Fibroblast growth factors (FGFs) and IL-6 act as important growth and survival factors for prostate cancer cells. Our fundamental hypothesis is that increased expression of FGFs and IL-6 by normal tissue in the peripheral zone of the prostate acts as stimulus to prostate cancer progression by providing critical growth and survival signals to prostate cancer cells and that individual variation in the control of expression of these progression factors may lead to differences in the incidence of prostate cancer. We hypothesize that cellular senscence of prostatic epithelial cells promotes prostate cancer progression via this mechanism. If so, variation in the extent of cellular senescence may explain differences in disease incidence. Androgens and estrogens have significant effects on transcription of IL-6 and it has been shown that there are changes in the concentrations of these hormones within the aging prostate. In addition, a polymorphism of the IL-6 promoter has been described in which the allele that is associated with increased IL-6 transcription is significantly more common in African-Americans. We therefore propose the following Specific Aims:
SPECIFIC AIM 1 : We will determine if there is a significant association of cellular senescence, cytokine expression and FGF content in benign prostate tissues from men with and without prostate cancer. We will then evaluate whether variations in these factors are associated with increasing age, the presence of prostate cancer and the race of the individual. Finally, we will seek to develop new markers of cellular senescence in prostatic epithelium to confirm these findings which will initially be based on measurement of senescence associated b-galactosidase.
SPECIFIC AIM 2 : We will determine if differences in intraprostatic androgandrogen and estrogen concentration are associated with alterations in tissue IL-6 levels in benign prostate tissue from men with and without prostate cancer. We will directly test the effects of androgens and estrogens on expression of IL-6 using prostatic xenografts in hypogonadal scid mice. We will then determine if IL-6 levels in benign prostate are associated with age, disease status, race and the IL-6 promoter genotype. The final goal will be to directly determine the effect of the IL-6 promoter genotype on IL-6 expression in the presence of androgens or estrogens.
