Exosomes Promote Disease Aggressiveness in African American Prostate Cancer

外泌体促进非裔美国人前列腺癌的疾病侵袭性

• 批准号: 9272480
• 负责人: Gagan Deep
• 金额: $ 15.03万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272480
• 关键词: Exosomes; Promote; Disease; Aggressiveness; African

 DESCRIPTION (provided by applicant): Prostate cancer (PCA) exhibits the most striking racial disparity as African American men are at higher risk of being diagnosed and dying of PCA, in comparison with Caucasian men. Although, multiple factors including socio-economic status contribute to this disparity but it is essential to identify the molecular and underlying biological differences that contribute to the more aggressive phenotype in African American PCA. There have been several studies investigating the genetic and epigenetic differences between African American and Caucasian PCA; however in the past, limited attention has been given to the role of tumor microenvironment contributing towards disease aggressiveness in African American PCA. In this regard, our preliminary studies discovered a unique capability of African American PCA cells to survive under hypoxic (low oxygen condition) conditions dependent upon cellular RAB5A expression, the master regulator of exosomes biogenesis, as the survival of African American PCA cells was completely compromised in RAB5A knock-down condition. More importantly, compared to Caucasian PCA cells, African American PCA cells secreted significantly higher amount of exosomes under hypoxic conditions. Interestingly, African American PCA cells seem to better adapt to hypoxia through exporting metabolic product lactic acid packaged in exosomes. Recent studies have also provided ample evidence that lactic acid is used not only as a fuel for bioenergy and biosynthesis but lactic acid also activates several mitogenic signaling pathways in various tumor microenvironment cellular components including endothelial cells, fibroblasts, macrophages and PCA cells in the normoxic areas. Taken together, we hypothesize that "African American PCA cells have the unique capability to survive hypoxia via RAB5A-mediated exosomes secretion loaded with lactic acid, and the secreted exosomes promote extensive tumor microenvironment remodeling and disease aggressiveness'. Following specific aims are proposed to test our hypothesis: (I) to characterize and establish RAB5A role in exosomes secretion and survival of African American PCA cells under hypoxia; and (II) to examine and establish the role of exosomes secreted by African American PCA cells in tumor microenvironment remodeling. Proposed studies will bring a paradigm shift in our approach to understand and treat PCA in African American men brining greater focus on tumor microenvironment both for prognosis as well as treatment purposes. Overall, present proposal is highly significant and will help to narrow the huge health disparity gap faced by African American PCA patients, and reduce the PCA-caused mortality and morbidity in these patients.

 描述（由申请人提供）：前列腺癌 (PCA) 表现出最显着的种族差异，因为与白人男性相比，非裔美国男性被诊断出 PCA 并死亡的风险更高。尽管包括社会经济地位在内的多种因素导致了这种差异，但有必要确定导致非裔美国人 PCA 更具攻击性表型的分子和潜在生物学差异。有几项研究调查了非裔美国人和白种人 PCA 之间的遗传和表观遗传差异；然而，过去，人们对肿瘤微环境对非裔美国人 PCA 疾病侵袭性的影响的关注有限。在这方面，我们的初步研究发现，非洲裔美国人 PCA 细胞在缺氧（低氧条件）条件下生存的独特能力依赖于细胞 RAB5A 表达（外泌体生物发生的主要调节因子），因为非洲裔美国人 PCA 细胞的生存在 RAB5A 敲低条件下完全受到损害。更重要的是，与白种人PCA细胞相比，非裔美国人PCA细胞在缺氧条件下分泌的外泌体数量明显更高。有趣的是，非洲裔美国人的 PCA 细胞似乎通过输出包装在外泌体中的代谢产物乳酸来更好地适应缺氧。最近的研究还提供了充分的证据表明，乳酸不仅用作生物能源和生物合成的燃料，而且还激活各种肿瘤微环境细胞成分中的多种有丝分裂信号通路，包括常氧区域的内皮细胞、成纤维细胞、巨噬细胞和 PCA 细胞。综上所述，我们假设“非裔美国人的 PCA 细胞通过 RAB5A 介导的负载乳酸的外泌体分泌具有独特的缺氧生存能力，并且分泌的外泌体促进广泛的肿瘤微环境重塑和疾病侵袭性”。提出以下具体目标来检验我们的假设：（I）表征和建立 RAB5A 在非裔美国人的外泌体分泌和生存中的作用 PCA细胞在缺氧状态下； (II) 检查并确定非裔美国人 PCA 细胞分泌的外泌体在肿瘤微环境重塑中的作用。拟议的研究将为我们理解和治疗非裔美国男性 PCA 的方法带来范式转变，从而更加关注肿瘤微环境，以实现预后和治疗目的。总体而言，本提案非常重要，将有助于缩小巨大的健康差距 非洲裔美国 PCA 患者所面临的问题，并降低这些患者 PCA 引起的死亡率和发病率。