pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth.
Signalling via growth factors, oncogenes and environmental stresses such as hypoxia, promotes the up-regulation of glycolysis, intracellular pH (pHi) and vascular endothelial growth factor (VEGF) via cooperative mechanisms. Somatic cell genetics was applied to a fibroblastic cell line (CCOL39) to disrupt either aerobic glycolysis, respiration, or a major pHi-regulating system, the Na-H exchanger (NHE1). We obtained stable mutants impaired either in phosphoglucose isomerase (pgi-), which produce virtually no lactic acid, or in respiration (res-), which over secrete lactic acid (three- to fourfold the wild-type rate). These mutations, which allowed us to analyse the incidence of lactic acid production on tumour development in nude mice, were analysed alone, or in combination, with the mutation nhe1- to evaluate in vivo the role of NHE1 on pHi control and cell proliferation. Ras-transformed pgi- cells (not forming lactic acid) form tumours like wild type transformed cells (100% incidence). The disruption of NHE1 however, strongly reduced tumour incidence to about 20%. In cells bearing both mutations, nhe1-, res-, and which therefore over-produce lactic acid, the situation is even more dramatic (0% incidence). In sharp contrast, association of nhe1- with pgi- restored 100% tumour incidence. We conclude that over-production of lactic acid is detrimental for tumour development and that NHE1, by controlling pHi, plays a key role in cell survival/proliferation and tumour growth. Finally we summarize our current knowledge on the signalling mechanisms leading to VEGF expression, another key component of tumour growth via neo-vascularization.
Pouysségur
J
J
Institute of Signalling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, Nice, France.
Franchi
A
A
Pagès
G
G
D000332:Aerobiosis; D000818:Animals; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000502:physiology*; D006019:Glycolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008222:Lymphokines / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors