Role of growth hormone in prostate cancer: rodent models

生长激素在前列腺癌中的作用：啮齿动物模型

• 批准号: 6479105
• 负责人: STEVEN M SWANSON
• 金额: $ 7.79万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479105
• 关键词: biological signal transduction; carcinogenesis; chemical carcinogen; genetic models; genetic strain; genetic susceptibility; genetically modified animals; genotype; hormone receptor; hormone regulation /control mechanism; insulinlike growth factor; laboratory mouse; laboratory rat; methylnitrosourea; model design /development; neoplasm /cancer genetics; prostate neoplasms; simian virus 40; somatotropin

Although the molecular mechanisms of prostate carcinogenesis are poorly understood, new pathways have recently been identified that affect prostate biology in ways relevant to cancer. An example is the growth hormone/insulin like growth factor-I (GH/IGF) axis that has recently been shown to affect prostate proliferation, differentiation and apoptosis. An obstacle to studying the role of the GH/IGF axis in prostate carcinogenesis is the lack of appropriate animal models in which GH signaling is disrupted in a genetic background of cancer susceptibility. Our objectives are to determine whether disruption of GH signaling renders susceptible rodent strains resistant to prostate carcinogenesis. Our hypothesis is that an active, functional GH/IGF axis is required for the development of prostate cancer. Our first aim is to test the susceptibility of the GH deficient Spontaneous Dwarf rat to N-methyl-N-nitrosourea (MNU) induced prostate carcinogenesis. We plan to adapt the well-established Wistar-Unilever rat model for prostate cancer to the Sprague-Dawley rat. Preliminary data by others strongly suggest that the Sprague-Dawley rat is similar to the Wistar-Unilever rat in its susceptible to MNU induced prostate cancer. Our second aim is to determine whether a functional GH receptor is required for carcinogenesis in mice carrying a simian virus 40 (SV4O) large T antigen (Tag) transgene. We propose to cross the GH receptor deficient Laron mouse with the C3(1)/SV40 Tag transgenic, which spontaneously develops cancers. In both rat and mouse models, we expect GH signaling. Results from these studies could provide a strong rational for developing novel therapeutics targeting the GH/IGF axis for prostate cancer treatment. Furthermore, these new genetically defined animal models could be used to address fundamental questions regarding the role of GH/IGF in prostate growth, differentiation and carcinogenesis.

虽然前列腺癌发生的分子机制知之甚少，但最近已经确定了新的途径，这些途径以与癌症相关的方式影响前列腺生物学。一个例子是生长激素/胰岛素样生长因子-I（GH/IGF）轴，其最近已显示影响前列腺增殖、分化和凋亡。研究GH/IGF轴在前列腺癌发生中的作用的一个障碍是缺乏适当的动物模型，其中GH信号在癌症易感性的遗传背景中被破坏。我们的目标是确定是否GH信号中断，使易感啮齿动物品系抗前列腺癌。我们的假设是，一个积极的，功能性的GH/IGF轴是需要前列腺癌的发展。 我们的第一个目的是测试GH缺乏的自发性侏儒大鼠对N-甲基-N-亚硝基脲（MNU）诱导的前列腺癌发生的敏感性。我们计划将完善的Wistar-Unilever大鼠前列腺癌模型应用于Sprague-Dawley大鼠。其他人的初步数据强烈表明，Sprague-Dawley大鼠与Wistar-Unilever大鼠在对MNU诱导的前列腺癌的易感性方面相似。我们的第二个目的是确定是否需要一个功能性生长激素受体在小鼠携带猿猴病毒40（SV 4 O）大T抗原（Tag）转基因的致癌作用。我们建议将GH受体缺陷的Laron小鼠与C3（1）/SV 40 Tag转基因小鼠杂交，其自发地发展癌症。在大鼠和小鼠模型中，我们预期GH信号传导。这些研究的结果可以为开发靶向GH/IGF轴的前列腺癌治疗新疗法提供强有力的依据。此外，这些新的基因定义的动物模型可用于解决有关GH/IGF在前列腺生长，分化和癌变中的作用的基本问题。

项目成果

Disruption of growth hormone signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse.

• DOI: 10.1210/en.2005-0607
• 发表时间: 2005-12
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Zhuohua Wang;G. Prins;K. Coschigano;J. Kopchick;Jeffrey E. Green;Vera H Ray;S. Hedayat;K. Christov-K.-Chri