Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism.
OBJECTIVE
Low extracellular pH is a hallmark of solid tumors. It has long been thought that this acidity is mainly attributable to the production of lactic acid. In this study, we tested the hypothesis that lactate is not the only source of acidification in solid tumors and explored the potential mechanisms underlying these often-observed high rates of acid production.


METHODS
We compared the metabolic profiles of glycolysis-impaired (phosphoglucose isomerase-deficient) and parental cells in both in vitro and two in vivo models (dorsal skinfold chamber and Gullino chamber).


RESULTS
We demonstrated that CO(2), in addition to lactic acid, was a significant source of acidity in tumors. We also found evidence supporting the hypothesis that tumor cells rely on glutaminolysis for energy production and that the pentose phosphate pathway is highly active within tumor cells. Our results also suggest that the tricarboxylic acid cycle is saturable and that different metabolic pathways are activated to provide for energy production and biosynthesis.


CONCLUSIONS
These results are consistent with the paradigm that tumor metabolism is determined mainly by substrate availability and not by the metabolic demand of tumor cells per se. In particular, it appears that the local glucose and oxygen availabilities each independently affect tumor acidity. These findings have significant implications for cancer treatment.
Helmlinger
Gabriel
G
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Sckell
Axel
A
Dellian
Marc
M
Forbes
Neil S
NS
Jain
Rakesh K
RK
D000143:Acids / Q000378:metabolism; D000746:Anemia, Hemolytic, Congenital Nonspherocytic; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D006224:Cricetinae; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D000143:Acids; D019344:Lactic Acid; D005947:Glucose