Ketones and lactate “fuel” tumor growth and metastasis

Bonuccelli, Gloria; Tsirigos, Aristotelis; Whitaker‐Menezes, Diana; Pavlides, Stephanos; Pestell, Richard G.; Chiavarina, Barbara; Frank, Philippe G.; Flomenberg, Neal; Howell, Anthony; Martinez‐Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P.

doi:10.4161/cc.9.17.12731

Cited by 491 publications

(235 citation statements)

References 47 publications

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“…22,[37][38][39][40] In turn, these nutrients stimulated mitochondrial biogenesis, OXPHOS and autophagy resistance in the epithelial cancer cells and protected the cancer cells against basal and chemotherapy-induced apoptosis. 33,34,[41][42][43][44][45] Thus, two-compartment tumor metabolism and mitochondrial "health" may be the basis of chemoresistance and therapy failure in cancer patients. 23,46 Given that two-compartment tumor metabolism may be a clinical barrier to effective cancer treatments, normalizing energy balance (homeostasis) should cut off the fuel supply to cancer cell mitochondria (Fig.…”

Section: Visualizing Two-compartment Tumor Metabolism: Hyperactivatiomentioning

confidence: 99%

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

et al. 2012

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Section: Visualizing Two-compartment Tumor Metabolism: Hyperactivatiomentioning

confidence: 99%

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

et al. 2012

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“…From a bioenergetic standpoint, lactate has indeed been shown to be a preferred oxidative substrate to glucose in oxygenated/oxidative cancer cells, thereby supporting cooperativeness between glycolytic and oxidative cells 20,21 and commensalism of oxidative cancer cells for glycolytic fibroblasts. 22 Lactate also acts as a paracrine signaling agent creating a pseudohypoxic response in oxidative cancer cells where it activates HIF-1 following its oxidation to pyruvate and pyruvate-mediated inhibition of prolylhydroxylases (PHDs). [23][24][25] The possibility for cancer cells to use different resources necessitates integration and coordination.…”

Section: Introductionmentioning

confidence: 99%

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

et al. 2016

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Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2a (HIF-2a), and HIF-2a then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling.

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“…39,40 In several studies, CAFs from different sources were shown to produce more ketone bodies than paired normal fibroblasts. Ketone elevation was also detected for BRCA1 mosMe fibroblasts in contrast to twin control fibroblasts in the current study, although cells were neither taken from malignant tissue nor co-cultured with cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

et al. 2016

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Constitutive epimutations of tumor suppressor genes are increasingly considered as cancer predisposing factors equally to sequence mutations. In light of the emerging role of the microenvironment for cancer predisposition, initiation, and progression, we aimed to characterize the consequences of a BRCA1 epimutation in cells of mesenchymal origin. We performed a comprehensive molecular and cellular comparison of primary dermal fibroblasts taken from a monozygous twin pair discordant for recurrent cancers and BRCA1 epimutation, whose exceptional clinical case we previously reported in this journal. Comparative transcriptome analysis identified differential expression of extracellular matrix-related genes and pro-tumorigenic growth factors, such as collagens and CXC chemokines. Moreover, genes known to be key markers of so called cancer-associated fibroblasts (CAFs), such as ACTA2, FAP, PDPN, and TNC, were upregulated in fibroblasts of the affected twin (BRCA1 mosMe ) in comparison to those of the healthy twin (BRCA1 wt ). Further analyses detected CAF-typical cellular features, including an elevated growth rate, enhanced migration, altered actin architecture and increased production of ketone bodies in BRCA1 mosMe fibroblasts compared to BRCA1 wt fibroblasts. In addition, conditioned medium of BRCA1 mosMe fibroblasts was more potent than conditioned medium of BRCA1 wt fibroblasts to promote cell proliferation in an epithelial and a cancer cell line. Our data demonstrate, that a CAF-like state is not an exclusive feature of tumor-associated tissue but also exists in healthy tissue with tumor suppressor deficiency. The naturally occurring phenomenon of twin fibroblasts differing in their BRCA1 methylation status revealed to be a unique powerful tool for exploring tumor suppressor deficiency-related changes in healthy tissue, reinforcing their significance for cancer predisposition.

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Ketones and lactate “fuel” tumor growth and metastasis

Cited by 491 publications

References 47 publications

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

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