Exosomes Promote Disease aggressiveness in African American Prostate Cancer

 描述(申请人提供)：前列腺癌(PCA)表现出最显著的种族差异，与高加索男性相比，非裔美国男性被诊断为前列腺癌并死于前列腺癌的风险更高。尽管包括社会经济地位在内的多种因素导致了这种差异，但识别导致非裔美国人PCa更具侵略性表型的分子和潜在生物学差异是至关重要的。已有多项研究调查了非裔美国人和高加索人前列腺癌之间的遗传和表观遗传学差异；然而，过去对肿瘤微环境在非裔美国人前列腺癌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，非洲裔美国人PCA细胞在低氧(低氧条件)条件下生存的独特能力取决于细胞RAB5A的表达，因为非裔美国人PCA细胞的生存在RAB5A敲除条件下完全受损。RAB5A是外切体生物发生的主要调节因子。更重要的是，与高加索人的前列腺癌细胞相比，非裔美国人的前列腺癌细胞在低氧条件下分泌的外切体数量明显更多。有趣的是，非裔美国人的前列腺癌细胞似乎通过输出外切体包装的代谢产物乳酸来更好地适应缺氧。最近的研究也提供了充分的证据表明，乳酸不仅被用作生物能量和生物合成的燃料，而且在常氧区的各种肿瘤微环境细胞成分中，乳酸还激活了几个有丝分裂信号通路，包括内皮细胞、成纤维细胞、巨噬细胞和前列腺癌细胞。综上所述，我们假设：非裔美国人的前列腺癌细胞通过RAB5A介导的富含乳酸的外切体分泌而具有独特的耐缺氧能力，并且分泌的外切体促进了广泛的肿瘤微环境重建和疾病侵袭性。为了验证我们的假说，我们提出了以下具体目标：(1)研究和确定RAB5A在非裔美国人前列腺癌细胞外体分泌和低氧生存中的作用；(2)研究和确定非裔美国人前列腺癌细胞分泌的外体在肿瘤微环境重建中的作用。拟议的研究将使我们理解和治疗非裔美国人前列腺癌的方法发生范式转变，使人们更多地关注肿瘤微环境，无论是出于预后还是治疗目的。总体而言，本建议具有重要意义，将有助于缩小非裔美国人PCa患者面临的巨大健康差距，并降低这些患者由PCa导致的死亡率和发病率。

 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.