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: 6733062
• 负责人: DAVID R ROWLEY
• 金额: $ 27.09万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733062
• 关键词: angiogenesis; athymic mouse; biological signal transduction; cell adhesion; cell cell interaction; cell growth regulation; cell proliferation; connective tissue growth factor; connective tissue stroma; enzyme activity; epithelium; fibroblast growth factor; genetically modified animals; hormone related neoplasm /cancer; human tissue; immunocytochemistry; mesenchyme; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic process; northern blottings; paracrine; prostate neoplasms; protease inhibitor; protein localization; stromal cells; transfection; transforming growth factors; tumor suppressor genes; western blottings

DESCRIPTION (provided by applicant): Prostate cancer is a disease typified by a reactive stroma response, which is likely tumor promoting. The reactive stroma is composed of myofibroblasts and fibroblasts, activated to remodel extracellular matrix and induce angiogenesis. This response is similar to generic wound repair responses. In the previous project period, we have defined reactive stroma in human prostate cancer progression and have developed new models to address mechanisms of reactive stroma biology. These studies have shown the induction of reactive stroma during prostatic intraepithelial neoplasia (PIN) and evolution with cancer progression. Elevated expression of TGF-beta1 by PIN epithelium was correlated with induction of adjacent reactive stroma. To address reactive stroma mechanisms, we developed the differential reactive stroma (DRS) model. The DRS model permits transgene gene expression in both the stromal and epithelial compartments of a human xenograft tumor in host mice. Our recent studies show that tumor incidence, angiogenesis, and tumor growth are dependent on reactive stroma. Different human prostate stromal cell lines produced differential tumorigenesis. Differential expression of connective tissue growth factor (CTGF) in stromal cells was associated with tumorigenesis. CTGF is a downstream mediator of TGF-beta1 action in stroma and a stimulator of angiogenesis. Inhibition of TGF-beta1 action in DRS tumors inhibited angiogenesis and tumor growth. Furthermore, FGF-2 action regulates reactive stroma, particularly in a TGF-beta1 microenvironment. It is our hypothesis that TGF-beta31 induced reactive stroma is a critical regulator of angiogenesis in early prostate cancer, and that both CTGF and FGF-2 are key co-regulatory factors of TFG-beta1 paracrine actions in reactive stroma. We propose three Specific Aims to address this hypothesis in detail: 1.) To test the hypothesis that the paracrine action of epithelial expressed TGF-beta1 is a key inducer of prostate reactive stroma and that TGF-beta1 induced reactive stroma drives angiogenesis and tumor progression; 2.) To test the hypothesis that FGF-2 functions as a co-regulator with TGF-beta1 in reactive stroma induced angiogenesis and tumor progression; 3.) To test the hypothesis that CTGF functions as a key downstream mediator of TGF-beta1 and FGF-2 action in reactive stroma. These studies will dissect the paracrine and autocrine actions of these growth factors in reactive stroma regulation of prostate cancer using novel transgenic and DRS model approaches. The proposed studies will expand our understanding of the role of interdependent epithelial-stromal signaling in prostate cancer and may lead to new therapeutic approaches targeted to specific mechanisms in the reactive stroma compartment.

描述（由申请人提供）：前列腺癌是一种以反应性基质反应为典型特征的疾病，可能具有肿瘤促进作用。反应性基质由肌成纤维细胞和成纤维细胞组成，被激活以重塑细胞外基质并诱导血管生成。这种反应类似于一般的伤口修复反应。在上一个项目期间，我们已经定义了人类前列腺癌进展中的反应性基质，并开发了新的模型来解决反应性基质生物学机制。这些研究表明，在前列腺上皮内瘤变（PIN）和癌症进展的演变过程中，反应性基质的诱导。PIN上皮细胞TGF-β 1的高表达与邻近反应性间质的诱导相关。为了解决反应性基质机制，我们开发了差异反应性基质（DRS）模型。DRS模型允许转基因基因在宿主小鼠的人异种移植肿瘤的基质和上皮区室中表达。我们最近的研究表明，肿瘤的发病率，血管生成和肿瘤生长依赖于反应性基质。不同的人前列腺基质细胞系产生不同的肿瘤发生。结缔组织生长因子（CTGF）在间质细胞中的差异表达与肿瘤发生有关。CTGF是间质中TGF-β 1作用的下游介质和血管生成的刺激物。在DRS肿瘤中抑制TGF-β 1的作用可抑制血管生成和肿瘤生长。此外，FGF-2作用调节反应性基质，特别是在TGF-β 1微环境中。我们假设TGF-β 31诱导的反应性基质是早期前列腺癌血管生成的关键调节因子，CTGF和FGF-2是反应性基质中TGF-β 1旁分泌作用的关键共调节因子。我们提出了三个具体目标来详细解决这个假设：1）。为了检验上皮表达的TGF-β 1的旁分泌作用是前列腺反应性基质的关键诱导物并且TGF-β 1诱导的反应性基质驱动血管生成和肿瘤进展的假设; 2.）为了检验FGF-2在反应性基质诱导的血管生成和肿瘤进展中作为TGF-β 1的共调节剂起作用的假设; 3.）为了检验CTGF在反应性基质中作为TGF-β 1和FGF-2作用的关键下游介质的假设。这些研究将使用新的转基因和DRS模型方法来剖析这些生长因子在前列腺癌反应性基质调节中的旁分泌和自分泌作用。拟议的研究将扩大我们的相互依存的上皮基质信号在前列腺癌中的作用的理解，并可能导致新的治疗方法，针对特定的机制，在反应性间质室。