ADAPTATION OF ENERGY METABOLISM IN BREAST CANCER BRAIN METASTASES

乳腺癌脑转移中能量代谢的适应

• 批准号: 7602166
• 负责人: Brunhilde H. Felding
• 金额: $ 0.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602166
• 关键词: Affect; Bioenergetics; Brain; Breast Cancer Cell; Cancer Cell Growth; Cancer Patient; Cell Respiration; Cell Survival; Cell model; Cells; Citric Acid Cycle; Computer Retrieval of Information on Scientific Projects Database; Data; Energy Metabolism; Enzymes; Equilibrium; Exhibits; Fright; Funding; Glucose; Glutathione; Glycolysis; Grant; Immunodeficient Mouse; Indium; Institution; Knowledge; Lesion; Malignant Neoplasms; Metabolic; Metastatic malignant neoplasm to brain; Molecular Profiling; Oxidation-Reduction; Oxidative Phosphorylation; Pentosephosphate Pathway; Pharmaceutical Preparations; Predisposition; Production; Property; Proteins; Proteomics; Reactive Oxygen Species; Research; Research Personnel; Resistance; Resources; Source; System; United States National Institutes of Health; Variant; base; bone; brain tissue; in vivo; malignant breast neoplasm; neoplastic cell; novel therapeutics; oxidation; prevent; protein expression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Brain metastases are among the most feared complications in breast cancer, as no therapy exists that prevents or eliminates breast cancer spreading to the brain. New therapeutic strategies depend on specific knowledge of tumor cell properties that allow breast cancer cell growth within the brain tissue. To provide information in this direction, we established a human breast cancer cell model for brain metastasis based on circulating tumor cells from a breast cancer patient and variants of these cells derived from bone or brain lesions in immunodeficient mice. The brain-derived cells showed an increased potential for brain metastasis in vivo and exhibited a unique protein expression profile identified by large-scale proteomic analysis. This protein profile is consistent with either a selection of predisposed cells or bioenergetic adaptation of the tumor cells to the unique energy metabolism of the brain. Increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways suggests that the brain metastatic cells derive energy from glucose oxidation. The cells further showed enhanced activation of the pentose phosphate pathway and the glutathione system, which can minimize production of reactive oxygen species resulting from an enhanced oxidative metabolism. These changes promoted resistance of brain metastatic cells to drugs that affect the cellular redox balance. Importantly, the metabolic alterations are associated with strongly enhanced tumor cell survival and proliferation in the brain microenvironment. Thus, our data support the hypothesis that predisposition or adaptation of the tumor cell energy metabolism is a key element in breast cancer brain metastasis, and raise the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy. [Cancer Res 2007;67(4):1472?86]

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