): With training in molecular biology and pathology, the current goal of the candidate is to become an independent physician scientist investigating the molecular pathology of cancer. This proposal will address the hypothesis that prostate cancer arises from aberrant stem cell maturation. One way to test this is to compare overall gene expression patterns between cancer cells and stem cells. Using new techniques such as subtraction hybridization, the applicants will attempt to isolate genes that are differentially expressed in the different cell populations. They will extend these comparisons to the analysis of total gene expression profiles using Gene Expression Micro-arrays (GEMS) and/or Serial Analysis of Gene Expression (SAGE) as the technology advances. Laser Capture Micro-dissection (LCM) can isolate individual cell populations from complex mixtures. Yet, isolation of stem cells is still hindered by the lack of suitable markers. Thus, the first portion of these studies is directed at isolating prostate stem cells. The rat prostate is ideal for attempts to identify prostate stem cell markers since the glandular tissue can be repeatedly cycled in vivo between involution (apoptosis) and re-growth (proliferation) by manipulating serum androgens. Using this model, the sponsor and others found that telomerase activity and the phospho-protein pp32 are candidate stem cell markers in the prostate. To improve the understanding of prostate stem cells and tissue organization, they will characterize the cellular localization of telomerase and pp32 expression as compared with that of other candidate stem cell markers and other well-characterized markers of prostate cell types. The applicants will monitor the dynamics of these markers through cycles of involution, growth and androgen restoration. Candidate rat stem cell markers will then be evaluated in the human to identify similar cell types. Putative stem cell and other cell types will be visualized and isolated by LCM. cDNA will be prepared for subtractive hybridization and library production. Pair-wise subtractive hybridizations will be made using isolated cell types with BPH, PIN, and carcinoma. The applicants' approach is unique in that the starting material for analysis is not a complex mixture of cell types within the prostate. These studies should produce new insights into altered stem cell maturation in BPH, PIN and carcinoma, and may provide new molecular targets for diagnosis, prognosis and treatment of prostate cancer.
| Rubin, Mark A; De Marzo, Angelo M (2004) Molecular genetics of human prostate cancer. Mod Pathol 17:380-8 |
| Meeker, Alan K; Hicks, Jessica L; Iacobuzio-Donahue, Christine A et al. (2004) Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin Cancer Res 10:3317-26 |
| DeMarzo, Angelo M; Nelson, William G; Isaacs, William B et al. (2003) Pathological and molecular aspects of prostate cancer. Lancet 361:955-64 |
| van Leenders, Geert J L H; Gage, Wesley R; Hicks, Jessica L et al. (2003) Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy. Am J Pathol 162:1529-37 |
| De Marzo, Angelo M; Meeker, Alan K; Zha, Shan et al. (2003) Human prostate cancer precursors and pathobiology. Urology 62:55-62 |
| Meeker, Alan K; Hicks, Jessica L; Platz, Elizabeth A et al. (2002) Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res 62:6405-9 |
| Luo, Jun; Zha, Shan; Gage, Wesley R et al. (2002) Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. Cancer Res 62:2220-6 |
| Meeker, Alan K; Gage, Wesley R; Hicks, Jessica L et al. (2002) Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. Am J Pathol 160:1259-68 |
| Zha, S; Gage, W R; Sauvageot, J et al. (2001) Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res 61:8617-23 |
| De Marzo, A M; Putzi, M J; Nelson, W G (2001) New concepts in the pathology of prostatic epithelial carcinogenesis. Urology 57:103-14 |
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