MESENCHYMAL DERIVED GROWTH FACTORS IN PROSTATIC CANCER

描述：（改编自研究者摘要）前列腺 发育依赖于基质-上皮相互作用。 基质细胞 诱导和指导上皮细胞增殖，导致导管分支， 分化为成熟的分泌腺泡。 机制不明。 基质-上皮相互作用也参与前列腺增生的机制。 癌症进展 基质因子参与上皮细胞的生长， 分化调控影响肿瘤局部增殖和侵袭 细胞 上一个项目集中在胎儿尿生殖窦 （前列腺原基）间充质衍生因子，UGIF（ps20）， 抑制前列腺上皮细胞，诱导分泌型 蛋白质，并改变表型形态。 在上一个项目期间， 纯化ps20蛋白，其生物学活性 表征，制备抗体探针，全长大鼠和人cDNA 克隆的、表达的重组蛋白和稳定的转染细胞系 生成的. 序列分析表明，ps20是一个新的成员， “WAP型四硫键核心结构域”家族共有一个共同的8位半胱氨酸 母题 WAP蛋白家族成员作为蛋白酶抑制剂起作用， 参与发育组织重塑，蛋白酶诱导生长因子 生物利用度、基质重塑和细胞分化。 减少 表达与癌症进展相关。 免疫定位 ps20对大鼠和人正常和患病平滑肌具有特异性 组织中 ps20在人卵巢癌间质中的表达不均匀 前列腺癌 假设ps20作为蛋白酶起作用， 抑制剂和细胞增殖和侵袭负调节剂。 到 继续定义ps20作用的机制，三个具体目标是 提出了 这些措施包括：1.）以确定特定的蛋白酶抑制剂 活性和关键相互作用蛋白; 2.）评估ps20诱导的 细胞增殖、粘附和基质侵袭的改变; 3.）到 评估人前列腺中ps20表达和定位的改变 癌症进展，和; 4.）ps20抑瘤作用的实验研究 异种移植人肿瘤模型和ps20转基因小鼠前列腺癌 模型 这项建议的目的是前一项建议的自然延伸。 发展阶段，旨在回答具体的基本问题 关于PS20的作用机制 这些研究将建立一个基础， 这是长期研究的基础，具体定义了PS20在 前列腺发育，前列腺癌进展，间质上皮 相互作用和平滑肌生物学。

DESCRIPTION: (adapted from the investigator's abstract) Prostate gland development is dependent on stromal-epithelial interactions. Stromal cells induce and direct epithelial proliferation leading to ductal branching and differentiation to mature secretory acini. Mechanisms are unknown. Stromal-epithelial interactions are also involved in mechanisms of prostate cancer progression. Stromal factors involved in epithelial growth and differentiation control affect local proliferation and invasion of carcinoma cells. The previous project period has focused on a fetal urogenital sinus (prostate anlagen) mesenchyme-derived factor, UGIF(ps20), which is growth inhibitory to prostatic epithelial cells, induces synthesis of secretory proteins, and alters phenotypic morphology. In the last project period, the ps20 protein was purified to homogeneity, its biological activity characterized, antibody probes made, the full length rat and human cDNA cloned, recombinant proteins expressed, and stable transfectant cell lines generated. Sequence analysis indicates that ps20 is a novel member of the "WAP-type four-disulfide core domain" family which share a common 8 cysteine motif. WAP protein family members function as protease inhibitors and are involved in developmental tissue remodeling, protease-induced growth factor bioavail-ability, matrix remodeling, and cell differentiation. Reduced expression is associated with cancer progression. Immuno-localization of ps20 is specific to smooth muscle in rat and human normal and diseased tissues. Heterogeneous loss of ps20 was observed in the stroma of human prostate cancer. It is hypothesized that ps20 functions as a protease inhibitor and a negative regulator of cell proliferation and invasion. To proceed in defining the mechanisms of ps20 action three Specific Aims are proposed. These include: 1.) to define the specific protease inhibitory activity and key interacting proteins; 2.) To assess ps20-induced alterations in cell proliferation, adhesion and matrix invasion; 3.) To assess alterations in ps20 expression and localization in human prostate cancer progression, and; 4.) To test ps20 as a tumor-suppressor with mouse xenograft human-tumor models and a ps20 transgenic mouse-prostate cancer model. The Aims of this proposal are a natural extension of the previous progress period and are designed to answer specific fundamental questions about ps20 mechanisms of action. These studies will build a foundation from which to base long range studies, to specifically define the role of ps20 in prostate development, prostatic cancer progression, stromal-epithelial interactions and smooth muscle biology.