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: 8112668
• 负责人: John A. Petros
• 金额: $ 39.59万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8112668
• 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!DNA突变基本上在所有成人实体瘤中都有发现，但仍有很大的需求