Mitochondrial DNA Mutations in Prostate Tumorigenesis and Stromal-Epithelial Inte

前列腺肿瘤发生和间质上皮间质中的线粒体 DNA 突变

• 批准号: 7617321
• 负责人: John A. Petros
• 金额: $ 40.28万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-17 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617321
• 关键词: Adult; Affect; Biological Models; Biology; Cancer Patient; Cells; Clinical; Collaborations; Complex; DNA; Data; Diagnostic; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; Fibroblast Growth Factor 1; Focal Adhesions; Gene Expression; Gene Expression Profile; Gene Mutation; Genetic; Goals; Growth; In Vitro; Injection of therapeutic agent; Instruction; Investigation; Laboratories; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Methods; Mitochondria; Molecular; Mutation; Nature; Neoplasm Metastasis; Nuclear; Nude Mice; Oxygen; PC3 cell line; Paracrine Communication; Patients; Phosphotransferases; Physiological; Positioning Attribute; Primary Neoplasm; Production; Prostate; Prostatic Neoplasms; Reactive Oxygen Species; Resources; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid Neoplasm; Specimen; Stromal Cells; Testing; Therapeutic; Up-Regulation; Work; authority; autocrine; beta-2 Microglobulin; bone; cancer cell; clinical material; design; effective therapy; experience; in vivo; in vivo Model; malignant phenotype; mitochondrial DNA mutation; perlecan; research study; respiratory; tool; tumor growth; tumorigenesis

Mitochondria! DNA mutations are found in essentially all adult solid tumors yet there remains a great need :or functional and mechanistic studies of these mutations and how they affect the malignant phenotype. Our jroad overarching goal is to understand these mechanisms in order to design more effective therapeutic and diagnostic tools for patient use. Because of our significant patient resources and our substantial previous experience and proven track record in these investigations, we are uniquely positioned to perform rigorous studies of mtDNA mutations in prostate cancer. We present preliminary data that mtDNA mutations enhance cellular reactive oxygen and prostate tumor growth, especially in the bone stromal microenvironment, an observation with obvious relevance to prostate cancer bone metastases. Further, we have begun to identify the (validated) gene expression signature of the interaction between mtDNA mutations in prostate cancer epithelial cells and bone stromal cells, thereby identifying specific signaling pathways (notably FGF-1 and FAK) responsible for this effect. Because these mutations are so common in prostate cancer and appear to be enhancing prostate tumor growth and metastasis, we will test the overall hypothesis that mtDNA mutations in prostate cancer are functionally important in prostate tumorigenesis and metastatic growth and survival in bone. In order to test this hypothesis, three specific aims are proposed. In the first aim we will use new mutations and new prostate cancer nuclear backgrounds to determine the effect of mutations in different respiratory complexes and whether the same signaling pathways already discovered are activated. The effect of mtDNA mutations on reactive oxygen (ROS) production, tumor growth and gene expression will be studied. In the second aim, we will manipulate ROS in both in vivo and in vitro experiments to determine whether this (ROS) is the key signaling pathway for the induction of FGF-1 and focal adhesion kinase (FAK) observed when prostate cancer cells with mtDNA mutation interact with bone stromal cells. The third aim is designed to determine whether clinical metastasis involves increased mtDNA mutation and how this affects adaptation in the bone metastatic site and cell signaling. RELEVANCE (See instructions): Mutations in mitochondria! DNA are common in prostate cancer and enhance the cancer's ability to grow, especially in the bone. Because there are so few effective treatments for bone metastases, we will study the ways that these mutations allow this fatal form of prostate cancer to grow. By understanding how this works it is hoped that new treatments may one day be designed targeting this highly malignant form of the disease.

线粒体！基本上在所有成人实体瘤中都发现了DNA突变，但仍然存在巨大的需求。 或这些突变的功能和机制研究以及它们如何影响恶性表型。我们 jroad的总体目标是了解这些机制，以便设计更有效的治疗和 患者使用的诊断工具。因为我们有大量的病人资源和大量的 在这些调查中，我们拥有丰富的经验和良好的记录，我们处于独特的地位，可以执行严格的 前列腺癌的mtDNA突变研究。我们目前的初步数据表明，mtDNA突变增强了 细胞活性氧和前列腺肿瘤生长，特别是在骨基质微环境中， 观察与前列腺癌骨转移有明显相关性。此外，我们已经开始确定 前列腺癌中线粒体DNA突变之间相互作用的（经验证的）基因表达特征 上皮细胞和骨基质细胞，从而鉴定特定的信号传导途径（特别是FGF-1和 FAK）对此负责。因为这些突变在前列腺癌中很常见， 增强前列腺肿瘤的生长和转移，我们将测试线粒体DNA的总体假设， 前列腺癌中的突变在前列腺肿瘤发生和转移性生长中具有重要的功能， 生存在骨头里为了检验这一假设，提出了三个具体目标。在第一个目标中，我们将 使用新的突变和新的前列腺癌细胞核背景来确定突变对 不同的呼吸复合物以及是否激活了已经发现的相同的信号通路。 线粒体DNA突变对活性氧（ROS）产生、肿瘤生长和基因表达的影响将 被研究。在第二个目标中，我们将在体内和体外实验中操纵ROS，以确定 这（ROS）是否是诱导FGF-1和黏着斑激酶（FAK）的关键信号通路 当mtDNA突变的前列腺癌细胞与骨基质细胞相互作用时观察到。第三个目标是 旨在确定临床转移是否涉及mtDNA突变增加以及这如何影响 骨转移部位的适应和细胞信号传导。 相关性（参见说明）： 线粒体突变！DNA在前列腺癌中很常见，并增强了癌症的生长能力， 尤其是在骨头里由于骨转移的有效治疗方法很少，我们将研究 这些突变使得这种致命的前列腺癌得以生长。通过了解这是如何运作的 希望有一天能设计出针对这种高度恶性疾病的新疗法。