Mesenchymal Derived Growth Factors in Prostatic Cancer

描述（由申请人提供）：前列腺癌是一种以反应性基质反应为代表的疾病，其可能促进肿瘤。反应性基质由肌成纤维细胞和成纤维细胞组成，被激活可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，我们定义了人类前列腺癌进展中的反应性基质，并开发了新模型来解决反应性基质生物学机制。这些研究表明，前列腺上皮内瘤变 (PIN) 过程中会诱导反应性基质，并随着癌症进展而演变。 PIN 上皮的 TGF-β1 表达升高与邻近反应性基质的诱导相关。为了解决反应性基质机制，我们开发了微分反应性基质（DRS）模型。 DRS 模型允许转基因基因在宿主小鼠的人类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，肿瘤发生、血管生成和肿瘤生长依赖于反应性基质。不同的人类前列腺基质细胞系产生不同的肿瘤发生。基质细胞中结缔组织生长因子（CTGF）的差异表达与肿瘤发生相关。 CTGF 是基质中 TGF-β1 作用的下游介质和血管生成的刺激剂。抑制 DRS 肿瘤中 TGF-β1 的作用可抑制血管生成和肿瘤生长。此外，FGF-2 作用可调节反应性基质，特别是在 TGF-β1 微环境中。我们假设 TGF-β31 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，并且 CTGF 和 FGF-2 是反应性基质中 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.) 检验上皮表达的 TGF-β1 的旁分泌作用是前列腺反应性基质的关键诱导物以及 TGF-β1 诱导的反应性基质驱动血管生成和肿瘤进展的假设； 2.) 检验 FGF-2 在反应性基质诱导的血管生成和肿瘤进展中与 TGF-β1 共同调节的假设； 3.) 检验 CTGF 作为反应性基质中 TGF-β1 和 FGF-2 作用的关键下游介质的假设。这些研究将使用新型转基因和 DRS 模型方法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对前列腺癌中相互依赖的上皮基质信号传导作用的理解，并可能导致针对反应性基质隔室中特定机制的新治疗方法。

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.