VEGF, FAK and RAP

背景和意义：前列腺癌（CaP）有很强的骨转移倾向， 很少涉及的网站。这一观察结果支持了佩吉特的“种子（癌细胞）和土壤（转移器官）” 假定在特定器官中发生临床转移的假设取决于：1） 癌细胞的特征; 2）宿主器官微环境和3）癌细胞之间的相互作用 和宿主的微环境。最近的证据表明，血管生成是一个重要的因素， CaP骨转移的发展和成骨细胞性质。此外，血管生成的程度与 CaP中的雄激素非依赖性和神经内分泌（NE）分化。由于血管内皮细胞的表达 生长因子（VEGF）是一种强有力的血管生成肽，与人CaP的转移能力相关，我们 假设肿瘤相关的VEGF表达和该过程的调节剂对于骨转移是重要的 发展支持这一观点，我们的初步数据表明：1）VEGF表达是CaP所必需的， 在体内生长并以器官特异性方式改变这种生长; 2）在靶器官中CaP细胞停滞后，肿瘤 VEGF表达在骨中优先被诱导; 3）小GTap参与介导VEGF和前列腺增生。 特异性抗原（PSA）表达可能在雄激素非依赖性CaP中起作用; 4）粘着斑激酶 (FAK)参与介导CaP中VEGF表达和早期骨定植。这些观察使我们 阐明指导假设VEGF及其调节因子FAK和Rap在CaP进展中发挥关键作用， 影响血管生成、雄激素依赖和神经内分泌分化。我们将通过以下方式检验这一假设： 研究的具体目标如下：目标1。了解肿瘤VEGF在CaP骨转移中的作用;目的2. 评估FAK在前列腺癌发生、发展中的作用及其与VEGF在这些过程中的关系;目的 3.确定Rap是否有助于CaP骨转移和雄激素非依赖性及其与VEGF的关系， 这些过程。计划互动将与1）项目2（S。Parsons），以评估VEGF在 NE-细胞促进生长和骨转移; 2）项目3（Weber），因为Rap影响两种肿瘤 血管生成和雄激素依赖性; 3）用于异种移植免疫组织化学评价的组织分析核心 和转基因CaP原发性肿瘤和骨转移，激光显微切割和骨形态测量，以确定 VEGF对成骨细胞表型的贡献; 4）细胞培养和动物核心将提供前列腺细胞系 和整个动物异种移植物成像; 5）在管理局的生物统计学支持下设计体内实验 核心结论：这些目标的实现将为前列腺的机制提供相关信息 癌症进展和转移，并可能导致干扰患者这一过程的治疗。

Background and Significance: Prostate cancer (CaP) has a strong predilection for bone metastasis with other distant sites being only rarely involved. This observation supports Paget's "seed (cancer cell) and soil (organ of metastasis)" hypothesis which postulates that development of clinical metastases in a specific organ depends on 1) the characteristics of the cancer cells; 2) the host organ microenvironment and 3) the interactions between the cancer cell and the host microenvironment. Recent evidence demonstrates that angiogenesis is an important factor in the development and osteoblastic nature of CaP bone metastasis. Moreover, the degree of angiogenesis correlates with both androgen independence and neuroendocrine (NE) differentiation in CaP. Since expression of vascular endothelial growth factor (VEGF), a powerful angiogenic peptide, is correlated with the metastatic ability of human CaP, we hypothesized that tumor related VEGF expression, and regulators of this process, are important for bone metastasis development. Supporting this notion, our Preliminary Data indicate that: 1) VEGF expression is necessary for CaP growth in vivo and alters this growth in an organ specific fashion; 2) Following CaP cell arrest in target organs, tumor VEGF expression is induced preferentially in bone; 3) Small GTPase Rap is involved in mediating VEGF and Prostate Specific Antigen (PSA) expression potentially playing a role in androgen independent CaP; 4) Focal Adhesion Kinase (FAK) is involved in mediating both VEGF expression and early bone colonization in CaP. These observations lead us to formulate the Guiding Hypothesis VEGF and its regulators FAK and Rap, play critical roles in CaP progression by affecting angiogenesis, androgen dependence and neuroendocrine differentiation. We will test this hypothesis by studies with the following Specific Aims: Aim 1. Understand the role of tumor VEGF in CaP bone metastasis; Aim 2. Evaluate the role of FAK in prostate carcinogenesis, progression and its relationship to VEGF in these processes; Aim 3. Establish if Rap contributes to CaP bone metastasis and androgen independence and its relationship to VEGF in these processes. Program Interactions will be with 1) Project 2 (S. Parsons) to evaluate the role of VEGF in the enhancement of growth and bone metastasis by NE-cells; 2) Project 3 (Weber), since Rap affects both tumor angiogenesis and androgen dependence; 3) Tissue Analysis Core for the immunohistochemical evaluation of xenograft and transgenic CaP primary tumors and bone metastases, laser microdissection and bone morphometry to determine the contribution of VEGF to the osteoblastic phenotype; 4) Cell Culture and Animal Core will provide prostate cell lines and whole animal xenograft imaging; 5) in vivo experiments are designed with biostatistics support of the Administrative Core. Conclusions: Completion of these aims will provide relevant information on the mechanisms underlying prostate cancer progression and metastasis and may lead to therapies that interfere with this process in patients.