2004 Fiscal Year Final Research Report Summary
Molecular analysis of compensatory mechanism which tumor cells exert in VEGF deficent/RipTag mouse
| Project/Area Number |
15590363
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Osaka Medical Center for Cancer and Cardiovascular Diseases |
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Principal Investigator |
INOUE Masahiro OMCC, Biochemistry, director, 主任研究員 (10342990)
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| Co-Investigator(Kenkyū-buntansha) |
MUKAI Mutsuko MUKAI,Mutsuko, 主任研究員 (20342991)
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| Project Period (FY) |
2003 – 2004
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| Keywords | angiogenesis / VEGF / transgenic mouse / gene knockout mouse / hypoxia |
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| Research Abstract |
While we transferred RipTag mice from university of California at San Francisco, we found profound reduction of tumor formation in Japan. Formation of tumor in RipTag mouse is known to be sensitive to the genetic background. Although we tried to resolve the problem by backcrossing it into C57B1/6N or DBA background, we did not observe remarkable recovery of tumor formation. Afterwards, it has been revealed that the same phenomenon was observed in the original mouse colony in UCSF. It is likely that some genomic change in RipTag mouse occurred. Re-establishment of the transgenic mouse is now under consideration. Meanwhile, analysis of the archive pancreas samples from RipTag/VEGF-/- mice revealed that there were residual tumors with quite low microvessel density without apparent necrosis. We found that the residual tumors contains broad hypoxic region. This finding suggests that inhibiting angiogenesis results in emergence of hypoxic region as well as reduction of tumor formation. In these hypoxic tumors, apoptosis was not significantly increased, tumor cells seems to survive by adapting to the hypoxic microenvironment. From clinical point of view, the results offered a serious issue that anti-angiogenesis therapy might induce drug resistance by selecting hypoxia tolerant cancer cells. Then, We started to investigate the molecular mechanism of hypoxia tolerance of malignant cells. We found various cell lines can be maintained in hypoxic conditions for a couple of weeks. These tumor cells were alive but no proliferation nor cell death was observed. We focused on the mTOR signaling, which is know to be suppressed in hypoxia, but the consequence has not been clarified yet. We revealed that suppression of mTOR signaling is critical for their survival under prolonged hypoxic conditions.
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Research Products
(17 results)
