Developing Functional Human Cell Models to Study Initiation and Progression of Prostate Cancer between AA and EA men

项目摘要 前列腺癌是最常见的男性癌症，也是第二大致癌原因。 美国男性死亡人数。这一日益严重的公共卫生挑战因 非裔美国人(AA)和欧洲裔美国人(EA)男性前列腺癌的发病率和死亡率。为 例如，AA男性的前列腺癌发病率几乎高出60%，死亡率高出2-3倍。而当 获得医疗服务可能会导致这些差异，其他研究表明，基于细胞的差异 可能会起到关键作用。不幸的是，没有原代人类前列腺细胞培养物可用于询问。 在早期癌变过程中潜在的细胞变化。有机培养模式对正常生长很有效 前列腺癌和晚期前列腺癌，但不能成功地进行原发前列腺癌。CR(条件重编程) 文化，这是由刘博士(派)和他的同事们开发的，正在改变着产生 体外人类癌症模型。CR技术允许从正常前列腺、原发前列腺癌 和先进的PCA。来自正常上皮的CR细胞在以下条件下可以完全分化： 模拟它们的自然环境，而来自原发性前列腺癌的CR细胞则显示出异常的核型 并在SCID小鼠体内形成肿瘤。在目前的应用中，为了努力定义它们的生物学基础 临床差异，我们首先建议探索原代AA和EA正常前列腺细胞的差异 对永生和转化的敏感性。然后，我们将测定生物库正常的反应 和肿瘤CR细胞对AA和EA患者睾酮的影响 成纤维细胞。然后，我们将比较来自AA和EA的肿瘤CR培养的遗传和生物学特性 患者，包括迁移/侵袭、非锚定生长、有无肿瘤形成 它们相应的成纤维细胞。最后，我们将从遗传学、表观遗传学和表型CR进行比较 来自AA和EA患者的细胞，这些患者患有转移性和抗去势的PCa。在完成此操作后 应用，我们将建立一个具有新的功能细胞模型的活生物库，包括匹配的 来自AA和EA患者的正常和肿瘤前列腺CR细胞及其相应的成纤维细胞，永生化 AA和EA前列腺细胞系以及转化的AA和EA细胞系的基因组和患者 临床信息。这些新的模型包括正常前列腺细胞、原发前列腺癌和晚期前列腺癌以及 将为启动和进展以及健康差距的研究提供宝贵的新资源 主成分分析的研究。

Project Summary Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer deaths in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa between African-American (AA) and European-American (EA) men. For example, the incidence of PCa is almost 60% higher in AA men and the mortality rate 2-3 times greater. While access to medical care may contribute to these differences, other studies suggest that cell-based differences may play a critical role. Unfortunately, no primary human prostate cell cultures are available for interrogating potential cellular alterations during early carcinogenesis. Organoid culture models work well for growing normal prostate cells and advanced PCa, but fail to succeed with primary PCa. CR (Conditional Reprogramming) culture, which was developed by Dr. Liu (PI) and his colleagues, is changing the landscape for generating in vitro human cancer models. CR technology allows to establish cell cultures from normal prostate, primary PCa and advanced PCa. CR cells from normal epithelium can fully differentiate when placed in conditions that mimic their natural environment, while CR cells from a primary prostate tumor exhibit an abnormal karyotype and form tumors in SCID mice. In the current application, in an effort to define the biological basis for their clinical disparities, we first propose to probe primary AA and EA normal prostate cells for differences in their susceptibility to immortalization and transformation. Then, we will determine response of biobanked normal and tumor CR cells to testosterone from AA and EA patients in presence or absence of their corresponding fibroblasts. Then, we will compare the genetic and biological properties of tumor CR cultures from AA and EA patients, including migration/invasion, anchorage-independent growth, tumor formation in presence or absence of their corresponding fibroblasts. Finally, we will compare genetically, epigenetically and phenotypically CR cells from AA and EA patients with metastatic and castration resistant PCa. Upon completion of this application, we will have established a living biobank with novel functional cell models, including matched normal and tumor prostate CR cells and their corresponding fibroblasts from AA and EA patients, immortalized AA and EA prostate cell lines and transformed AA and EA cell lines with annotated genomic and patient’s clinical information. These novel models include prostate cells at normal, primary PCa and advanced PCa and will provide an invaluable and novel resource for studies of initiation and progression and health disparity studies of PCa.