Growth hormone actions in prostate carcinogenesis

摘要 生长激素/胰岛素样生长因子-1（GH/IGF-1）轴与年龄相关疾病有关 包括前列腺癌患有Laron综合征的人缺乏功能性生长激素受体（GHR）， 降低了癌症和糖尿病的发病率。具有Ghr纯合无效突变的小鼠也受到保护， C3（1）/TAg前列腺癌模型中的癌症。同样，缺乏功能性生长激素基因的大鼠 前列腺癌在Probasin/TAg模型中。GHR在多种组织中表达，包括肝脏和 前列腺GH激活肝脏中的GHR是刺激IGF-1释放到肝脏中的主要机制。 流通许多GH作用是由IGF-1在靶组织中的后续作用介导的，包括 前列腺此外，来自人类的证据表明，循环IGF-1升高会增加 包括前列腺癌在内的几种癌症的发展。生长激素受体在正常前列腺组织中的表达 这表明GHR的局部信号传导在前列腺癌中也很重要 细胞最近的研究表明，前列腺癌细胞局部生长激素合成的上调是前列腺癌的一个重要因素。 癌症进展的共同特征进一步支持了局部GH/GHR作用的潜在重要性， 前列腺癌然而，GH/IGF-1轴在前列腺癌中的作用的几个重要方面仍然存在 不确定现有的研究尚未解决在不同的生长激素水平下对GH信号传导的潜在持续需求。 前列腺癌进展的阶段，前列腺癌细胞中局部GHR信号传导的作用，或前列腺癌细胞中局部GHR信号传导的作用。 GHR激活下游的转导机制在前列腺癌中很重要。This project will use 创新的遗传方法在小鼠中，以解决目前知识的这些局限性。既往啮齿动物研究 也是有限的，因为他们只关注由TP 53和RB 1功能破坏驱动的肿瘤。 肿瘤抑制剂。该项目将进一步确定完整GHR信号的要求是否扩展到 前列腺癌的小鼠模型由PI 3 K/AKT通路的激活驱动， 在人类前列腺癌中。完成这些研究将是确定最佳方案的重要一步。 使用靶向GH/IGF-1轴的pegvisomant或其他药剂治疗和/或预防 前列腺癌

Abstract The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis has been implicated in age related diseases including prostate cancer. Humans with Laron syndrome lack functional growth hormone receptors (GHRs) and have reduced rates of cancer and diabetes. Mice with homozygous null mutations in Ghr are also protected from cancer in the C3(1)/TAg prostate cancer model. Similarly, rats lacking a functional GH gene are protected prostate cancers in the Probasin/TAg model. GHRs are expressed in multiple tissues including the liver and prostate. Activation of GHRs in the liver by GH is the main mechanism that stimulates the release of IGF-1 into circulation. Many GH actions are mediated by the subsequent actions of IGF-1 in target tissues including the prostate. Furthermore, evidence from humans indicates that elevated circulating IGF-1 confers an increased risk for the development of several cancers including prostate cancer. The expression of GHRs in the normal prostate and by prostate cancer cells suggests that local signaling by GHRs may also be important in prostate cancer cells. Recent studies demonstrating that up-regulation of local GH synthesis by prostate cancer cells is a common feature of cancer progression further supports the potential importance of local GH/GHR actions in prostate cancer. However, several important aspects of the role of GH/IGF-1 axis in prostate cancer remain uncertain. Available studies have not addressed the potential ongoing requirement for GH signaling at different stages of prostate cancer progression, the role of local GHR signaling in prostate cancer cells, or the signal transduction mechanisms downstream of GHR activation important in prostate cancer. This project will use innovative genetic approaches in mice to address these limitations of current knowledge. Previous rodent studies were also limited because they focused only on tumors driven by disruption the function of the TP53 and RB1 tumor suppressors. This project will further determine if the requirement for intact GHR signaling extends to mouse models for prostate cancers driven by activation of the PI3K/AKT pathway that is also commonly observed in human prostate cancers. Completion of these studies will be an important step toward identifying the best ways to employ pegvisomant or other agents targeting the GH/IGF-1 axis for the treatment and/or prevention of prostate cancer.