Metabolic differences in breast cancer stem cells and differentiated progeny

Abstract

Purpose In general, tumor cells display a more glycolytic phenotype compared to the corresponding normal tissue. However, it is becoming increasingly clear that tumors are composed of a heterogeneous population of cells. Breast cancers are organized in a hierarchical manner, with the breast cancer stem cells (BCSCs) at the top of the hierarchy. Here, we investigate the metabolic phenotype of BCSCs and their differentiated progeny. In addition, we determine the effect of radiation on the metabolic state of these two cell populations. Methods Luminal, basal, and claudin-low breast cancer cell lines were propagated as mammospheres enriched in BCSCs. Lactate production, glucose consumption and ATP content was compared with differentiated cultures. A metabolic flux analyzer was used to determine the oxygen consumption, extracellular acidification rates, maximal mitochondria capacity and mitochondrial proton leak. The effect of radiation treatment of the metabolic phenotype of each cell population was also determined. Results BCSCs consume more glucose, produce less lactate and have higher ATP content compared to their differentiated progeny. BCSCs have higher maximum mitochondrial capacity and mitochondrial proton leak compared to their differentiated progeny. Radiation treatment enhances the higher energetic state of the BCSCs, while decreasing mitochondrial proton leak. Conclusions Our study indicated that breast cancer cells are heterogeneous in their metabolic phenotypes and BCSCs reside in a distinct metabolic state compared to their differentiated progeny. BCSCs display a reliance on oxidative phosphorylation, while the more differentiated progeny display a more glycolytic phenotype. Radiation treatment affects the metabolic state of BCSCs. We conclude that interfering with the metabolic requirements of BCSCs may prevent radiation-induced reprogramming of breast cancer cells during radiation therapy, thus improving treatment outcome.

Cancer metabolism in space and time: Beyond the Warburg effect

“…that CICs and CSCs have a high ox ida tive me tab o lism. In ovar ian, glioma and breast can cer mod els, CICs/ CSCs are much more de pen dent on OX PHOS in terms of in creased mi to chon dr ial ROS pro duc tion, in creased mi to chon dr ial mem brane po ten tial, higher num ber of mi to chon dria and lower lac tate pro duc tion than their dif fer en ti ated prog eny [235,239,240]. In ovar ian tu mors, de pen dence of CSCs (CD44 CD117 ) on OX PHOS does not ex clude in creased glu cose con sump tion nor a higher ex pres sion of glu cose trans porters and gly colytic en zymes.…”

Mitochondria as therapeutic targets for cancer stem cells

“…Glioblastoma CSCs also depend on OXPHOS for their energy production and survival [67] . Besides, breast CSCs have higher ATP content compared to their differentiated progeny [68] . Based on these studies, CSCs mitochondria showed the different roles and features according to the cancer type.…”

Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

“…The Warburg phenotype had stronger associations with triple negative breast carcinomas (TNBC) than luminal breast cancers, suggesting a correlation between metabolic phenotype and the biology of breast cancer [12]. Furthermore, the metabolic phenotype of breast cancer stem cells (BCSCs) and their differentiated progeny was also investigated [13]. BCSCs consume more glucose, produce less lactate, and have higher ATP content compared to their differentiated progeny [13].…”

“…Furthermore, the metabolic phenotype of breast cancer stem cells (BCSCs) and their differentiated progeny was also investigated [13]. BCSCs consume more glucose, produce less lactate, and have higher ATP content compared to their differentiated progeny [13].…”