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

 描述（由申请人提供）：在美国，前列腺癌（PCa）是男性中最常诊断的癌症，每年导致约30，000人死亡。尽管早期检测和基于前列腺素的治疗通常导致快速反应并降低PCa的死亡率，但目前用于晚期PCa或复发性PCa的治疗仍然不能治愈。即使手术切除明显成功的患者也可能在数月或数年后局部或远处复发。此外，在剥夺肿瘤的雄性激素后，PCa变成雄激素非依赖性（AI）或去势抵抗性PCa（CRPC）。不幸的是，对于许多病例，原发性肿瘤的大小或组织学不能提供可靠的预后，因为在大多数癌症被临床诊断时，很少有肿瘤细胞可能已经扩散。因此，很大比例的患者经常进行化疗和治疗，以在大转移发生之前消除残留或播散的细胞，作为预防措施。KISS 1是一种转移抑制因子，其表达水平具有预后相关性，并且与包括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，KISS 1表达使播散的肿瘤细胞保持休眠状态，并强烈抑制定植和大转移的发展。这些特征使KISS 1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者。通过活检诊断为前列腺癌的患者可以根据KISS 1表达水平或KISS 1启动子甲基化状态分为应该治疗的患者和可能只是仔细随访（观察等待）的患者。我们的研究将通过建立KISS 1表观遗传沉默、KISS 1表达和癌症进展之间的相关性，提供一种可重复且低成本检测的诊断标记或预后标记。我们期望将KISS 1表达状态鉴定为区分惰性和侵袭性癌症的新生物标志物，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KISS 1可逆表达的机制。我们的研究将展示KISS 1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KISS 1表达在PCa进展中的调节机制，可以为低KISS 1表达的PCa患者制定有效的治疗策略。根据这些机制防止KISS 1沉默或重新表达KISS 1的方法可以适用于除去除雄性激素外不适合治疗的男性，以及治疗后复发性前列腺癌的男性。通过调节前列腺癌中KISS 1的表达，可以大大提高前列腺癌对雄性激素剥夺的反应，并可以减少前列腺癌的转移扩散。KISS 1在保持肿瘤细胞处于休眠状态沿着预防CRPC复发的双重作用为前列腺癌患者提供了一种新的方法，以接近更易于管理的器官局限性疾病，用于长期PCa管理，这将改善患者的总体生存率。

 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.