Exosomes Promote Disease aggressiveness in African American Prostate Cancer

 描述（由申请人提供）：前列腺癌（PCA）表现出最显著的种族差异，因为与白人男性相比，非洲裔美国男性被诊断为PCA并死于PCA的风险更高。虽然，包括社会经济地位在内的多种因素导致了这种差异，但必须确定导致非裔美国人PCA更具侵袭性表型的分子和潜在生物学差异。已经有几项研究调查了非洲裔美国人和高加索人PCA之间的遗传和表观遗传差异;然而，在过去，对肿瘤微环境在非洲裔美国人PCA中促进疾病侵袭性的作用的关注有限。在这方面，我们的初步研究发现了非洲裔美国人PCA细胞在缺氧（低氧条件）条件下存活的独特能力，这取决于细胞RAB 5A表达，RAB 5A是外泌体生物发生的主要调节因子，因为非洲裔美国人PCA细胞的存活在RAB 5A敲低条件下完全受损。更重要的是，与高加索PCA细胞相比，非裔美国人PCA细胞在缺氧条件下分泌显著更高量的外泌体。有趣的是，非裔美国人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，而且乳酸还激活各种肿瘤微环境细胞组分中的几种促有丝分裂信号通路，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PCA细胞具有通过RAB 5A介导的载有乳酸的外泌体分泌在缺氧中存活的独特能力，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”。提出了以下具体目标来检验我们的假设：（I）表征和建立RAB 5A在外泌体分泌和缺氧下非洲裔美国人PCA细胞的存活中的作用;以及（II）检查和建立由非洲裔美国人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人PCA的方法带来范式转变，从而更加关注肿瘤微环境的预后和治疗目的。总体而言，本提案意义重大，将有助于缩小非裔美国人PCA患者面临的巨大健康差距，并降低这些患者中PCA引起的死亡率和发病率。

 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.