Influence of Androgen Deprivation and Tumor Microenvironment on Epigenetic Silencing of Tumor Metastasis Suppressor KISS1 during Prostate Cancer Progression

 描述(申请人提供)：在美国，前列腺癌(PCA)是最常见的男性癌症，每年导致约30,000人死亡。虽然早期发现和基于激素的治疗通常会导致PCa的快速反应并降低死亡率，但目前对晚期PCa或复发的PCa的治疗仍然不能治愈。即使接受了表面上成功的手术切除的患者，也可能在几个月或几年后在局部或远处复发。此外，在剥夺了肿瘤中的男性激素后，前列腺癌成为雄激素非依赖性(AI)，或抗去势的前列腺癌(CRPC)。不幸的是，对于许多病例，原发肿瘤的大小或组织学不能提供可靠的预后，因为当大多数癌症被临床诊断时，可能很少有肿瘤细胞已经扩散。因此，作为一种预防措施，很大比例的患者在发生大转移之前，通常会通过化疗和治疗来消除残留或播散的细胞。Kiss1是一种转移抑制因子，其表达水平与预后相关，并与包括PCa在内的几种人类癌症的侵袭性呈负相关。更引人注目的是，KISS1的表达维持了播散性肿瘤细胞的休眠状态，并强烈地抑制了侵袭和宏观转移的发展。这些特点使KISS1成为在治疗背景下控制前列腺癌转移扩散的非常独特的候选药物。根据KISS1基因表达水平或KISS1启动子甲基化状态，经活检确诊为前列腺癌的患者可分为需要治疗的患者和可能密切关注(观察等待)的患者。我们的研究将通过建立KISS1表观遗传沉默、KISS1表达与肿瘤进展之间的相关性，提供一个重复性好、检测成本低的诊断标记或预后标记。我们期望将KISS1的表达状态确定为区分惰性癌症和侵袭性癌症的新的生物标志物，以避免不必要的化疗相关的严重副作用。本研究的另一个目的是揭示调节KISS1可逆表达的机制。我们的研究将展示KISS1基因沉默是如何发展的，以及在癌症进展过程中调节其表达的可能机制是什么。全面研究KISS1在PCa进展中的表达调控机制，可以为低表达KISS1的PCa患者提供有效的治疗策略。根据这种机制，防止KISS1沉默或重新表达KISS1的方法可能适用于除了去除男性激素之外没有资格接受治疗的男性，以及治疗后前列腺癌复发的男性。通过调节KISS1在前列腺癌中的表达，可以大大提高前列腺癌对男性激素剥夺的反应，减少前列腺癌的转移扩散。KISS1在保持肿瘤细胞休眠和防止CRPC复发方面的双重作用，为前列腺癌患者提供了一条新的途径，使其能够处理更容易处理的器官受限疾病，进行长期的PCa治疗，从而提高患者的整体生存。

 DESCRIPTION (provided by applicant): In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males and it results in approximately 30,000 deaths per year. Although early detection and hormone-based therapies generally result in rapid responses and reduce mortality from PCa, current therapies for advanced PCa or recurrent PCa are still not curative. Even patients who have undergone apparently successful surgical resection may experience recurrence locally or at distant sites months or years later. Moreover, subsequent to depriving the tumor of male hormones, the PCa becomes androgen-independent (AI), or castration-resistant PCa (CRPC). Unfortunately for many cases, the size or the histology of the primary tumor does not provide reliable prognosis since few tumor cells may have already disseminated by the time most cancers are clinically diagnosed. Thus, a large percentage of patients often go through chemotherapies and treatments to eliminate residual or disseminated cells before macro-metastases develop just as a precaution. KISS1, a metastasis suppressor, its expression levels have prognostic relevance and are negatively correlated to invasiveness in several human cancers, including PCa. More strikingly, KISS1 expression maintains disseminated tumor cells in a dormant state and strongly inhibits colonization and macro-metastases development. These characteristics make KISS1 a very unique candidate in controlling the metastatic spread of prostate cancer in a therapeutic context. Patients diagnosed with prostate cancer by biopsy can be separated into those who should be treated from those who might just be followed carefully (watchful waiting) according to KISS1 expression level or KISS1 promoter methylation status. Our study will provide a reproducible and low cost-to-detect diagnostic marker or prognostic marker through establishing the correlation among KISS1 epigenetic silencing, KISS1 expression and cancer progression. It is our expectation to identify KISS1 expression status as a new biomarker that distinguishes indolence and aggressive cancers to avoid unnecessary chemotherapy associated severe side effects. The other objective of this study is to reveal the mechanisms that modulate the reversible expression of KISS1. Our studies will demonstrate how KISS1 gene silencing develops and what are possible mechanisms regulating its expression during cancer progression. The comprehensive investigation of the regulatory mechanism of KISS1 expression in PCa progression can lead to the development of effective treatment strategies for low KISS1 expressing PCa patients. The approach to prevent KISS1 silencing or re-express KISS1 according to the mechanisms could apply to males who are not eligible for therapy other than by removal of male hormones, and who have recurrent prostate cancers after therapies. With the modulation of KISS1 expression in prostate cancers, the response of prostate cancer to male hormone deprivation could be greatly improved and the metastatic spread of prostate cancer can be reduced. The dual roles of KISS1 in keeping tumor cells in dormancy along with preventing CRPC recurrence at the same time provide a new way for prostate cancer patients to approach more manageable organ-confined diseases for long term PCa management, which will improve overall patient's survival.