2005 Fiscal Year Final Research Report Summary
Analysis of the mechanisms of action of angiogenesis inhibitor, endostatin and its dynamic localization in tumor blood vessels.
| Project/Area Number |
16591250
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General surgery
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
YAMAGUCHI Noriko Tokyo Med. & Dent.Univ., Med.Res.Inst., Instructor, 難治疾患研究所, 助手 (90251553)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
AOYAGI Masaru Tokyo Med. & Dent.Univ., Graduate School, Associate Professor, 大学院・医歯学総合研究科, 助教授 (40134704)
HORI Hisae Tokyo Med. & Dent.Univ., Med.Res.Inst., Instructor, 難治疾患研究所, 助手 (80014190)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Keywords | Angiogenesis / Cancer / Endostatin / Collagen |
|---|
| Research Abstract |
Endostatin is an endogenous angiogenesis inhibitor and showed quite strong anti-cancer activity. In mouse tumor model, endostatin inhibits tumor progression, tumor metastasis and induces tumor regression. The final goal of this research is to elucidate the functional mechanisms of endostatin on molecular level, then to contribute the development of new anti-cancer drugs. During 2004 to 2005, we achieved those progression described below.
In addition to anti-cancer activity, endostatin showed the strong anti-inflammatory activity in animal model for rheumatoid arthritis. We confirmed the efficacy of endostatin in two different experimental models. Also, we discovered that endostatin has inhibitory activity against some kinds of matrix metalloproteinases, MMP-2, 9, 12, 13, 14 through the examination of functional study. Inhibitory activity against matrix metalloproteinases was considered to be one of the mechanisms of anti-inflammatory effects. MMP-14 is expressed on cell membrane and has been reported to participate the considerable contribution for tumor invasion and metastasis. Therefore, it is possible that endostatin binds MMP-14 and inhibits tumor invasion and metastasis through its blocking enzyme activity. We analyzed that the co-localization of endostatin and MMP-14 was observed by confocal microscopy after endostatin was exposed to HUVEC. However, we could not detect the co-localization. The experimental data for HUVEC migration inhibition assay demonstrated that some preparations of HUVEC did not respond to endostatin. We hypothesized that there was the difference of gene expression profile between responder and non-responder. Using gene chip microarray, gene expression was estimated and the results for comparison revealed that accelerated expression was observed in 1.86% of genes, 2.9% of genes showed decreased expression and 95% were unchanged for the responder cells in comparison with the non-responder cells.
|
