Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells

Schlappack, OK; Zimmermann, Astrid; Hill, Richard P.

doi:10.1038/bjc.1991.378

Cited by 153 publications

(98 citation statements)

References 45 publications

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“…Other factors, such as pH and low glucose may play a role (Schlappack et al, 1991). Also, hypoxia per se does not necessarily imply metastatic ability.…”

Section: Discussionmentioning

confidence: 99%

Relationship of hypoxia to metastatic ability in rodent tumours

2001

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SummaryThe relationship between tumour oxygenation in vivo and metastatic potential was investigated in 2 rodent tumour models, KHT-C fibrosarcoma and SCC-VII squamous cell carcinoma. The oxygen status in these rodent tumours transplanted intramuscularly in syngeneic mice was measured using the Eppendorf pO 2 Histograph. The results indicate a considerable heterogeneity in oxygenation between individual tumours within each tumour cell line. At different tumour sizes, animals were killed and lung lobes were examined for macroscopic and microscopic lung metastases. In the KHT-C tumours, a significant increase in early pulmonary metastasis formation was observed in mice with hypoxic primary tumours. Hypoxic SCC-VII tumours did not give rise to enhanced lung metastasis formation despite oxygenation in a range similar to the KHT-C tumours. However, the overall metastasis incidence in the SCC-VII model was very low. The results obtained in the KHT-C model, which show that hypoxic tumours are more likely to metastasize, are in agreement with recent clinical data suggesting that a hypoxic environment might be implicated in metastatic ability of human tumours.

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“…Other factors, such as pH and low glucose may play a role (Schlappack et al, 1991). Also, hypoxia per se does not necessarily imply metastatic ability.…”

Section: Discussionmentioning

confidence: 99%

Relationship of hypoxia to metastatic ability in rodent tumours

2001

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“…However, it has been shown previously that exposure to acidic pH e in vitro may enhance the lung colonization potential of rodent tumor cells (27,28). In these experiments, KHT and B16 cells were exposed to pH e 6.5 for 48 hours and then allowed to recover at pH e 7.4 for 0, 24, or 48 hours before being inoculated i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Rodent tumor cells exposed to acidic pH e in vitro were found to show enhanced lung colonization potential when inoculated i.v. in syngeneic host mice (27,28) whereas acidification of rodent tumors in vivo, obtained by administrating meta-iodo-benzylguanidine and/or glucose to the host mice, did not result in enhanced incidence of spontaneous lung metastases (29). Despite these conflicting observations, several studies have indicated that tumor cells exposed to acidic pH e in vitro may show increased expression of several genes known to promote invasive growth and metastasis, including genes encoding matrix degrading enzymes and proangiogenic factors (5,30).…”

Section: Introductionmentioning

confidence: 96%

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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“…However, cells in less extreme conditions of nutrient deprivation are likely to develop tolerance to the effect of PDT, due to GRP induction. These nutritionally deprived cells are known to have an increased metastatic potential (Schlappack et al, 1991), and may therefore serve as resistant foci for tumour progression. Unlike the problem of hypoxic inhibition of PDT (Mitchell et al, 1985;Wyld et al, 1998), there is a potential solution; infusions of glucose may elevate tumour glucose levels appreciably and therefore reduce the proportion of hypoglycaemic cells.…”

Section: Discussionmentioning

confidence: 99%

Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation

et al. 2002

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Photodynamic therapy is a cancer treatment based on the interaction of light, oxygen and a photosensitiser. Protoporphyrin. IX is an endogenous photosensitiser derived from the pro-drug aminolaevulinic acid. Tumours contain areas of hypoxia and hypoglycaemia. Tumour cells adapt to these conditions by stress protein induction which may induce resistance to cancer therapies. The effect of chronic hypoglycaemia on sensitivity to aminolaevulinic acid-induced photodynamic therapy in vitro was studied in MCF-7, human breast cancer cells. Following chronic exposure to 0, 1 or 25 mM, glucose, cells were treated with aminolaevulinic acid and the generation of intracellular protoporphyrin. IX measured by spectrofluorimetry. Aminolaevulinic acid-induced photodynamic therapy sensitivity was compared between cells following chronic exposure to 0, 1 or 25 mM glucose. Percentage cell survival was determined by clonogenic assay. Cells cultured in low glucose generated higher levels of protoporphyrin IX compared to standard glucose medium (0 mM glucose: 0.88610 75 ng cell 71 , 1 mM: 0.86610 75 ng cell 71 , 25 mM: 0.605610 75 ng cell 71 , P50.05). However, photodynamic therapy sensitivity was reduced in glucose deprived cells (0 mM glucose: 61% survival, 1 mM: 80.5% and 25 mM: 39.6%, P50.05). Chronic exposure to low glucose induces photodynamic therapy resistance despite increased intracellular concentrations of protoporphyrin IX and may reflect cellular adaptation to chronic glucose deprivation.

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Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells

Abstract: Summary Exposure to oxygen deprivation in vitro has been reported to cause drug resistance in CHO cells (Rice et al., 1986; PNAS 83, 5978) and enhancement of experimental metastatic (colonisation) ability of murine tumour cells (Young et al., 1988; PNAS 85, 9533

Cited by 153 publications

References 45 publications

Relationship of hypoxia to metastatic ability in rodent tumours

Relationship of hypoxia to metastatic ability in rodent tumours

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

Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation

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