MESENCHYMAL DERIVED GROWTH FACTORS IN PROSTATIC CANCER

前列腺癌中的间充质衍生生长因子

• 批准号: 6150128
• 负责人: DAVID R ROWLEY
• 金额: $ 20.69万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150128
• 关键词: athymic mouse; cell adhesion; cell cell interaction; cell growth regulation; cell line; cell proliferation; enzyme activity; epithelium; gel electrophoresis; gene expression; genetically modified animals; growth factor; hormone related neoplasm /cancer; human tissue; immunocytochemistry; mesenchyme; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; neoplastic process; northern blottings; prostate neoplasms; protease inhibitor; protein localization; stromal cells; tissue /cell culture; transfection; tumor suppressor genes; western blottings; xenotransplantation

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.

描述：(改编自研究者的摘要)前列腺体 发育依赖于基质-上皮的相互作用。基质细胞 诱导和引导上皮细胞增殖，导致导管分支和 分化为成熟的分泌型腺泡。机制尚不清楚。 间质-上皮的相互作用也参与了前列腺的发生机制。 癌症进展。基质因子参与上皮细胞生长和生长 分化控制影响肿瘤的局部增殖和侵袭 细胞。之前的项目期关注的是胎儿的泌尿生殖窦。 (前列腺癌)间充质衍生因子，UGIF(Ps20)，即生长 抑制前列腺上皮细胞，诱导分泌合成 蛋白质，并改变表型形态。在上一个项目期间， Ps20蛋白纯化至均一，其生物学活性 鉴定、制备抗体探针，制备大鼠和人全长cDNA 克隆、表达和稳定表达重组蛋白的细胞系 已生成。序列分析表明，ps20是该基因的新成员。 “WAP型四个二硫键核心区”家族共享一个共同的8-半胱氨酸 Motif。WAP蛋白家族成员作为蛋白酶抑制剂发挥作用，是 参与发育组织重塑，蛋白酶诱导的生长因子 生物利用度、基质重塑和细胞分化。减少 表达与癌症进展有关。肿瘤的免疫定位 Ps20是大鼠和人类正常和疾病组织中特异的平滑肌 纸巾。在人的间质中观察到了PS20的异质性丢失。 前列腺癌。据推测，ps20作为一种蛋白酶发挥作用。 抑制物和细胞增殖和侵袭的负调节因子。至 继续定义ps20行动的机制有三个具体目标 建议。其中包括：1.)为了确定特定的蛋白酶抑制 活性和关键相互作用蛋白；评估Ps20诱导的 细胞增殖、黏附和基质侵袭的改变；至 评估PS20在人前列腺中的表达和定位的变化 癌症进展，以及；4.)用小鼠检测Ps20作为肿瘤抑制因子 人-肿瘤异种移植模型和ps20转基因小鼠前列腺癌 模特。这项提案的目的是先前提案的自然延伸 进展阶段，旨在回答特定的基本问题 关于PS20的作用机制。这些研究将从以下方面奠定基础 其中建立了长期研究的基础，以具体定义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。