Adaptation of Energy Metabolism in Breast Cancer Brain Metastases

Abstract

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]

Cancer, Oxidative Stress, and Metastasis

“…Consistent with these observations, some cancer cells undergo metabolic changes during invasion in vitro and metastasis in vivo that would be expected to reduce the generation of ROS (Chen et al 2007;Lu et al 2010;Qu et al 2011;Kamarajugadda et al 2012Kamarajugadda et al , 2013Dong et al 2013;Shi et al 2014). For example, HIF-1 activity is transiently increased during metastasis due to high ROS levels (Montagner et al 2012;Zhao et al 2014).…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Pri mary can cer cells of ten dis play ex ten sive meta bolic het ero gene ity and en gage dis tinct meta bolic pat terns de pend ing on their site of metas ta sis: in breast can cer, aer o bic gly col y sis was the dom i nant meta bolic phe no type specif i cally iden ti fied in liver metas ta sis, com pared to bone and lung metas tases that were more de pen dent on OX PHOS [199]. In an in de pen dent study [187], metasta tic breast can cer cells with a se lec tive tro pism for the brain dis played in creased gly col y sis cou pled to TCA cy cle and in creased mi to chon dr ial res pi ra tion, PPP flux and fatty acid β ox i da tion com pared to parental cir cu lat ing can cer cells. These ev i dences sug gest that there might be a high de gree of or gan se lec tiv ity in the se lec tion of meta bolic traits en abling suc cess ful metasta tic dis sem i na tion [200].…”

“…For in stance, PGC 1α/es tro gen re lated re cep tor α (ERRα) axis is crit i cal for breast can cer cells by in creas ing glu t a mine de rived car bon flux into li po ge n e sis no tably un der hy poxia, thereby sus tain ing their pro lif er a tion [183], but also by pro mot ing VEGF se cre tion and an gio gen e sis [184][185][186], thereby paving a plau si ble road for can cer cell dis sem i na tion. Breast cir cu lat ing can cer cells and par tic u larly those with a brain tro pism rely on PGC 1α en hanced mi to chon dr ial ac tiv ity dur ing metasta tic spread [132,187]. Con versely, PGC 1α ex press ing melanoma cells have a low metasta tic po ten tial in de pen dently on its in flu ence on mi to chon dr ial me tab o lism [188] while PGC 1α sup presses metasta tic spread of prostate can cer cells through the en hance ment of mi to chon dr ial cata bolic path ways, coun ter act ing the ac qui si tion of ma lig nant traits by highly gly colytic prostate car ci no mas.…”

BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

“…BI-1 is involved in the upregulation of glucose uptake, downregulation of PDH activity, and accumulation of lactate, creating an acidic environment or Warburg effect, which describes the propensity of most cancer cells to avidly take up glucose and convert it primarily to lactate, despite the available oxygen (Deberardinis et al, 2008;Kroemer and Pouyssegur, 2008). Alterations in mitochondrial glucose metabolism produce acidic environments and cancer metastasis in other systems, too (Chen et al, 2007). As BI-1 can inhibit mitochondrial glucose metabolism (Figure 3), low O 2 consumption in BI-1 cells may relate to BI-1-induced cell protection, which may explain why BI-1 cells are less susceptible than control cells to ischemia or oxygen/glucose deprivation (Chae et al, 2004;Dohm et al, 2006).…”