l-Lactate Transport and Metabolism in Mitochondria of Hep G2 Cells—The Cori Cycle Revisited

Passarella, Salvatore; Schurr, Avital

doi:10.3389/fonc.2018.00120

Cited by 36 publications

(29 citation statements)

References 29 publications

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“…While lactate accumulated in the TME is generally considered as metabolic “waste,” muscle cells, neurons and certain tumor cells are known to be able to take up and oxidize lactate (225–227). Consistent with these findings, emerging evidence suggests that lactate is a key carbon source in vivo and can be oxidized in the mitochondria to generate energy and feed into cataplerotic routes of the TCA cycle (228–236). Enforced expression of phosphoenolpyruvate carboxykinase 1 (PCK1), which presumably increases gluconeogenesis from lactate and thus alleviates the stress from glucose restriction in the TME, has been shown to enhance anti-tumor T cell responses in animal models (167).…”

Section: Metabolic Optimization Of the Clinical Manufacture And Applimentioning

confidence: 71%

A Metabolism Toolbox for CAR T Therapy

Gnanaprakasam

Sherman

et al. 2019

Front. Oncol.

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The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) through genetic engineering is one of the most promising new therapies for treating cancer patients. A robust CAR T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with CAR T cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of CAR T cells by competing for nutrients within the tumor microenvironment (TME). To substantially improve clinical outcomes of CAR T immunotherapy while treating solid tumors, it is essential to metabolically prepare CAR T cells to overcome the metabolic barriers imposed by the TME. In this review, we discuss a potential metabolism toolbox to improve the metabolic fitness of CAR T cells and maximize the efficacy of CAR T therapy.

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Section: Metabolic Optimization Of the Clinical Manufacture And Applimentioning

confidence: 71%

A Metabolism Toolbox for CAR T Therapy

Gnanaprakasam

Sherman

et al. 2019

Front. Oncol.

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“…The increased S-lactate and S-pyruvate in the carbohydrate patients stems primarily from two sources. Firstly, lactate is the product of glycolysis, especially in muscle cells, and is transported to the liver for conversion back to glucose, known as the Cori cycle [31]. The intended effect of preOP is to contra act and reduce insulin resistance that follows surgical stress [32].…”

Section: Discussionmentioning

confidence: 99%

Metabolic consequences of perioperative oral carbohydrates in breast cancer patients — an explorative study

et al. 2019

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Background: The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present explorative study investigated the systemic and tumor metabolic changes after preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival. Methods: The study setting was on university hospital level with primary and secondary care functions in southwest Norway. Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n = 25) or standard preoperative fasting (n = 35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group. Results: Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n = 18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p = 0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r = 0.680; p = 0.002). In all tumors (n = 29), glutamate was increased in tumors with high proliferation (t-test; p = 0.009), independent of intervention group. Moreover, there was a positive correlation between tumor size and proliferation markers in the carbohydrate group only. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth.

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“…The increased S-lactate and S-pyruvate in the carbohydrate patients stems primarily from two sources. Firstly, lactate is the product of glycolysis, especially in muscle cells, and is transported to the liver for conversion back to glucose, known as the Cori cycle [29]. Secondly, it may come from excretion of intracellular lactate and pyruvate from breast cancer cells into the systemic circulation via mono carboxylate transporter type 4 (MCT-4), which is a known part of the Warburg effect [13].…”

Section: Discussionmentioning

confidence: 99%

Metabolic consequences of perioperative oral carbohydrates in breast cancer patients: An explorative study

Lende

Austdal

Bathen

et al. 2019

Preprint

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Background: The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present study investigated the systemic and tumor metabolic changes after preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival. Design: Explorative study. Setting: University hospital with primary and secondary care functions in south-west Norway.Interventions and Outcome Measures: Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n=25) or standard pre-operative fasting (n=35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group. Results: Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n=18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p=0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r=0.680; p=0.002). In all tumors (n=29), glutamate was increased in tumors with high proliferation (t-test; p=0.009), independent of intervention group. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth. Conclusions: Preoperative carbohydrate load increases systemic levels of lactate and pyruvate and tumor levels of glutathione and glutamate in ER-positive patients. These biological changes may contribute to the inferior clinical outcomes observed in luminal T2 breast cancer patients. Registration of trial: CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03886389?cond=Breast+cancer+diet&rank=1

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l-Lactate Transport and Metabolism in Mitochondria of Hep G2 Cells—The Cori Cycle Revisited

Cited by 36 publications

References 29 publications

A Metabolism Toolbox for CAR T Therapy

A Metabolism Toolbox for CAR T Therapy

Metabolic consequences of perioperative oral carbohydrates in breast cancer patients — an explorative study

Metabolic consequences of perioperative oral carbohydrates in breast cancer patients: An explorative study

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