Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer
Open Access
- 15 April 2011
- journal article
- Published by Taylor & Francis Ltd in Cell Cycle
- Vol. 10 (8), 1271-1286
- https://doi.org/10.4161/cc.10.8.15330
Abstract
Previously, we showed that high-energy metabolites (lactate and ketones) “fuel” tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells. To mechanistically understand how these metabolites affect tumor cell behavior, here we used genome-wide transcriptional profiling. Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with “stemness,” including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced “gene signatures” were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the “cancer stem cell” phenotype, resulting in significant decreases in patient survival. One possible mechanism by which these high-energy metabolites might induce stemness is by increasing the pool of Acetyl-CoA, leading to increased histone acetylation, and elevated gene expression. Thus, our results mechanistically imply that clinical outcome in breast cancer could simply be determined by epigenetics and energy metabolism, rather than by the accumulation of specific “classical” gene mutations. We also suggest that high-risk cancer patients (identified by the lactate/ketone gene signatures) could be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the anti-oxidant and “mitochondrial poison” metformin. Finally, we propose that this new approach to personalized cancer medicine be termed “Metabolo-Genomics,” which incorporates features of both 1) cell metabolism and 2) gene transcriptional profiling. Importantly, this powerful new approach directly links cancer cell metabolism with clinical outcome, and new therapeutic strategies for inhibiting the TCA cycle and mitochondrial oxidative phosphorylation in cancer cells.Keywords
This publication has 54 references indexed in Scilit:
- Stromal–epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironmentThe International Journal of Biochemistry & Cell Biology, 2011
- A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cellsJournal of Cell Science, 2011
- Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-Depleted Murine Embryonic Stem CellsPLoS Computational Biology, 2010
- Metformin and Other Biguanides in Oncology: Advancing the Research AgendaCancer Prevention Research, 2010
- Metformin Prevents Tobacco Carcinogen–Induced Lung TumorigenesisCancer Prevention Research, 2010
- Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotypeBritish Journal of Cancer, 2010
- Quantitative mitochondrial redox imaging of breast cancer metastatic potentialJournal of Biomedical Optics, 2010
- Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong RemissionCancer Research, 2009
- NCBI GEO: mining tens of millions of expression profiles--database and tools updateNucleic Acids Research, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005