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)和 降低了癌症和糖尿病的发病率。GHR纯合子零突变的小鼠也受到保护 C3(1)/Tag前列腺癌模型中的肿瘤。同样，缺乏功能性生长激素基因的大鼠也受到保护 前列腺癌在前盆/TAG模型中。生长激素受体在多种组织中表达，包括肝脏和 前列腺。生长激素激活肝脏中的生长激素受体是刺激胰岛素样生长因子-1释放到 发行量。许多GH作用是由IGF-1在靶组织中随后的作用所介导的，包括 前列腺。此外，来自人类的证据表明，循环中的IGF-1升高会增加风险 导致包括前列腺癌在内的多种癌症的发生。生长激素受体在正常前列腺组织中的表达 前列腺癌细胞的研究表明，GHR的局部信号也可能在前列腺癌中起重要作用。 细胞。最近的研究表明，前列腺癌细胞对局部生长激素合成的上调是一种 癌症进展的共同特征进一步支持了局部GH/GHR作用在 前列腺癌。然而，GH/IGF-1轴在前列腺癌中作用的几个重要方面仍然存在。 不确定。现有的研究还没有解决在不同的地方对生长激素信号的潜在持续需求 前列腺癌进展的阶段，局部GHR信号在前列腺癌细胞中的作用，或信号 GHR激活下游的转导机制在前列腺癌中很重要。该项目将使用 在小鼠身上采用创新的遗传方法来解决当前知识的这些局限性。以往的啮齿动物研究 也是有限的，因为他们只关注由TP53和RB1功能中断驱动的肿瘤 肿瘤抑制因子。该项目将进一步确定对完整的GHR信令的要求是否扩展到 PI3K/AKT通路激活也是常见的前列腺癌小鼠模型 在人类前列腺癌中。这些研究的完成将是确定最佳方案的重要一步 使用聚乙二醇胺或其他靶向生长激素/胰岛素样生长因子-1轴的药物治疗和/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.