ADAPTATION OF ENERGY METABOLISM IN BREAST CANCER BRAIN METASTASES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 脑转移是乳腺癌最可怕的并发症之一，因为没有任何治疗方法可以预防或消除乳腺癌扩散到大脑。新的治疗策略依赖于对肿瘤细胞特性的特定了解，这些特性允许乳腺癌细胞在脑组织内生长。为了提供这方面的信息，我们建立了一个人乳腺癌细胞模型的脑转移的基础上循环肿瘤细胞从乳腺癌患者和这些细胞的变体来自骨或脑病变的免疫缺陷小鼠。脑源性细胞显示出体内脑转移的可能性增加，并显示出通过大规模蛋白质组学分析鉴定的独特蛋白质表达谱。这种蛋白质谱与易感细胞的选择或肿瘤细胞对脑的独特能量代谢的生物能量适应是一致的。参与糖酵解、三羧酸循环和氧化磷酸化途径的酶的表达增加表明脑转移细胞从葡萄糖氧化获得能量。细胞进一步显示戊糖磷酸途径和谷胱甘肽系统的增强的活化，这可以使由增强的氧化代谢引起的活性氧物质的产生最小化。这些变化促进了脑转移细胞对影响细胞氧化还原平衡的药物的抵抗。重要的是，代谢改变与脑微环境中强烈增强的肿瘤细胞存活和增殖相关。因此，我们的数据支持的假设，易感性或适应的肿瘤细胞的能量代谢是一个关键因素，在乳腺癌脑转移，并提出了针对功能分化的乳腺癌脑病变作为一种新的治疗策略的可能性。[Cancer Res 2007;67（4）：1472？八十六]

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]