This grant application is submitted in response to the RFA CA-94-028.
The aim of this proposal is to investigate changes in expression of cathepsin B and generation of angiogenesis as markers that change in the progressive stages from premalignant lesions through prostatic carcinogenesis. These markers will be investigated further in a retrospective study to determine if they may be used to predict whether a low grade prostate tumor is a latent tumor, an aggressive tumor, or may transition from a latent to an invasive cancer. There are several features of cathepsin B in human prostate cancer that supports its function as such a marker: l) there is a change in cell-types expressing cathepsin B in tumors vs normal or benign hyperplastic prostates, 2) there is a change in cathepsin B subcellular localization in prostate tumor cells, and 3) cathepsin B localizes in microvessels and is also a marker for the increased angiogenesis associated with prostate tumors. Thus, we propose to examine premalignant (prostatic intraepithelial neoplasia, PIN) and early neoplastic lesions to determine when in the progressive stages of prostate carcinogenesis changes in cellular expression of cathepsin B and its subcellular localization can be detected. These data will be evaluated with comparable localization studies of the cystatins (endogenous cysteine protease inhibitors) and a second lysosomal protease, cathepsin D, to better determine when in the progressive carcinogenic process in the prostate there may be a shift in the balance of control of neoplastic cell proteolysis. An increase in angiogenesis will be examined as an independent marker of prostatic tumor progression. Because of the increased use of PSA and transrectal ultrasound imaging in detecting early prostatic cancers, it is important that early stage tumors be assessed by reliable markers to predict if they are latent or aggressive minors or if they may progress to be aggressive cancers. The retrospective study will examine whether cathepsin B, cystatin, and cathepsin D localization or microvessel determinations can be used in a predictive manner as to whether a prostate cancer appears to be latent or has a high probability of progressing to a more aggressive stage. Such information could help determine whether a patient should be treated aggressively for his disease or that no intervention may be the better course and the patient spared the morbidity and possible mortality associated with prostate surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051348-05
Application #
2905865
Study Section
Special Emphasis Panel (SRC (28))
Program Officer
Mullins, Christopher V
Project Start
1995-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Sinha, A A; Quast, B J; Reddy, P K et al. (1999) Intravenous injection of an immunoconjugate (anti-PSA-IgG conjugated to 5-fluoro-2'-deoxyuridine) selectively inhibits cell proliferation and induces cell death in human prostate cancer cell tumors grown in nude mice. Anticancer Res 19:893-902
Sinha, A A; Quast, B J; Wilson, M J et al. (1998) Codistribution of procathepsin B and mature cathepsin B forms in human prostate tumors detected by confocal and immunofluorescence microscopy. Anat Rec 252:281-9
Sinha, A A; Quast, B J; Wilson, M J et al. (1998) Immunocytochemical localization of an immunoconjugate (antibody IgG against prostatic acid phosphatase conjugated to 5-fluoro-2'-deoxyuridine) in human prostate tumors. Anticancer Res 18:1385-92
Wilson, M J; Sinha, A A (1997) Human prostate tumor angiogenesis in nude mice: metalloprotease and plasminogen activator activities during tumor growth and neovascularization of subcutaneously injected matrigel impregnated with human prostate tumor cells. Anat Rec 249:63-73