We have found that fibroblasts associated with prostatic carcinomas can dramatically influence prostatic tumor progression. Using both an in vivo tissue recombinant model and an in vitro co-culture model, we have demonstrated that carcinoma-associated fibroblasts from human prostatic cancer can alter morphology, reduce death and stimulate proliferation of initiated, non-tumorgenic human prostatic epithelial cells. This effect is not detected when normal fibroblasts from the prostate are grown with the same epithelial cells under the same experimental conditions. We hypothesize that a signal from carcinoma-associated fibroblasts can stimulate tumor progression in human cancers. At the present time the nature of this signal is unknown. Likewise, properties of the initiated, non- tumorgenic epithelial cells which allow them to respond to these signals is also unknown. We wish to characterize the fibroblast and epithelial cells described above and identify the determinants that allow for the dramatic tumor progression that occurs when these two cell populations are grown together.
Specific Aims 1 and 2 will examine several phenotypic, biologic and molecular properties of the carcinoma-associated fibroblasts and the initiated, non-tumorgenic epithelial cells and identify those aspects of fibroblast-epithelial cell interaction that stimulates tumor progression.
Specific Aim 3 will determine if prostatic fibroblasts or epithelial cells from individuals with familial prostate cancer differ from cells of normal individuals in their ability to stimulate tumor progression. Finally, Specific Aim 4 will seek to determine the molecular mechanism by which carcinoma-associated fibroblasts (CAF) stimulate tumor progression when incubated with initiated, non-tumorgenic human prostatic epithelial cells (Tag-HPE). The initiation of prostate cancer is a very frequent event occurring in the majority of men over age 65. However, the mechanism by which these slow-growing lesions convert to a life-threatening disease is in known. Therefore, the mechanisms that control tumor progression in prostate cancer are of the utmost importance to study. In this proposal, we have focused our attention on identifying fibroblast-induced signals which contribute to prostatic tumor progression.
| Meng, M V; Grossfeld, G D; Williams, G H et al. (2001) Minichromosome maintenance protein 2 expression in prostate: characterization and association with outcome after therapy for cancer. Clin Cancer Res 7:2712-8 |
