, accompanied by enhanced vascularization. We further showed that disruption of the PGE_2 receptor EP2 reduced polyp multiplicity and size drastically, as well as induction of COX-2 and VEGF. We also found induction of COX-2 and mPGES in the stromal cells of hamarotomatous tumors in the stomach, duodenum, and colon of Lkb1, Smad4, and Cdx2 knockout mice, respectively. These results suggest that angiogenesis, mediated by PGE_2 production by fibroblasts and EP2 receptors, is important in the growth of intestinal tumors, irrespective of the causative genetic changes. On the other hand, we showed development of hyperplastic tumors with macrophage infiltration in the stomach of transgenic mice that overexpress COX-2 and mPGES in the mucosal epithelium of the stomach. COX-2 inhibitors or antibiotics inhibited tumor formation, and macrophages activated by PGE_2 and bacteria in the stomach mucosa induced epithelial cell proliferation. Recent reports suggest that fibroblasts and macrophages are involved not only in growth, but also in progression of tumors. We previously found that invasion of the cancerous epithelial cells were accompanied by stromal cell accumulation in the polyps of the Apc/Smad4 compound mutant mice. We have shown that the stromal cells at the invasion front are not fibroblasts or macrophages, which suggests involvement of a novel type of stromal cells in the early stage of colon cancer invasion.
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