Type B lactic acidosis and metastatic breast cancer

Warner, Ellen

doi:10.1007/bf01832361

Cited by 16 publications

(14 citation statements)

References 26 publications

(17 reference statements)

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“…[23][24][25][26][27][28][29][30][31][32][33] In fact, lactic-acidosis (due to the over-production and/or accumulation of serum lactate) is often the cause of death in patients with metastatic breast cancer, or other types of metastatic cancer. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] However, a causative role for L-lactate production in tumor metastatic progression has not yet been suggested or demonstrated.…”

Section: Methodsmentioning

confidence: 99%

Ketones and lactate “fuel” tumor growth and metastasis

Bonuccelli¹,

Tsirigos²,

et al. 2010

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Section: Methodsmentioning

confidence: 99%

Ketones and lactate “fuel” tumor growth and metastasis

Bonuccelli¹,

Tsirigos²,

et al. 2010

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“…[14][15][16][17] In fact, lactic acidosis is specifically associated with breast cancer metastasis. [18][19][20][21][22][23] Consistent with the idea that cancer cells use their mitochondria to generate energy, the metastatic phenotype is directly associated with an increase in oxidative mitochondrial metabolism in cancer cells, 24,25 especially in cancer cells that undergo brain metastasis. 26 The brain is a particularly lactate-rich microenvironment, because astrocytes take up glucose, and then secrete lactate to Figure 7.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 97%

Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer

et al. 2011

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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.

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“…As such, in the "reverse Warburg effect," cancer-associated fibroblasts and the tumor stroma should Consistent with our current observations, increased serum and tumor L-lactate is a specific marker of poor clinical outcome in variety of cancer types, [61][62][63][64] and lactic acidosis is a life-threatening complication in patients with metastatic breast cancer. [65][66][67][68][69][70] Thus, these previous results may have been due to L-lactate overproduction in the tumor microenvironment, rather than in epithelial tumor cells.…”

mentioning

confidence: 99%