PROSTATE SPECIFIC MEMBRANE ANTIGEN

前列腺癌是最常见的成年男性癌症，预计 今年将有超过4万人死于这种疾病。我们的长期计划 目的：确定与前列腺癌相关的独特因素 罹患癌症的倾向并了解其后遗症 关于恶性潜在性的异质性，因为它表现出广泛的 癌症从缓慢生长到快速进展的骨质疏松症 转移和死亡。我们最近发现了一种抗原，它是 在前列腺细胞中高表达，前列腺特异性膜抗原， PSM。我们已经鉴定PSM是一种独特的叶酸水解酶。我们有 发现在癌症中，编码来自于 在正常细胞中，编码胞浆形式 占主导地位。这一发现的含义是，前列腺可能 是微环境“叶酸缺乏症”的危险组织，而叶酸 缺乏与致癌易感性增加有关。 在癌症中，叶酸水解酶活性越来越多地驻留在细胞外， 潜在地作为一种手段从 多聚谷氨酸被死亡的癌细胞所丢失。作为叶酸 缺乏与有限的增长潜力有关的比率 这两个专业的表达可能对成长的光谱有贡献 前列腺癌的潜在风险。我们建议进一步刻画 这种独特的叶酸水解酶及其调节和叶酸的定义 不同表达水平的细胞生长潜能的调控 膜和胞浆形式的蛋白质。我们还建议- 在小鼠前列腺中表达PSM以确定其表达的影响 原位前列腺的生物学。我们还建议生成淘汰赛 以确定其在其他部位表达的重要性 在小鼠体内，主要是肾脏和大脑。

Prostate cancer is the most common adult male cancer and it is expected that over 40,000 men will die from this disease this year. Our long term objectives re to identify factors associated with the prostate's unique propensity to develop cancer and to understand their subsequent heterogeneity with respect to malignant potential, as it exhibits a broad gradient of cancers from slowly growing to rapidly progressive bony metastasis and death. We have recently identified an antigen that is highly expressed in prostate cells, Prostate Specific Membrane antigen, PSM. We have identified PSM as a unique folate hydrolase. We have discovered that in cancers the mRNA encoding the membrane from predominates, while in normal cells the form encoding the cytosolic form predominates. The implications of this finding are that the prostate may be a tissue at risk for microenvironmental "folate deficiency", and folate deficiency is associated with increased susceptibility to carcinogenesis. In cancer increasingly folate hydrolase activity resides outside the cell, potentially serving as a means to reacquire folate from polygammaglutamated folate being lost by dying cancer cells. As folate deficiency is associated with limited growth potential the ratio expression of these two majors may contribute to the spectrum of growth potential seen with prostate cancer. We propose to further characterize this unique folate hydrolase and its regulation and to define the folate modulation of growth potential of cells expressing different levels of membrane and cytosolic forms of the protein. We also propose to over- express PSM in the mouse prostate to determine how its expression effects the biology of the prostate in situ. We also propose to generate knockouts of murine PSM to ascertain the importance of its expression at other sites which in the mouse is predominantly the kidney and brain.