Cytokines and FGFs in prostate cancer progression

成纤维细胞生长因子（FGF）和IL-6作为前列腺癌细胞的重要生长和存活因子。我们的基本假设是，前列腺外周区正常组织中FGF和IL-6表达的增加通过向前列腺癌细胞提供关键的生长和存活信号而刺激前列腺癌进展，并且这些进展因子表达控制的个体差异可能导致前列腺癌发病率的差异。 我们推测前列腺上皮细胞的细胞敏感性通过这种机制促进前列腺癌的进展。 如果是这样的话，细胞衰老程度的变化可能解释疾病发病率的差异。雄激素和雌激素对IL-6的转录具有显著影响，并且已经显示在老化前列腺内这些激素的浓度存在变化。 此外，还描述了IL-6启动子的多态性，其中与IL-6转录增加相关的等位基因在非裔美国人中明显更常见。因此，我们提出了以下具体目标：具体目标1：我们将确定是否有一个显着的关联细胞衰老，细胞因子表达和FGF含量在良性前列腺组织的男性和非前列腺癌。 然后，我们将评估这些因素的变化是否与年龄增加，前列腺癌的存在和个体的种族有关。 最后，我们将寻求开发新的前列腺上皮细胞衰老的标志物，以证实这些发现，这将最初基于衰老相关的β-半乳糖苷酶的测量。具体目标2：我们将确定前列腺内雄激素和雌激素浓度的差异是否与前列腺癌和非前列腺癌男性良性前列腺组织中组织IL-6水平的改变有关。 我们将使用性腺功能减退的scid小鼠的前列腺异种移植物直接测试雄激素和雌激素对IL-6表达的影响。 然后我们将确定良性前列腺中的IL-6水平是否与年龄、疾病状态、种族和IL-6启动子基因型相关。 最终目标是直接确定在雄激素或雌激素存在下IL-6启动子基因型对IL-6表达的影响。

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.