Mechanistic Evaluation of the Androgen Receptor Inhibition Driven Hypoxic Prostate Microenvironment

研究背景：该学生将专注于了解在各种疾病或治疗条件下前列腺内低氧浓度下雄激素受体的作用。雄激素受体是正常生理条件下与睾酮结合调节雄性表型发育和维持的关键蛋白。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期间，氧合的变化导致并改变了前列腺细胞及其周围和前列腺内支持细胞的生物反应。我们小组和其他人的研究表明，雄激素受体信号调节前列腺的微环境，因此，无论是阉割还是治疗，抑制都会导致血管迅速萎缩和微血管密度降低，这是血管内皮细胞死亡的结果。这一结果部分来自于前列腺细胞内的信号分子的诱导，这些信号分子随着氧合的变化而激活，从而增加细胞增殖、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对雄激素受体抑制剂的反应有重要影响。我们的实验室专注于PTEN，其缺乏已被证明是侵袭性前列腺癌的主要分子标志。我们的研究表明，pten缺失的前列腺癌细胞中血管生成促进因子的丰度增加，导致目前使用的前列腺癌治疗方法（包括放疗和雄激素受体抑制剂）的疗效降低。pten缺失和血管生成促进因子增加的背景是本研究的重点，并可能确定对雄激素信号抑制剂耐药的机制，我们需要进一步了解pten缺失肿瘤病灶和周围微环境在发展和治疗耐药中的作用和作用。目的和目的：拟议的工作主体将描述pten缺失对雄激素受体单独抑制和血管生成促进因子失活后前列腺微环境重塑和免疫细胞成分改变的影响。该研究将从机制上探讨各种血管生成促进因子及其在前列腺内的冗余性，以及双重抑制对微环境和治疗反应的重要性。应用和收益：作为该项目的一部分，学生将开发几个新的pten缺陷前列腺细胞模型，这将是研究界的资源，并重要地模拟相关生物学和前列腺微环境。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.