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

前列腺癌进展过程中雄激素剥夺和肿瘤微环境对肿瘤转移抑制因子 KISS1 表观遗传沉默的影响

• 批准号: 9072642
• 负责人: Honghe Wang
• 金额: $ 14.7万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072642
• 关键词: Adhesions; Adverse effects; Affect; Amino Acids; Androgens; Apoptosis; Binding; Biochemical; Biological Markers; Biopsy; Bladder; Cancer Patient; Castration; Cell Line; Cell Proliferation; Cells; Cessation of life; Characteristics; Choristoma; Cleaved cell; Clinical; Clinical Research; Decision Making; Development; Diagnosis; Disease; Distant; Early Diagnosis; Epigenetic Process; Epithelium; Excision; Future; Gene Expression; Gene Silencing; Growth; Histology; Hormones; Human; Hypermethylation; Inhibition of Cancer Cell Growth; Intervention; Investigation; KISS1 gene; KISS1R gene; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Metastasis Suppressor Genes; Metastatic Prostate Cancer; Methylation; Molecular Target; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Pathway interactions; Patient observation; Patients; Pattern; Phenotype; Primary Neoplasm; Primary carcinoma of the liver cells; Prognostic Marker; Prostate; Proteins; Puberty; Recurrence; Renal Cell Carcinoma; Residual state; Resistance; Role; Sampling; Site; Staging; Testing; Therapeutic; Thyroid Gland; Time; United States; androgenic; angiogenesis; base; cancer cell; cancer diagnosis; cancer recurrence; cancer therapy; castration resistant prostate cancer; chemotherapy; clinical application; clinically significant; cost; deprivation; diagnostic biomarker; effective therapy; epithelial to mesenchymal transition; expectation; experience; follow-up; improved; male; malignant breast neoplasm; man; melanoma; men; metastasis prevention; mortality; neoplastic cell; novel strategies; outcome forecast; overexpression; prevent; prognostic; promoter; prostate cancer cell; public health relevance; receptor; research study; response; survival outcome; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft

 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.

 描述（由申请人提供）：在美国，前列腺癌 (PCa) 是男性中最常见的癌症，每年导致约 30,000 人死亡，尽管早期检测和基于激素的治疗​​通常会导致快速反应并减少死亡。由于 PCa 的死亡率高，目前针对晚期 PCa 或复发性 PCa 的治疗方法仍然无法治愈，即使已接受明显成功的手术切除的患者也可能在数月或数年后出现局部或远处部位的复发。不幸的是，对于许多病例来说，原发性肿瘤的大小或组织学并不能提供可靠的预后，因为很少有肿瘤细胞可能已经扩散。因此，作为预防措施，大多数癌症在出现大转移之前通常会接受化疗和针对残留或播散细胞的治疗。作为转移抑制因子，其表达水平具有预后相关性，并且与包括 PCa 在内的多种人类癌症的强烈侵袭性呈负相关，更引人注目的是，KISS1 的表达使播散的肿瘤细胞保持在休眠状态，并抑制定植和大转移的发展。在治疗背景下控制前列腺癌转移扩散的非常独特的候选人可以将通过活检诊断为前列腺癌的患者分为应该接受治疗的患者和可能需要仔细随访的患者（注意）。我们的研究将根据 KISS1 表达水平或 KISS1 启动子甲基化状态，通过 KISS1 表观遗传沉默、KISS1 表达和癌症进展之间的相关性，提供可重复且低成本检测的诊断标记或预后标记。确定 KISS1 表达状态作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 KISS1 可逆表达的机制。 KISS1。我们的研究将证明 KISS1 基因沉默是如何发生的，以及在癌症进展过程中调节其表达的可能机制。对 PCa 进展中 KISS1 表达的调节机制的全面研究可以帮助开发针对低 KISS1 表达的 PCa 的有效治疗策略。根据该机制防止 KISS1 沉默或重新表达 KISS1 的方法可适用于除去除雄性激素之外不适合接受治疗的男性，以及治疗后患有复发性前列腺癌的男性。调节前列腺癌中KISS1的表达，可以大大改善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。KISS1在保持肿瘤细胞休眠和预防CRPC复发方面具有双重作用。同时为前列腺癌患者提供了一种新的方法，以实现更易于控制的器官局限性疾病的长期前列腺癌治疗，这将提高患者的总体生存率。