Published online 2013 Jul 9. doi: 10.1002/path.4218
PMCID: PMC3757307
Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Abstract
The common preference of cancers for lactic acid-generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti-cancer immune response through maintaining a relatively low pH in their micro-environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro-environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti-cancer immune response. Cancer-generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a ‘waste product’. This paradigm shift can have major impact on therapeutic strategy development
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: Warburg effect, aerobic glycolysis, glutaminolysis, lactic acid, immune suppression, tumour micro-environment
http://www.ncbi.nlm.nih.gov/pmc/article ... rt=classic
Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Re: Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Introduction
Deregulated proliferation of cancer cells is generally associated with altered energy metabolism. Glucose is a primary source of energy. Under aerobic conditions, normal cells metabolize glucose to pyruvate via glycolysis in the cytosol, and subsequently convert pyruvate to carbon dioxide in the mitochondria for oxidative phosphorylation; under anaerobic conditions, conversion of pyruvate to lactic acid is favoured with relatively low amounts of pyruvate being diverted to the mitochondria. In contrast, cancer cells primarily derive energy from glucose via glycolysis to lactic acid, even under highly aerobic conditions, a property first observed by Otto Warburg 1. This ‘aerobic glycolysis’, also known as the ‘Warburg effect’ 2, is much less energy-efficient than the oxidative phosphorylation pathway 3. It is usually accompanied by marked increases in glucose uptake and consumption 4, a phenomenon commonly exploited in tumour imaging using 18-fluorodeoxyglucose positron electron tomography 5. In addition, cancer cells derive energy from up-regulated non-glucose-dependent pathways, such as increased glutaminolysis under aerobic conditions 2,6,7. Aerobic glycolysis and increased glutaminolysis are collectively regarded as ‘reprogrammed energy metabolism’, a phenomenon now generally accepted as a key metabolic hallmark of cancer 3,8,9. Both pathways lead to the production and secretion of lactic acid, markedly contributing to metabolic acidosis commonly found in solid cancers 2,6,7. Extracellular pH values in tumours can be as low as pH 6.0–6.5, in contrast to pH 7.5 present in normal cell environments 10–12.
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Why do cancers opt for altered energy metabolism?
The preference of cancers for aerobic glycolysis over the more energy-efficient oxidative phosphorylation pathway has been a subject of major interest since it was first observed in the 1920s 13. Many researchers have speculated on the advantages of aerobic glycolysis for cancers, but the causal relationship of this altered metabolism to cancer development is still unclear 3. Otto Warburg speculated that the metabolic alteration was necessitated by a mitochondrial defect in the cancer cells impairing normal oxidative phosphorylation 14. However, further studies have since shown that mitochondrial defects only partially account for the phenomenon. Although certain malignancies indeed harbour mitochondrial defects that make aerobic glycolysis a necessity 15, the majority of cancers are able to revert back to oxidative phosphorylation when lactic acid generation is inhibited 16.
Tumours commonly encounter fluctuating oxygen levels, periodically alternating between normoxic and hypoxic conditions 17. This raises the distinct possibility that aerobic glycolysis has arisen as an adaptation to hypoxic conditions. Use of oxygen-independent glycolysis would confer a proliferative advantage to cancer cells, making them less susceptible to hypoxic stress during episodes of spontaneous hypoxia 13, even if that would come at a cost of energy inefficiency during times of adequate oxygenation. This theory has been extended by suggesting cooperation between normoxic and hypoxic cancer cells within a tumour aimed at maximizing energy efficiency 2. It is proposed that the hypoxic cells are the primary utilizers of glucose, converting it via glycolysis to lactate. Furthermore, lactate secreted by the hypoxic cells would be taken up by normoxic cancer cells and then converted back to pyruvate for oxidation via the citric acid cycle 2,18. This theory, however, does not fully account for the preference of cancers for glycolysis under conditions of abundant oxygenation.
Components of glucose uptake and glycolytic pathways can be up-regulated by oncogenes such as Ras, Akt, and Myc 3. This observation is particularly intriguing, since oncogenic activation is often thought of as an early event in cancer development and progression, and aerobic glycolysis may hence actually predate the onset of hypoxic selection and have a functional role in the early stages of the disease. Other proposals have been put forward, primarily focusing on the mechanisms by which aerobic glycolysis could confer a proliferative advantage to cancer cells 3,13,19. As this pathway is much less efficient than oxidative phosphorylation in generating ATP, ie by approximately 18-fold, the question is raised as to how a reduced supply of ATP can lead to improved proliferative potential. One proposal states that the advantage of aerobic glycolysis lies in incomplete utilization of glucose, allowing upstream intermediates to be redirected for biosynthesis, thereby providing cancer cells with an abundance of building blocks for synthesis of essential cellular components such as macromolecules 19. While such an explanation appears sound, there is still controversy regarding how common such a mechanism is in normal proliferating cells 20. Another proposal states that acidification of the micro-environment by lactic acid, resulting from up-regulation of glycolysis, can be expected to lead to the development of acid-resistant phenotypes exhibiting a powerful, selective growth advantage that promotes unconstrained proliferation and tissue invasion of cancer cells 13.
Increased glutaminolysis would also have several advantages for cancers: glutamine is the most abundant amino acid in plasma and forms an important additional energy source in tumour cells, especially when glycolytic energy production is low; increased availability of the degradation products of glutamine, ie glutamate and aspartate, as precursors for nucleic acid and serine synthesis; and the insensitivity of glutaminolysis to high concentrations of reactive oxygen species 2,6,7.
Of major interest is the finding that the reprogrammed energy metabolism plays an important role in cancer growth-promoting angiogenesis. Angiogenic endothelial cells, like tumour cells, are largely dependent on aerobic glycolysis and increased glutaminolysis for energy. The preference for these pathways allows the development of neovasculature from endothelial, tumour-blood-vessel-lining cells under hypoxic conditions. In addition, lactic acid generated by the pathways has been found to markedly promote angiogenesis by increasing the production of interleukin-8/CXCL8, driving the autocrine stimulation of endothelial cell proliferation and maturation of new blood vessels 21,22.
Deregulated proliferation of cancer cells is generally associated with altered energy metabolism. Glucose is a primary source of energy. Under aerobic conditions, normal cells metabolize glucose to pyruvate via glycolysis in the cytosol, and subsequently convert pyruvate to carbon dioxide in the mitochondria for oxidative phosphorylation; under anaerobic conditions, conversion of pyruvate to lactic acid is favoured with relatively low amounts of pyruvate being diverted to the mitochondria. In contrast, cancer cells primarily derive energy from glucose via glycolysis to lactic acid, even under highly aerobic conditions, a property first observed by Otto Warburg 1. This ‘aerobic glycolysis’, also known as the ‘Warburg effect’ 2, is much less energy-efficient than the oxidative phosphorylation pathway 3. It is usually accompanied by marked increases in glucose uptake and consumption 4, a phenomenon commonly exploited in tumour imaging using 18-fluorodeoxyglucose positron electron tomography 5. In addition, cancer cells derive energy from up-regulated non-glucose-dependent pathways, such as increased glutaminolysis under aerobic conditions 2,6,7. Aerobic glycolysis and increased glutaminolysis are collectively regarded as ‘reprogrammed energy metabolism’, a phenomenon now generally accepted as a key metabolic hallmark of cancer 3,8,9. Both pathways lead to the production and secretion of lactic acid, markedly contributing to metabolic acidosis commonly found in solid cancers 2,6,7. Extracellular pH values in tumours can be as low as pH 6.0–6.5, in contrast to pH 7.5 present in normal cell environments 10–12.
Go to:
Why do cancers opt for altered energy metabolism?
The preference of cancers for aerobic glycolysis over the more energy-efficient oxidative phosphorylation pathway has been a subject of major interest since it was first observed in the 1920s 13. Many researchers have speculated on the advantages of aerobic glycolysis for cancers, but the causal relationship of this altered metabolism to cancer development is still unclear 3. Otto Warburg speculated that the metabolic alteration was necessitated by a mitochondrial defect in the cancer cells impairing normal oxidative phosphorylation 14. However, further studies have since shown that mitochondrial defects only partially account for the phenomenon. Although certain malignancies indeed harbour mitochondrial defects that make aerobic glycolysis a necessity 15, the majority of cancers are able to revert back to oxidative phosphorylation when lactic acid generation is inhibited 16.
Tumours commonly encounter fluctuating oxygen levels, periodically alternating between normoxic and hypoxic conditions 17. This raises the distinct possibility that aerobic glycolysis has arisen as an adaptation to hypoxic conditions. Use of oxygen-independent glycolysis would confer a proliferative advantage to cancer cells, making them less susceptible to hypoxic stress during episodes of spontaneous hypoxia 13, even if that would come at a cost of energy inefficiency during times of adequate oxygenation. This theory has been extended by suggesting cooperation between normoxic and hypoxic cancer cells within a tumour aimed at maximizing energy efficiency 2. It is proposed that the hypoxic cells are the primary utilizers of glucose, converting it via glycolysis to lactate. Furthermore, lactate secreted by the hypoxic cells would be taken up by normoxic cancer cells and then converted back to pyruvate for oxidation via the citric acid cycle 2,18. This theory, however, does not fully account for the preference of cancers for glycolysis under conditions of abundant oxygenation.
Components of glucose uptake and glycolytic pathways can be up-regulated by oncogenes such as Ras, Akt, and Myc 3. This observation is particularly intriguing, since oncogenic activation is often thought of as an early event in cancer development and progression, and aerobic glycolysis may hence actually predate the onset of hypoxic selection and have a functional role in the early stages of the disease. Other proposals have been put forward, primarily focusing on the mechanisms by which aerobic glycolysis could confer a proliferative advantage to cancer cells 3,13,19. As this pathway is much less efficient than oxidative phosphorylation in generating ATP, ie by approximately 18-fold, the question is raised as to how a reduced supply of ATP can lead to improved proliferative potential. One proposal states that the advantage of aerobic glycolysis lies in incomplete utilization of glucose, allowing upstream intermediates to be redirected for biosynthesis, thereby providing cancer cells with an abundance of building blocks for synthesis of essential cellular components such as macromolecules 19. While such an explanation appears sound, there is still controversy regarding how common such a mechanism is in normal proliferating cells 20. Another proposal states that acidification of the micro-environment by lactic acid, resulting from up-regulation of glycolysis, can be expected to lead to the development of acid-resistant phenotypes exhibiting a powerful, selective growth advantage that promotes unconstrained proliferation and tissue invasion of cancer cells 13.
Increased glutaminolysis would also have several advantages for cancers: glutamine is the most abundant amino acid in plasma and forms an important additional energy source in tumour cells, especially when glycolytic energy production is low; increased availability of the degradation products of glutamine, ie glutamate and aspartate, as precursors for nucleic acid and serine synthesis; and the insensitivity of glutaminolysis to high concentrations of reactive oxygen species 2,6,7.
Of major interest is the finding that the reprogrammed energy metabolism plays an important role in cancer growth-promoting angiogenesis. Angiogenic endothelial cells, like tumour cells, are largely dependent on aerobic glycolysis and increased glutaminolysis for energy. The preference for these pathways allows the development of neovasculature from endothelial, tumour-blood-vessel-lining cells under hypoxic conditions. In addition, lactic acid generated by the pathways has been found to markedly promote angiogenesis by increasing the production of interleukin-8/CXCL8, driving the autocrine stimulation of endothelial cell proliferation and maturation of new blood vessels 21,22.
Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm).
Debbie
Re: Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Cont…
Go to:
Introduction
Deregulated proliferation of cancer cells is generally associated with altered energy metabolism. Glucose is a primary source of energy. Under aerobic conditions, normal cells metabolize glucose to pyruvate via glycolysis in the cytosol, and subsequently convert pyruvate to carbon dioxide in the mitochondria for oxidative phosphorylation; under anaerobic conditions, conversion of pyruvate to lactic acid is favoured with relatively low amounts of pyruvate being diverted to the mitochondria. In contrast, cancer cells primarily derive energy from glucose via glycolysis to lactic acid, even under highly aerobic conditions, a property first observed by Otto Warburg 1. This ‘aerobic glycolysis’, also known as the ‘Warburg effect’ 2, is much less energy-efficient than the oxidative phosphorylation pathway 3. It is usually accompanied by marked increases in glucose uptake and consumption 4, a phenomenon commonly exploited in tumour imaging using 18-fluorodeoxyglucose positron electron tomography 5. In addition, cancer cells derive energy from up-regulated non-glucose-dependent pathways, such as increased glutaminolysis under aerobic conditions 2,6,7. Aerobic glycolysis and increased glutaminolysis are collectively regarded as ‘reprogrammed energy metabolism’, a phenomenon now generally accepted as a key metabolic hallmark of cancer 3,8,9. Both pathways lead to the production and secretion of lactic acid, markedly contributing to metabolic acidosis commonly found in solid cancers 2,6,7. Extracellular pH values in tumours can be as low as pH 6.0–6.5, in contrast to pH 7.5 present in normal cell environments 10–12.
https://www.ncbi.nlm.nih.gov/pmc/articl ... rt=classic
Go to:
Introduction
Deregulated proliferation of cancer cells is generally associated with altered energy metabolism. Glucose is a primary source of energy. Under aerobic conditions, normal cells metabolize glucose to pyruvate via glycolysis in the cytosol, and subsequently convert pyruvate to carbon dioxide in the mitochondria for oxidative phosphorylation; under anaerobic conditions, conversion of pyruvate to lactic acid is favoured with relatively low amounts of pyruvate being diverted to the mitochondria. In contrast, cancer cells primarily derive energy from glucose via glycolysis to lactic acid, even under highly aerobic conditions, a property first observed by Otto Warburg 1. This ‘aerobic glycolysis’, also known as the ‘Warburg effect’ 2, is much less energy-efficient than the oxidative phosphorylation pathway 3. It is usually accompanied by marked increases in glucose uptake and consumption 4, a phenomenon commonly exploited in tumour imaging using 18-fluorodeoxyglucose positron electron tomography 5. In addition, cancer cells derive energy from up-regulated non-glucose-dependent pathways, such as increased glutaminolysis under aerobic conditions 2,6,7. Aerobic glycolysis and increased glutaminolysis are collectively regarded as ‘reprogrammed energy metabolism’, a phenomenon now generally accepted as a key metabolic hallmark of cancer 3,8,9. Both pathways lead to the production and secretion of lactic acid, markedly contributing to metabolic acidosis commonly found in solid cancers 2,6,7. Extracellular pH values in tumours can be as low as pH 6.0–6.5, in contrast to pH 7.5 present in normal cell environments 10–12.
https://www.ncbi.nlm.nih.gov/pmc/articl ... rt=classic
https://jeccr.biomedcentral.com/article ... 20-01815-4Low extracellular pH (pHe) has also been shown to modulate tumor cell function. Several studies revealed that acidosis increased the local invasiveness of tumors and the metastatic spread of tumors in vivo [5, 6]. Tumor cells kept at low pH led to a significant higher number of lung metastases [7, 8].
Debbie
Re: Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Cont..
Why do cancers opt for altered energy metabolism?
The preference of cancers for aerobic glycolysis over the more energy-efficient oxidative phosphorylation pathway has been a subject of major interest since it was first observed in the 1920s 13. Many researchers have speculated on the advantages of aerobic glycolysis for cancers, but the causal relationship of this altered metabolism to cancer development is still unclear 3. Otto Warburg speculated that the metabolic alteration was necessitated by a mitochondrial defect in the cancer cells impairing normal oxidative phosphorylation 14. However, further studies have since shown that mitochondrial defects only partially account for the phenomenon. Although certain malignancies indeed harbour mitochondrial defects that make aerobic glycolysis a necessity 15, the majority of cancers are able to revert back to oxidative phosphorylation when lactic acid generation is inhibited 16.
Tumours commonly encounter fluctuating oxygen levels, periodically alternating between normoxic and hypoxic conditions 17. This raises the distinct possibility that aerobic glycolysis has arisen as an adaptation to hypoxic conditions. Use of oxygen-independent glycolysis would confer a proliferative advantage to cancer cells, making them less susceptible to hypoxic stress during episodes of spontaneous hypoxia 13, even if that would come at a cost of energy inefficiency during times of adequate oxygenation. This theory has been extended by suggesting cooperation between normoxic and hypoxic cancer cells within a tumour aimed at maximizing energy efficiency 2. It is proposed that the hypoxic cells are the primary utilizers of glucose, converting it via glycolysis to lactate. Furthermore, lactate secreted by the hypoxic cells would be taken up by normoxic cancer cells and then converted back to pyruvate for oxidation via the citric acid cycle 2,18. This theory, however, does not fully account for the preference of cancers for glycolysis under conditions of abundant oxygenation.
Components of glucose uptake and glycolytic pathways can be up-regulated by oncogenes such as Ras, Akt, and Myc 3. This observation is particularly intriguing, since oncogenic activation is often thought of as an early event in cancer development and progression, and aerobic glycolysis may hence actually predate the onset of hypoxic selection and have a functional role in the early stages of the disease. Other proposals have been put forward, primarily focusing on the mechanisms by which aerobic glycolysis could confer a proliferative advantage to cancer cells 3,13,19. As this pathway is much less efficient than oxidative phosphorylation in generating ATP, ie by approximately 18-fold, the question is raised as to how a reduced supply of ATP can lead to improved proliferative potential. One proposal states that the advantage of aerobic glycolysis lies in incomplete utilization of glucose, allowing upstream intermediates to be redirected for biosynthesis, thereby providing cancer cells with an abundance of building blocks for synthesis of essential cellular components such as macromolecules 19. While such an explanation appears sound, there is still controversy regarding how common such a mechanism is in normal proliferating cells 20. Another proposal states that acidification of the micro-environment by lactic acid, resulting from up-regulation of glycolysis, can be expected to lead to the development of acid-resistant phenotypes exhibiting a powerful, selective growth advantage that promotes unconstrained proliferation and tissue invasion of cancer cells 13.
Increased glutaminolysis would also have several advantages for cancers: glutamine is the most abundant amino acid in plasma and forms an important additional energy source in tumour cells, especially when glycolytic energy production is low; increased availability of the degradation products of glutamine, ie glutamate and aspartate, as precursors for nucleic acid and serine synthesis; and the insensitivity of glutaminolysis to high concentrations of reactive oxygen species 2,6,7.
Of major interest is the finding that the reprogrammed energy metabolism plays an important role in cancer growth-promoting angiogenesis. Angiogenic endothelial cells, like tumour cells, are largely dependent on aerobic glycolysis and increased glutaminolysis for energy. The preference for these pathways allows the development of neovasculature from endothelial, tumour-blood-vessel-lining cells under hypoxic conditions. In addition, lactic acid generated by the pathways has been found to markedly promote angiogenesis by increasing the production of interleukin-8/CXCL8, driving the autocrine stimulation of endothelial cell proliferation and maturation of new blood vessels 21,22.
Manipulating extracellular tumour pH: an effective target for cancer therapy
https://pubs.rsc.org/en/content/article ... c8ra02095g
**Review Molecular and metabolic features of oncocytomas: Seeking the blueprints of indolent cancers☆
** https://www.sciencedirect.com/science/a ... 2817300105
Why do cancers opt for altered energy metabolism?
The preference of cancers for aerobic glycolysis over the more energy-efficient oxidative phosphorylation pathway has been a subject of major interest since it was first observed in the 1920s 13. Many researchers have speculated on the advantages of aerobic glycolysis for cancers, but the causal relationship of this altered metabolism to cancer development is still unclear 3. Otto Warburg speculated that the metabolic alteration was necessitated by a mitochondrial defect in the cancer cells impairing normal oxidative phosphorylation 14. However, further studies have since shown that mitochondrial defects only partially account for the phenomenon. Although certain malignancies indeed harbour mitochondrial defects that make aerobic glycolysis a necessity 15, the majority of cancers are able to revert back to oxidative phosphorylation when lactic acid generation is inhibited 16.
Tumours commonly encounter fluctuating oxygen levels, periodically alternating between normoxic and hypoxic conditions 17. This raises the distinct possibility that aerobic glycolysis has arisen as an adaptation to hypoxic conditions. Use of oxygen-independent glycolysis would confer a proliferative advantage to cancer cells, making them less susceptible to hypoxic stress during episodes of spontaneous hypoxia 13, even if that would come at a cost of energy inefficiency during times of adequate oxygenation. This theory has been extended by suggesting cooperation between normoxic and hypoxic cancer cells within a tumour aimed at maximizing energy efficiency 2. It is proposed that the hypoxic cells are the primary utilizers of glucose, converting it via glycolysis to lactate. Furthermore, lactate secreted by the hypoxic cells would be taken up by normoxic cancer cells and then converted back to pyruvate for oxidation via the citric acid cycle 2,18. This theory, however, does not fully account for the preference of cancers for glycolysis under conditions of abundant oxygenation.
Components of glucose uptake and glycolytic pathways can be up-regulated by oncogenes such as Ras, Akt, and Myc 3. This observation is particularly intriguing, since oncogenic activation is often thought of as an early event in cancer development and progression, and aerobic glycolysis may hence actually predate the onset of hypoxic selection and have a functional role in the early stages of the disease. Other proposals have been put forward, primarily focusing on the mechanisms by which aerobic glycolysis could confer a proliferative advantage to cancer cells 3,13,19. As this pathway is much less efficient than oxidative phosphorylation in generating ATP, ie by approximately 18-fold, the question is raised as to how a reduced supply of ATP can lead to improved proliferative potential. One proposal states that the advantage of aerobic glycolysis lies in incomplete utilization of glucose, allowing upstream intermediates to be redirected for biosynthesis, thereby providing cancer cells with an abundance of building blocks for synthesis of essential cellular components such as macromolecules 19. While such an explanation appears sound, there is still controversy regarding how common such a mechanism is in normal proliferating cells 20. Another proposal states that acidification of the micro-environment by lactic acid, resulting from up-regulation of glycolysis, can be expected to lead to the development of acid-resistant phenotypes exhibiting a powerful, selective growth advantage that promotes unconstrained proliferation and tissue invasion of cancer cells 13.
Increased glutaminolysis would also have several advantages for cancers: glutamine is the most abundant amino acid in plasma and forms an important additional energy source in tumour cells, especially when glycolytic energy production is low; increased availability of the degradation products of glutamine, ie glutamate and aspartate, as precursors for nucleic acid and serine synthesis; and the insensitivity of glutaminolysis to high concentrations of reactive oxygen species 2,6,7.
Of major interest is the finding that the reprogrammed energy metabolism plays an important role in cancer growth-promoting angiogenesis. Angiogenic endothelial cells, like tumour cells, are largely dependent on aerobic glycolysis and increased glutaminolysis for energy. The preference for these pathways allows the development of neovasculature from endothelial, tumour-blood-vessel-lining cells under hypoxic conditions. In addition, lactic acid generated by the pathways has been found to markedly promote angiogenesis by increasing the production of interleukin-8/CXCL8, driving the autocrine stimulation of endothelial cell proliferation and maturation of new blood vessels 21,22.
The extremely high rate of glycolysis may break the capacity of proton pumps in tumour cells, which means that tumour cells cannot timely transport acidic metabolites (such as H+, H2CO3, lactate etc.) outside and hence decreases pHi.Jun 19, 2018
Manipulating extracellular tumour pH: an effective target for cancer therapy
https://pubs.rsc.org/en/content/article ... c8ra02095g
**Review Molecular and metabolic features of oncocytomas: Seeking the blueprints of indolent cancers☆
** https://www.sciencedirect.com/science/a ... 2817300105
Debbie