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Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?

Choi SY, Collins CC, Gout PW, Wang Y - J. Pathol. (2013)

Bottom Line: 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.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.This paradigm shift can have major impact on therapeutic strategy development.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.

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Related in: MedlinePlus

A proposed model for the central, regulatory immunosuppressive role of cancer-generated lactic acid with both experimentally demonstrated (in black) and potential (in grey) consequences. The excess lactic acid produced by cancer cells through reprogrammed metabolism results in an acidified tumour micro-environment. This decrease in pH promotes multiple cancer processes, including angiogenesis, invasion, and metastasis. More importantly, the acidic tumour micro-environment also suppresses the anti-cancer immune response, particularly through decreased cytotoxic T-cell function, reduced dendritic cell maturation, and enhanced helper cell activities. This locally suppressed immunity then enables cancer cells to survive and serves as a basis for subsequent malignant progression. As such, cancer-generated lactic acid promotes tumour evasion of immune destruction and should be viewed as a critical immunosuppressive metabolite rather than a ‘waste product’.
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fig01: A proposed model for the central, regulatory immunosuppressive role of cancer-generated lactic acid with both experimentally demonstrated (in black) and potential (in grey) consequences. The excess lactic acid produced by cancer cells through reprogrammed metabolism results in an acidified tumour micro-environment. This decrease in pH promotes multiple cancer processes, including angiogenesis, invasion, and metastasis. More importantly, the acidic tumour micro-environment also suppresses the anti-cancer immune response, particularly through decreased cytotoxic T-cell function, reduced dendritic cell maturation, and enhanced helper cell activities. This locally suppressed immunity then enables cancer cells to survive and serves as a basis for subsequent malignant progression. As such, cancer-generated lactic acid promotes tumour evasion of immune destruction and should be viewed as a critical immunosuppressive metabolite rather than a ‘waste product’.

Mentions: The primary cause responsible for the acidic pH and pH-dependent T-cell function-suppressive effect in a tumour micro-environment has been identified as lactic acid 26–30. It has also been demonstrated that cancer-generated lactic acid and the resultant acidification of the micro-environment increase the expression of ARG1 in tumour-associated macrophages, characteristic of the M2 helper phenotype 31. Furthermore, another study showed that under physiological or slightly alkaline conditions, glycolysis was selectively up-regulated by neuroblastoma cells, whereas oxidative phosphorylation was preferred by the cells when the extracellular pH was acidic; these effects were independent of changes in oxygen concentration or glucose supply 32. Thus, aerobic glycolysis can serve as a negative feedback loop that adjusts the pericellular pH in tumours towards a broad acidic range by increased lactic acid production and secretion. Taken together, the studies suggest that cancer cells can enhance their survival by inhibiting the anti-cancer immune response through actively maintaining a slightly acidic micro-environment. They apparently can do this by altering their energy metabolism to regulate their lactic acid production/secretion 32. The locally suppressed immunity then serves as a basis for the establishment of the malignancy and its subsequent malignant progression (see Figure 1).


Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?

Choi SY, Collins CC, Gout PW, Wang Y - J. Pathol. (2013)

A proposed model for the central, regulatory immunosuppressive role of cancer-generated lactic acid with both experimentally demonstrated (in black) and potential (in grey) consequences. The excess lactic acid produced by cancer cells through reprogrammed metabolism results in an acidified tumour micro-environment. This decrease in pH promotes multiple cancer processes, including angiogenesis, invasion, and metastasis. More importantly, the acidic tumour micro-environment also suppresses the anti-cancer immune response, particularly through decreased cytotoxic T-cell function, reduced dendritic cell maturation, and enhanced helper cell activities. This locally suppressed immunity then enables cancer cells to survive and serves as a basis for subsequent malignant progression. As such, cancer-generated lactic acid promotes tumour evasion of immune destruction and should be viewed as a critical immunosuppressive metabolite rather than a ‘waste product’.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757307&req=5

fig01: A proposed model for the central, regulatory immunosuppressive role of cancer-generated lactic acid with both experimentally demonstrated (in black) and potential (in grey) consequences. The excess lactic acid produced by cancer cells through reprogrammed metabolism results in an acidified tumour micro-environment. This decrease in pH promotes multiple cancer processes, including angiogenesis, invasion, and metastasis. More importantly, the acidic tumour micro-environment also suppresses the anti-cancer immune response, particularly through decreased cytotoxic T-cell function, reduced dendritic cell maturation, and enhanced helper cell activities. This locally suppressed immunity then enables cancer cells to survive and serves as a basis for subsequent malignant progression. As such, cancer-generated lactic acid promotes tumour evasion of immune destruction and should be viewed as a critical immunosuppressive metabolite rather than a ‘waste product’.
Mentions: The primary cause responsible for the acidic pH and pH-dependent T-cell function-suppressive effect in a tumour micro-environment has been identified as lactic acid 26–30. It has also been demonstrated that cancer-generated lactic acid and the resultant acidification of the micro-environment increase the expression of ARG1 in tumour-associated macrophages, characteristic of the M2 helper phenotype 31. Furthermore, another study showed that under physiological or slightly alkaline conditions, glycolysis was selectively up-regulated by neuroblastoma cells, whereas oxidative phosphorylation was preferred by the cells when the extracellular pH was acidic; these effects were independent of changes in oxygen concentration or glucose supply 32. Thus, aerobic glycolysis can serve as a negative feedback loop that adjusts the pericellular pH in tumours towards a broad acidic range by increased lactic acid production and secretion. Taken together, the studies suggest that cancer cells can enhance their survival by inhibiting the anti-cancer immune response through actively maintaining a slightly acidic micro-environment. They apparently can do this by altering their energy metabolism to regulate their lactic acid production/secretion 32. The locally suppressed immunity then serves as a basis for the establishment of the malignancy and its subsequent malignant progression (see Figure 1).

Bottom Line: 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.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.This paradigm shift can have major impact on therapeutic strategy development.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.

Show MeSH
Related in: MedlinePlus