The progression of prostate cancer from intraepithelial neoplasia to metastatic disease involves the generation of a phenotype that comprises changes in cell adhesion, cell motlity, cell invasion, cell proliferation and the capacity to promote blood vessel formation. The process of prostate cancer progression involves the accumulation of metastasis promoting genes and the inactivation of metastasis suppressing genes. In the current proposal, we focus on two such gene families that we believe represent prototype molecules for the regulation of prostate cancer cell motility and cell cycle progression. The first are thymosin b15 and it's closely related isoform thymosin b16 which increase during prostate cancer progression and which we have evidence can regulate tumor cell motility. The second is antizyme, which is lost in the later stages of prostate cancer progression and which we find can negatively modulate the cell cycle by facilitating degradation of cell cycle proteins. This proposal is devoted to the detailed study of these two molecular classes and the nature of the cellular and molecular processes that they influence in order to regulate the metastatic pathway. We will investigate the hypothesis that alteration of the intracellular b-thymosin profile in prostate cancer cells can promote increased cell motility and increased metastatic potential. We will also study the role of secreted thymosin b15 in promoting endothelial cell migration and tumor angiogenesis. With regard to antizyme, we, will determine whether the cell cycle arrest observed in response to antizyme upregulation in vitro is sufficient to cause decreased tumor growth and metastasis in vivo. We will also study the role of an endogenous antizyme inhibitor to see if it can counter the negative growth effects of antizyme. Our approach will be to construct prostate cancer cells lines that express wild-type and mutated forms of antizyme, antizyme inhibitor and the four major thymosin 13 isoforms and to determine the effects of these molecules on cell migration, cell proliferation and tumor angiogenesis in in vitro and in vivo models of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37CA037393-20
Application #
6333116
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
1983-07-01
Project End
2006-04-30
Budget Start
2001-05-11
Budget End
2002-04-30
Support Year
20
Fiscal Year
2001
Total Cost
$392,467
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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