ADAPTATION OF ENERGY METABOLISM IN BREAST CANCER BRAIN METASTASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脑转移是乳腺癌最可怕的并发症之一，因为目前还没有预防或消除乳腺癌扩散到大脑的治疗方法。新的治疗策略依赖于对肿瘤细胞特性的具体了解，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脑转移模型，该模型基于一名乳腺癌患者的循环肿瘤细胞以及来自免疫缺陷小鼠骨或脑损伤的这些细胞的变体。脑源性细胞在体内显示出增加脑转移的潜力，并通过大规模蛋白质组学分析确定了独特的蛋白质表达谱。这种蛋白质图谱与预先准备好的细胞的选择或肿瘤细胞对大脑独特的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中获得能量。细胞进一步表现出增强的戊糖磷酸途径和谷胱甘肽系统的激活，这可以最大限度地减少氧化代谢增强导致的活性氧物种的产生。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抗药性。重要的是，代谢改变与脑微环境中肿瘤细胞的存活和增殖显著增强有关。因此，我们的数据支持了肿瘤细胞能量代谢的易感性或适应性是乳腺癌脑转移的关键因素的假说，并提出了将乳腺癌脑病变的功能分化作为一种新的治疗策略的可能性。[癌症资源2007；67(4)：1472？86]

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]