The relationship between extracellular lactate and tumour pH in a murine tumour model of ischaemia-reperfusion

Parkins, C. S.; Stratford, Michael R.L.; Dennis, Madeleine F.; Stubbs, Marion; Chaplin, David J.

doi:10.1038/bjc.1997.53

Cited by 42 publications

(30 citation statements)

References 15 publications

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“…The presence of additional factors that contribute to low pH in avascular regions of tumours is suggested by the recent results of Parkins et al (1997) who found a decline in extracellular pH after vascular occlusion of an experimental tumour. The initial decline in pH correlated with lactate production (under conditions in which carbon dioxide production was unlikely to occur), but the subsequent decline in pH was independent of lactate concentration.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies of tumours grown from variant cells that are glycolysis deficient (because of decreased glucose uptake and phosphoglucose isomerase deficiency) and that produce negligible amounts of lactic acid showed that these tumours also had an acidic microenvironment (Newell et al, 1993). Values of pHe and lactate concentration have also been studied during periods of vascular clamping and reperfusion of an experimental tumour (Parkins et al, 1997). The initial fall in the pHe in the avascular tumour correlated with lactate production, but the subsequent continued fall in pHe did not.…”

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confidence: 99%

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The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase

Yamagata

Hasuda²,

Stamato³

et al. 1998

Br J Cancer

188

119

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Summary Solid tumours develop an acidic extracellular environment with high concentration of lactic acid, and lactic acid produced by glycolysis has been assumed to be the major cause of tumour acidity. Experiments using lactate dehydrogenase (LDH)-deficient rastransfected Chinese hamster ovarian cells have been undertaken to address directly the hypothesis that lactic acid production is responsible for tumour acidification. The variant cells produce negligible quantities of lactic acid and consume minimal amounts of glucose compared with parental cells. Lactate-producing parental cells acidified lightly-buffered medium but variant cells did not. Tumours derived from parental and variant cells implanted into nude mice were found to have mean values of extracellular pH (pHe) of 7.03 ± 0.03 and 7.03 ± 0.05, respectively, both of which were significantly lower than that of normal muscle (pHe = 7.43 ± 0.03; P < 0.001). Lactic acid concentration in variant tumours (450 ± 90 ,ug g-1 wet weight) was much lower than that in parental tumours (1880 ± 140 gg/g-1) and similar to that in serum (400 ± 35 ,ug/g-1).These data show discordance between mean levels of pHe and lactate content in tumours; the results support those of Newell et al (1993) and suggest that the production of lactic acid via glycolysis causes acidification of culture medium, but is not the only mechanism, and is probably not the major mechanism responsible for the development of an acidic environment within solid tumours.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase

Yamagata

Hasuda²,

Stamato³

et al. 1998

Br J Cancer

188

119

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“…However, acidic pH and lactate have also been associated with enhanced metastatic tumour progression both in experimental models (Schlappack et al, 1991;Jang and Hill, 1997) and clinically (Parkins et al, 1997;Walenta et al, 2000;Brizel et al, 2001). We wanted to determine whether the glucose þ MIBG-based tumour-acidifying treatment, used to improve efficacy of cancer therapies, would affect the spontaneous metastatic potential of two murine tumour cell lines, KHT-C and B16F1, previously shown to increase their experimental metastatic potential following acidic culture conditions (Schlappack et al, 1991;Jang and Hill, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In separate studies, the ability of murine B16F1 melanoma and KHT fibrosarcoma cells to form lung metastases after intravenous injection was shown to increase significantly after exposure to acidic conditions in culture (Schlappack et al, 1991;Jang and Hill, 1997). In humans, elevated tumour lactate concentrations, which generally correlate with reduced pH e , have been found to predict the likelihood of metastatic disease in head and neck and cervical carcinomas (Parkins et al, 1997;Walenta et al, 2000;Brizel et al, 2001). In addition to upregulated expression of invasion-enhancing proteins such as gelatinases, this increase in metastases may be related to acidosis-induced elevation of interleukin-8 (IL-8) and/or vascular endothelial growth factor (VEGF), factors known for their angiogenic potential (Shi et al, 1999;Xu and Fidler, 2000;Fukumura et al, 2001;Shi et al, 2001).…”

mentioning

confidence: 99%

Effects of tumour acidification with glucose+MIBG on the spontaneous metastatic potential of two murine cell lines

Kalliomäki

Hill

2004

Br J Cancer

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In addition to hypoxia, acidic extracellular pH (pH e ) is recognised as one of the microenvironmental characteristics of solid tumours. A number of studies have examined ways to increase tumour acidity in order to improve tumour-specific targeting of certain drugs and the effectiveness of hyperthermia. However, previous data have shown that exposure of murine tumour cells to acid conditions in culture can enhance their metastatic potential when injected subsequently into mice, raising the concern that deliberate tumour acidification might increase the probability of metastasis. In this study, we examined the effects of in vivo tumour acidification and hypoxia on the spontaneous metastatic potential of the murine KHT-C fibrosarcoma and B16F1 melanoma cell lines. A tumourspecific increase in extracellular acidity, demonstrated by measurements with pH electrodes, was achieved by daily intraperitoneal injections of meta-iodo-benzylguanidine (MIBG) and/or glucose. This method of tumour acidification during tumour growth did not significantly enhance the spontaneous metastatic potential of the two murine cell lines.

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“…It is well known that lactate secretion by tumor cells is one of the important causes of acidification of the immediate microenvironment of primary tumors [70]. However, since primary mouse tumors derived from cells lacking lactate dehydrogenase are also capable of acidifying the tumor microenvironment [71], other mechanism(s) must be involved in regulating extracellular acidification during tumor progression.…”

Section: Ha/cd44mentioning

confidence: 99%

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Bourguignon

2008

Seminars in Cancer Biology

271

279

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Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. In cancer patients HA concentrations are usually higher in malignant tumors than in corresponding benign or normal tissues, and in some tumor types the level of HA is predictive of malignancy. HA is often bound to CD44 isoforms which are ubiquitous, abundant, and functionally important cell surface receptors. This article reviews the current evidence for HA/CD44-mediated activation of the ankyrin-based cytoskeleton and RhoGTPase signaling during tumor progression. A special focus is placed on the role of HA-mediated CD44 interaction with unique downstream effectors (e.g., the cytoskeletal protein, ankyrin and/or various GTPases (e.g., RhoA, Rac1 and Cdc42)) in coordinating intracellular signaling pathways (e.g., Ca 2+ mobilization, Rho signaling, PI3 kinase-AKT activation, NHE1-mediated cellular acidification, transcriptional upregulation and cytoskeletal function) and generating the concomitant onset of tumor cell activities (e.g., tumor cell adhesion, growth, survival, migration and invasion) and tumor progression. I believe this information will provide valuable new insights into poorly understood aspects of solid tumor malignancy. Furthermore, the new knowledge concerning HA/CD44-mediated oncogenic signaling events will have potentially important clinical utility, and could establish CD44 and its associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential. It could also serve as ground work for the future development of new drug targets to inhibit HA/ CD44-mediated tumor metastasis and cancer progression.

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The relationship between extracellular lactate and tumour pH in a murine tumour model of ischaemia-reperfusion

Cited by 42 publications

References 15 publications

The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase

The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase

Effects of tumour acidification with glucose+MIBG on the spontaneous metastatic potential of two murine cell lines

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

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