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

Yamagata, Masayo; Hasuda, Katsumi; Stamato, Thomas D.; Tannock, I. F.

doi:10.1038/bjc.1998.289

Cited by 187 publications

(133 citation statements)

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“…Increased activity of LDH, being linked with intratumoral hypoxia and acidity (Yamagata et al, 1998), should be related with aggressive tumour features as shown in a previous study on CA9 in NSCLC . As HIFas regulate glycolysis and LDH transcription, we further assessed the HIF association with LDH expression.…”

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confidence: 52%

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

et al. 2003

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Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1a and 2a, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1a (or HIF2a) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.

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confidence: 52%

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

et al. 2003

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“…Acidification of the extracellular matrix in the tumor is therefore expected either as a result of carbonic acid or lactate release from cancer cells. (28,29) The pH in the tumor vein was significantly lower than that of the tumor artery. All nine cases with CA9 and/or LDH-5 overexpression had very low pH values in the tumor vein, supporting the concept that these enzymes are responsible for the acidic conditions prevailing in the tumor ambient.…”

Section: Discussionmentioning

confidence: 95%

Oxygen and glucose consumption in gastrointestinal adenocarcinomas: Correlation with markers of hypoxia, acidity and anaerobic glycolysis

Koukourakis¹,

Pitiakoudis²,

Giatromanolaki

et al. 2006

Cancer Science

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This study gives an insight into tumor metabolic activity by investigating oxygen and glucose content, together with their metabolic products carbon dioxide and acids-pH, in the arterial and venous blood of a tumor. Nineteen patients with gastrointestinal adenocarcinomas undergoing surgery were studied. Biochemical analysis showed that in a large subgroup of tumors, oxygen consumption was reduced while that of glucose was increased in malignant, as compared to normal tissues; these features were more evident in tumors overexpressing lactate dehydrogenase ( During the past 15 years important developments in the biology of hypoxia brought forward a group of key transcription factors, namely the hypoxia inducible factors (HIFs) that, being upregulated by hypoxia, control the expression of a variety of genes related to glycolysis and angiogenesis.(2) Apart from hypoxia, however, the HIF pathway is also under oncogenic regulation. Activation of a single oncogene, Akt, is sufficient to stimulate aerobic glycolysis in tumors (3) while Akt is known to activate, under hypoxic conditions, HIF1α as well (4) and this in turn upregulates enzymes involved in anaerobic glycolysis and glucose intrusion. Moreover, the epidermal growth factor pathway stimulates the increased transcription of HIF mRNA. Among others, HIF controls important genes involved in glycolysis and pH regulation, such as: (i) the expression of lactate dehydrogenase A subunit and, hence, the LDH-5 cellular content that promotes the metabolic shift of pyruvate transformation to lactate for energy acquisition; (6) (ii) the expression of glucose transporters (GLUT) membrane pumps involved in glucose absorption, which is used as a fuel; (7) and (iii) the expression of carbonic anhydrase 9 (CA9) that, by regulating the hydration of carbon dioxide to carbonic acid, plays an important role in the acidification of a tumor environment. (8)

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“…This increase in the intracellular pH is concomitant with an increment of DNA synthesis (8,13,14), cell cycle progression (15)(16)(17), serum and substrate-independent growth (8) and the in vivo growth of the tumor (8,18) and all these phenomena trigger a pathological and disorganized increase in density and cell number. However, tumors are able to create an acidic environment even in conditions of reduced production of lactate, suggesting that the aerobic metabolism is not the major mechanism responsible for the development of an acidic microenvironment within solid tumors such as oral squamous cell carcinoma (OSCC) (19,20). On the one hand, the same favourable conditions are maintained for the tumor cells, and on the other hand the selection of highly malignant cancer cells (which can survive in a hostile environment) is facilitated (21).…”

Section: Introductionmentioning

confidence: 99%

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

Pérez-Sayáns¹

2009

Int J Oncol

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Abstract. Acidity is one of the main characteristics of OSCC (oral squamous cell carcinoma) as a solid tumor. The VATPase is the primary regulator of the tumor microenvironment, by means of proton extrusion to the extracellular medium. The decrease in extracellular pH confers the cells a resistant, highly invasive and metastatic phenotype. However, the acid medium confers an optimum pH to the degradative enzymes (such as proteases and MMPs) for their proper functioning. The C subunit (ATP6V1C) of V1 intra-membrane domain of the V-ATPase, is primarily responsible for its enzymatic function, through the control of a reversible dissociation of V0 and V1 domains. In this review, we describe the importance of V-ATPases in the control of tumor microenvironment, the potential strategies as protein targeting to improve the effectiveness of drug treatment and the role of the C subunit as the primarily responsible of the enzymatic control. The inhibition of the V-ATPase activity through PPIs (proton inhibitors) seems to reduce the destructive and metastatic capacity in tumors, such as hepatocellular carcinoma. Nevertheless, none of these inhibitors was proven to be useful in OSCC; therefore, it is highly important to carry out further studies in order to develop specific inhibitors of the C subunit, to control the devastating effects of OSCC. IntroductionThe main characteristics of the solid tumors (such as oral cancer) are the acidity and hypoxia, phenomena that result from the progression of metastatic cancer (1), the sensitivity to chemotherapeutic agents (2) and proliferation (3). In fact, a mechanism of resistance to cytotoxic drugs is the alteration of the pH gradient between the extracellular environment and cell cytoplasm (4).The cytosolic pH seems to be strictly regulated by four mechanisms: the family of sodium-proton exchangers (NHE), the family of bicarbonate transporters (BCT), the family of monocarboxylate transporters (MCT) and the proton pumps (ATPase) (5,6) ( Fig. 1). The lactate production has been commonly seen as the first acidification mechanism of the microenvironment (7). The lactate accumulation results in the activation of the aerobic glycolytic metabolism (8) which increases the amount of cellular lactate that is transported outside the cell through the H + /lactate co-transporter (MCT) (9). The increase in aerobic glycolysis (8,10) provides to the tumor a metabolic environment characterized by low levels of serum, hypoxia and an acid extracellular pH. This microenvironment increases the invasive ability of the tumor and the expression of growth and angiogenic factors/receivers (11). All this is correlated to an increment of the intracellular pH, an aggravation of the initial development of the interstitial acid microenvironment and a reversed transmembrane pH gradient (11,12). This increase in the intracellular pH is concomitant with an increment of DNA synthesis (8,13,14), cell cycle progression (15-17), serum and substrate-independent growth (8) and the in vivo growth of the tumor (8,18) and ...

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

Cited by 187 publications

References 16 publications

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

Oxygen and glucose consumption in gastrointestinal adenocarcinomas: Correlation with markers of hypoxia, acidity and anaerobic glycolysis

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

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