Mechanistic Evaluation of the Androgen Receptor Inhibition Driven Hypoxic Prostate Microenvironment

研究背景：该研究将侧重于了解在各种疾病或治疗条件下前列腺内发现的低氧浓度下雄激素受体的作用。雄激素受体是在正常生理条件下与睾酮结合以调节雄性表型的发育和维持的关键蛋白质。在不同的前列腺疾病，包括癌症，或治疗条件，如放射或雄激素剥夺治疗，在氧合的结果和改变前列腺细胞和周围的生物反应和前列腺内的支持细胞。我们的研究小组和其他人已经证明，雄激素受体信号调节前列腺的微环境，从而抑制，阉割或治疗性地导致血管内皮细胞死亡导致快速血管萎缩和微血管密度降低。这部分是由于前列腺细胞内信号分子的诱导，这些信号分子在氧合变化后被激活，以增加细胞增殖、存活、血管生成、代谢和侵袭。重要的是，前列腺细胞的遗传背景显著有助于对雄激素受体抑制剂的反应。我们的实验室专注于PTEN，其缺陷已被证明是侵袭性前列腺癌的主要分子标志。我们的研究已经表明，具有PTEN缺失的前列腺癌细胞具有增加的血管生成促进因子的丰度，其有助于降低目前使用的前列腺癌治疗（包括放射疗法和雄激素受体抑制剂）的功效。这种PTEN缺失和血管生成促进因子增加的背景是本研究的重点，并可能定义对雄激素信号传导抑制剂的抗性机制，我们需要进一步了解PTEN缺失的肿瘤灶和周围微环境对发展和治疗抗性的贡献和作用的机制。拟议的工作机构将表征PTEN的影响-在单独的雄激素受体抑制和与血管生成促进因子的失活联合后，因素从机制上讲，该研究将调查各种血管生成促进因子及其在前列腺内的冗余度，以及对微环境和治疗反应的双重抑制的重要性。应用与效益：作为该项目的一部分，学生将开发几种新的PTEN缺陷前列腺细胞模型，这将是研究社区的资源，并重要地模拟相关生物学和前列腺的微环境。这项研究将深入了解血管生成促进因子之间存在的冗余机制，从而深入了解正常发育，伤口愈合，炎症和癌症生物学。

Research context: The studentship will focus on understanding the role of the androgen receptor under concentrations of low oxygen that can be found within the prostate during various disease or treatment conditions. The androgen receptor is a key protein that under normal physiological conditions bind to testosterone to regulate the development and maintenance of the male phenotype. During different prostate diseases, including cancer, or treatment conditions such as radiation or androgen-deprivation therapy, a resulting change in oxygenation results and changes the biological response of the prostate cells and surrounding and supporting cells within the prostate.Research from our group and others have demonstrated that the androgen receptor signalling regulates the microenvironment of the prostate gland, whereby inhibition, either castration or therapeutically, results in rapid vascular atrophy and reduced microvessel density as a result of vascular endothelial cell death. This result, in part, from induction of signalling molecules within the prostate cells that are activated follow a change in oxygenation to increase cell proliferation, survival, angiogenesis, metabolism and invasion. Importantly, the genetic background of the prostate cells significantly contributes to the response to inhibitors of androgen receptor. Our lab focuses on PTEN, where its deficiency has been shown to be a major molecular hallmark for aggressive prostate cancer. Our research has shown that prostate cancer cells with PTEN-loss have increased abundance of angiogenic promoting factors that contribute to reduced efficacy of currently used treatments pf prostate cancer including radiotherapy and androgen receptor inhibitors. This context of PTEN-loss and increased angiogenic promoting factors is a focus of this study and may define a mechanism of resistance to androgen-signaling inhibitors, where we need further mechanistic understanding of contribution and role of PTEN-depleted tumour foci and the surrounding microenvironment on development and treatment resistance.Aims and objectives: The proposed body of work will characterize the influence of PTEN-loss on the remodelling of the prostate microenvironment and alterations in the immune cell component following androgen receptor inhibition alone and in combination with inactivation of angiogenesis promoting factors. Mechanistically the study will investigate various angiogenesis promoting factors and their redundancy within the prostate and importance of dual inhibition on the microenvironment and therapeutic response. Application and benefit: As part of this project, the student will develop several novel models of PTEN-deficient prostate cells that will be a resource to the research community and importantly model relevant biology and the microenvironment of the prostate. The research will provide insight into the mechanisms of redundancy that exist between angiogenesis promoting factors leading to insights into normal development, wound healing, inflammation and cancer biology.