Mesenchymal Derived Growth Factors in Prostatic Cancer

描述(申请人提供)：前列腺癌是一种以反应性间质反应为典型的疾病，很可能是肿瘤的促进剂。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和诱导血管生成。这种反应类似于一般的伤口修复反应。在之前的项目期间，我们已经定义了人类前列腺癌进展中的反应性间质，并开发了新的模型来解决反应性间质生物学的机制。这些研究表明，在前列腺上皮内瘤变(PIN)过程中，反应性间质被诱导，并随着肿瘤的进展而演变。PIN上皮细胞转化生长因子-β1的高表达与邻近反应性间质的诱导相关。为了探讨反应性间质的机制，我们发展了差异反应性间质(DRS)模型。DRS模型允许转基因基因在宿主小鼠的人异种移植瘤的间质和上皮室中表达。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间质。不同的人前列腺间质细胞系产生了不同的肿瘤发生。结缔组织生长因子(CTGF)在基质细胞中的差异表达与肿瘤的发生有关。CTGF是转化生长因子-β1在基质中作用的下游介导物，也是血管生成的刺激因子。抑制DRS肿瘤中转化生长因子-β1的作用可抑制血管生成和肿瘤生长。此外，成纤维细胞生长因子-2的作用调节反应间质，特别是在转化生长因子-β1微环境中。我们的假设是，转化生长因子-β31诱导的反应性间质是早期前列腺癌血管生成的关键调节因子，CTGF和成纤维细胞生长因子-2是反应性间质中TFG-β1旁分泌作用的关键共同调节因子。我们提出了三个具体目标来详细解决这一假设：1)目的：1.验证上皮细胞表达的转化生长因子-β1的旁分泌作用是前列腺反应性间质形成的关键诱因，以及转化生长因子-β1诱导的反应性间质驱动血管生成和肿瘤进展的假说。验证在反应性间质诱导的血管生成和肿瘤进展中，成纤维细胞生长因子-2与转化生长因子-β1起协同调节作用的假说；验证CTGF在反应性间质中作为转化生长因子-β1和成纤维细胞生长因子-2作用的关键下游介体的假说。这些研究将使用新的转基因和DRS模型方法剖析这些生长因子在前列腺癌的反应性间质调节中的旁分泌和自分泌作用。拟议的研究将扩大我们对相互依赖的上皮-间质信号在前列腺癌中的作用的理解，并可能导致针对反应间质部分的特定机制的新的治疗方法。

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.