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Principal Investigator: Dr. Alexander Nikitin
Contact Information: E-mail: an58@cornell.edu
- Phone: 607-253-4347
Sponsor: NIH-NCI
Grant Number: 1R01CA112354-01A1
Title: Modeling Ovarian Carcinoma by Defined Genetic Alterations
Annual Direct Cost: $177,750
Project Period: 09/01/05-08/31/10
In the year 2004, epithelial ovarian cancer (HOC) is expected
to be the 4th leading cancer type among cancer-related deaths in women in the
United States. Due to its symptomless development and the lack of accurate
animal models, EOC pathogenesis remains among the least understood of all major
cancers.
Alterations in signaling pathways mediated by p53, p16/Rb and HGF/c-met occur
frequently and are reported to be associated with the poor clinical prognosis.
However, their specific roles in EOC formation remain uncertain. Recently we
have demonstrated that the ovarian surface epithelium (OSE) - selective
inactivation of tumor suppressor p53 results in carcinogenesis, and that
inactivation of the retinoblastoma (Rb) gene dramatically accelerates this
process. In this model, neoplasms closely resemble the aggressive variant of
human serous adenocarcinoma. Our preliminary results indicate that, in addition
to its role in cell proliferation, apoptosis and genomic instability, the
cooperation between defective p53 and Rb pathways predisposes OSE to expression
of such advanced cancer traits as increased motility and invasion. These traits
remain dormant until Hepatocyte Growth Factor (HGF), produced by accumulating
stromal cells, activates c-met signaling. To test this hypothesis, we propose
(1) to determine contributions of p53 and p16/Rb towards motility and invasion
during epithelial ovarian carcinogenesis, and (2) to evaluate roles of HGF and
c-met in EOC invasion and intraperitoneal spreading. These studies should
advance our understanding of the EOC pathogenesis by demonstrating new
biological mechanisms by which defective p53 and Rb pathways may additionally
facilitate the course of neoplastic progression and by establishing the role of
HGF/c-met signaling as a permissive event leading to invasion during the OSE
carcinogenesis.
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