Causes and consequences of tumour acidity and implications for treatment

Stubbs, Marion; McSheehy, Paul M.J.; Griffiths, John R.; Bashford, C. L.

doi:10.1016/s1357-4310(99)01615-9

Cited by 710 publications

(504 citation statements)

References 18 publications

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“…Several strategies for reducing the pH e of tumors are currently being evaluated to improve the efficacy of these treatments and it has been shown that tumor acidification with glucose and/or mitochondrial inhibitors may enhance the antitumor effects of heat, weakly acidic chemotherapeutic agents, and aminolevulinic acid-mediated photodynamic therapy (29,49,50). Our study suggests that treatment strategies involving deliberate tumor acidification should be avoided as acidic pH e may enhance the metastatic potential of tumor cells.…”

Section: Discussionmentioning

confidence: 80%

Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice

et al. 2006

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Extracellular pH (pH e ) is lower in many tumors than in the corresponding normal tissue. The significance of acidic pH e in the development of metastatic disease was investigated in the present work. Human melanoma cells (A-07, D-12, and T-22) were cultured in vitro at pH e 6.8 or 7.4 (control) before being inoculated into the tail vein of BALB/c nu/nu mice for formation of experimental pulmonary metastases. Cell invasiveness was studied in vitro by using Matrigel invasion chambers and angiogenesis was studied in vivo by using an intradermal assay. Protein secretion was measured by ELISA and immunocapture assays. Cells cultured at acidic pH e showed increased secretion of proteinases and proangiogenic factors, enhanced invasive and angiogenic potential, and enhanced potential to develop experimental metastases. Acidity-induced metastasis was inhibited by treatment with the general matrix metalloproteinase (MMP) inhibitor GM6001, the general cysteine proteinase inhibitor E-64, or blocking antibody against vascular endothelial growth factor-A (VEGF-A) or interleukin-8 (IL-8). Our study indicates that acidic pH e promotes experimental pulmonary metastasis in A-07, D-12, and T-22 human melanoma cells by a common mechanism involving acidity-induced up-regulation of the proteolytic enzymes MMP-2, MMP-9, cathepsin B, and cathepsin L and acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8. One consequence of this observation is that treatment strategies involving deliberate tumor acidification to improve the efficacy of chemotherapy, photodynamic therapy, and hyperthermia should be avoided. Moreover, the possibility that the pH e of the primary tumor may be an important prognostic parameter for melanoma patients merits clinical investigation. (Cancer Res 2006; 66(13): 6699-707)

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Section: Discussionmentioning

confidence: 80%

Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice

et al. 2006

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“…Elevated LDH serum levels are also linked with resistance to and high rate of relapse after chemotherapy in lymphomas (Kondo et al, 2001;Wilder et al, 2001), breast and ovarian cancer (Ryberg et al, 2001;Yuce et al, 2001), as well as in small cell lung cancer (Argiris et al, 2001;Tas et al, 2001b). The ominous prognostic significance of serum LDH in malignancy could be attributed to several reasons: (i) increased LDH activity results in lactic acid production and acidification of the extracellular water space, which is a very common feature in cancer (Vaupel et al, 1989;Stubbs et al, 2000). Acidic extracellular pH has been shown to activate gelatinase activity and production of cathepsin D, which contribute to an increased cancer cell invasive ability (Rozhin et al, 1994;Martinez-Zagulian et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis of LDH-5 together with CA9 expression revealed that overexpression of either of the enzymes is independently linked with poor survival. Acidification of the tumour environment expected in both conditions explains in part such an aggressive tumour behaviour (Rozhin et al, 1994;Martinez-Zagulian et al, 1996;Stubbs et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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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“…A difference in location and area of positive staining (Wykoff et al, 2000;Olive et al, 2001 and also the present study) supports this explanation. von Hippel-Lindau mutations, which result in an upregulation of HIF-1a (Cockman et al, 2000) and downstream components like CA IX (Ashida et al, 2002), and the relationship between CA IX expression and acidic pH found in tumours (Stubbs et al, 2000) could potentially contribute to the published differences.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

et al. 2004

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This study aimed to evaluate tumour hypoxia by comparing [ 18 F]Fluoromisonidazole uptake measured using positron emission tomography ([ 18 F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.9 and 7.3 cm 3 . Hypoxic volumes were defined using a 3D region of interest on 2 h postinjection [ 18 F]FMISO-PET images, applying different thresholds (1.2 -3.0). Monoclonal antibodies to pimonidazole (PIMO) and carbonic anhydrase IX (CA IX), exogenous and endogenous markers of hypoxia, respectively, were used for IHC staining. Marker-positive fractions were microscopically measured for each tumour, and hypoxic volumes were calculated. A heterogeneous distribution of hypoxia was observed both with histology and

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Causes and consequences of tumour acidity and implications for treatment

Cited by 710 publications

References 18 publications

Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice

Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice

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

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

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