Development and Characterization of 3D Organoid Lines from Circulating Tumor Cells of African-American Prostate Cancer Patients

非裔美国前列腺癌患者循环肿瘤细胞 3D 类器官系的开发和表征

基本信息

批准号：
9273217
负责人：
Gagan Deep
金额：
$ 20万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273217
关键词：
African American Age Anabolism Area Attention B-Lymphocytes Biogenesis Biological Biological Assay Cancer Etiology Cancer Patient Caucasians Cell Line Cell Proliferation Cell Survival Cells Development Diagnosis Disease Employee Strikes Endothelial Cells Epigenetic Process Exhibits Fibroblasts Formalin Genetic Gleason Grade for Prostate Cancer Health Hypoxia Lactic acid Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Measures Mediating Metabolic Molecular Morbidity - disease rate Neoplasm Circulating Cells Non-Malignant Organoids Outcome Oxygen Patients Phenotype Prostate Prostatectomy Proteins Public Health Role Serum Signal Pathway Socioeconomic Status Survival Rate Testing Tube Tumor Tissue exosome health disparity high risk men knock-down macrophage men mortality nanoparticle new therapeutic target outcome forecast prostate cancer cell racial disparity research study tumor microenvironment

项目摘要

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（由适用提供）：与高加索男性相比，非洲裔美国男性被诊断和死亡的风险更高，前列腺癌（PCA）表现出最引人注目的种族差异。虽然，包括社会经济状况在内的多种因素有助于这种差异，但必须确定分子和潜在的生物学差异，从而有助于非裔美国人PCA中更具侵略性的表型。已经进行了几项研究，研究了非裔美国人和高加索PCA之间的遗传和表观遗传差异。然而，过去，人们对肿瘤微环境的作用有限，从而促进非裔美国人PCA疾病的侵略性。在这方面，我们的初步研究发现了非洲裔美国PCA细胞在低氧（低氧状况）条件下生存的独特能力，取决于细胞RAB5A表达，这是外泌体生物发生的主要调节剂，因为非裔美国人PCA细胞的生存在RAB5A敲门型条件下完全损害。更重要的是，与高加索PCA细胞相比，非裔美国人PCA细胞在低氧条件下分泌的外泌体数量明显更高。有趣的是，非裔美国人PCA细胞似乎通过输出外泌体中包装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，乳酸不仅被用作生物能和生物合成的燃料，而且乳酸酸还激活了各种肿瘤微环境细胞成分中的几种有丝分裂信号通路，包括内皮细胞，成纤维细胞，成纤维细胞，巨噬细胞，巨噬细胞和正常氧化区域的PCA细胞。两者合计，我们假设“非洲裔美国PCA细胞具有独特的能力，可以通过Rab5a介导的含有乳酸的rab5a介导的外泌体分泌缺氧，而分泌的外泌体具有广泛的肿瘤微环境重塑和疾病的侵略性。 PCA在缺氧下；（II）检查和建立非裔美国人PCA细胞在肿瘤微环境中的作用面对非裔美国人PCA患者，并降低了这些患者的PCA引起的死亡率和发病率。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer.

DOI：
10.2741/4565
发表时间：
2017-06-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
0
作者：
通讯作者：

Exosomal microRNA profiling to identify hypoxia-related biomarkers in prostate cancer.

DOI：
10.18632/oncotarget.24532
发表时间：
2018-03-02
期刊：
Oncotarget
影响因子：
0
作者：
Panigrahi GK;Ramteke A;Birks D;Abouzeid Ali HE;Venkataraman S;Agarwal C;Vibhakar R;Miller LD;Agarwal R;Abd Elmageed ZY;Deep G
通讯作者：
Deep G

Dysregulated gene expression predicts tumor aggressiveness in African-American prostate cancer patients.

DOI：
10.1038/s41598-018-34637-8
发表时间：
2018-11-05
期刊：
Scientific reports
影响因子：
4.6
作者：
Ali HEA;Lung PY;Sholl AB;Gad SA;Bustamante JJ;Ali HI;Rhim JS;Deep G;Zhang J;Abd Elmageed ZY
通讯作者：
Abd Elmageed ZY

Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment.