Cytokines and FGFs in prostate cancer progression

成纤维细胞生长因子(FGFs)和白介素6(IL-6)是前列腺癌细胞重要的生长和生存因子。我们的基本假设是前列腺周围正常组织中FGFs和IL-6的表达增加，通过向前列腺癌细胞提供关键的生长和生存信号来刺激前列腺癌的进展，并且这些进展因子表达的控制的个体差异可能导致前列腺癌发病率的差异。我们假设前列腺上皮细胞的细胞感觉通过这一机制促进前列腺癌的进展。如果是这样的话，细胞衰老程度的不同可能解释了疾病发病率的差异。雄激素和雌激素对IL-6的转录有显着影响，已有研究表明，在衰老的前列腺中，这些激素的浓度有变化。此外，IL-6启动子的一种多态性已被描述，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，我们提出以下具体目标：特异性目标1：我们将确定前列腺癌患者和非前列腺癌患者的良性前列腺组织中细胞衰老、细胞因子表达和成纤维细胞生长因子含量是否存在显著相关性。然后，我们将评估这些因素的变化是否与年龄增长、前列腺癌的存在和个体的种族有关。最后，我们将寻求开发前列腺上皮细胞衰老的新标记物来证实这些发现，这些发现最初将基于衰老相关的β-半乳糖苷酶的测量。具体目的2：我们将确定前列腺癌患者和非前列腺癌患者前列腺内雄激素和雌激素浓度的差异是否与良性前列腺组织中IL-6水平的变化有关。我们将利用性腺功能低下的SCID小鼠异种前列腺移植模型，直接检测雄激素和雌激素对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启动子基因型有关。最终目标将是直接确定在雄激素或雌激素存在的情况下，IL-6启动子基因对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.