Abstract
The extracellular pH (pHe) of solid tumours is often lower than in normal tissues, with median pH values of about 7.0 in tumours and 7.5 in normal tissue. Despite this more acidic tumour microenvironment, non-invasive measurements of intracellular pH (pHi) have shown that the pHi of solid tumours is neutral or slightly alkaline compared to normal tissue (pHi 7.0–7.4). This gives rise to a reversed cellular pH gradient between tumours and normal tissue, which has been implicated in many aspects of tumour progression. One such area is tumour invasion: the incubation of tumour cells at low pH has been shown to induce more aggressive invasive behaviour in vitro. In this paper the authors use mathematical models to investigate whether altered proteolytic activity at low pH is responsible for the stimulation of a more metastatic phenotype. The authors examined the effect of culture pH on the secretion and activity of two different classes of proteinases: the metalloproteinases (MMPs), and the cysteine proteinases (such as cathepsin B). The modelling suggests that changes in MMP activity at low pH do not have significant effects on invasive behaviour. However, the model predicts that the levels of active-cathepsin B are significantly altered by acidic pH. This result suggests a critical role for the cysteine proteinases in tumour progression.
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References
Warburg O. The metabolism of tumours. London: Constable 1930.
Tannock IF, Rotin D. Acid pH in tumours and its potential for therapeutic exploitation. Cancer Res 1989; 49: 4373–84.
Kallinowski F, Vaupel P, Runkel S. Glucose uptake, lactate release, ketone body turnover, metabolic micromilieu and pH distributions in human breast cancer xenografts in nude rats. Cancer Res 1988; 48: 7264–72.
Hoffman FA. Metabolic changes in malignancy. In Liotta LA (ed): Cancer Growth and Progression. Boston: Kluwer Academic Publishers 1989; 18–27.
Hawkins RA, Hoh C, Glaspy J et al. PET-FDG imaging in cancer. Appl Radiol 1992; 5: 51–7.
Stubbs M, Rodrigues L, Howe FA et al. Metabolic consequences of a reversed pH gradient in rat tumours. Cancer Res 1994; 54: 4011–16.
Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 1989; 49: 6449–65.
Boyer MJ, Tannock IF. Regulation of intracellular pH in tumor cell lines: Influence of microenvironmental conditions. Cancer Res 1992; 52: 4441–47.
Rotin D, Steele-Norwood D, Grinstein S, Tannock I. Requirement of the Na+/H+ exchanger for tumor growth. Cancer Res 1989; 49: 205–11.
Gerweck LE, Seetharaman K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 1996; 56: 1194–98.
Busa WB, 1986, Mechanisms and consequences of pH-mediated cell regulation. Ann Rev Physiol 1986; 48: 389–402.
Gillies RJ, Martinez-Zaguilan R, Peterson EP, Perona R. Role of intracellular pH in mammalian cell proliferation. Cell Physiol Biochem 1992; 2: 159–79.
Martinez-Zaguilan R, Seftor EA, Seftor REB et al. Acidic pH enhances the invasive behaviour of human melanoma cells. Clin Exp Metastasis 1996; 14: 176–86.
Liotta LA, Stetler-Stevenson WG. Principles of molecular cell biology of cancer: Cancer metastasis. Cancer: Principles & Practice of Oncology. Philadelphia: Lippincott Co. 1993; 134–49.
Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997; 89: 1260–70.
Kato Y, Nakayama Y, Umeda M, Miyazaki K. Induction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines. J Biol Chem 1992; 267: 11424–30.
Powell WC, Matrisian LM. Complex roles of matrix metalloproteinases in tumour progression. Curr Topics Microbiol Immunol 1996; 213: 1–21.
Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991; 5: 1245–54.
Duffy MJ. The role of proteolytic enzymes in cancer invasion and metstasis. Clin Exp Metstasis 1992; 10: 145–55.
Mignatti P, Rifkin DB. Membrane and matrix localization of proteinases in tumour invasion. Physiol Rev 1993; 73: 161–95.
Stetler-Stevenson WG, Liotta LA, Kleiner Jr DE. Extracellular matrix: Role of matrix metalloproteinases in tumour invasion and metstasis. FASEB J 1993; 7: 1434–41.
Sato H, Takino T, Okada Y et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994; 370: 61–5.
Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol 1995; 73: 728–35.
Ishihara A, Nabeshima K, Koono M. Partial purification and characterization of serum protease form tumor-bearing rats which cleaves type IV collagen. Invasion Metastasis 1986; 6: 225–45.
Rozhin J, Sameni M, Ziegler G, Sloane BF. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res 1994; 54: 6517–25.
Ward JP, King JR. Mathematical modelling of avascular tumour growth. IMA J Math Appl Med Biol 1997; 14: 39–69.
Adam JA. A mathematical model of tumour growth. 2. Effects of geometry and spatial non-uniformity on stability. Math. Biosci 1987; 86: 183–211.
Burton AC. Rate of growth of solid tumours as a problem of diffusion. Growth 1966; 30: 159–76.
Chaplain MAJ, Sleeman BD. A mathematical model for the production and secretion of tumour angiogenesis factor in tumours. IMA J Math Appl Med Biol 1990; 7: 93–108.
Byrne HM, Chaplain MAJ. Mathematical models for tumour angiogenesis – numerical simulations and non-linear wave solutions. Bull Math Biol 1995; 57: 461–86.
Sherratt JA, Nowak MA. Oncogenes, anti-oncogenes and the immune response to cancer: A mathematical model. Proc R Soc Lond 1992; B248: 261–71.
Grossman Z, Berke G. Tumour escape from immune elimination. J Theor Biol 1980; 51: 317–40.
Owen MR, Sherratt JA. Pattern formation and spatiotemporal irregularity in a model for macrophage-tumour interaction. J Theor Biol 1997; 189: 63–80.
Adam JA, Bellomo N. A Survey of Models for Tumour-Immune System Dynamics. Boston: Birkhauser 1997.
Perumpanani AJ, Sherratt JA, Norbury J, Byrne HM, 1996, Biological inferences from a mathematical model for malignant invasion. Invasion Metastasis 1996; 16: 209–21.
Gatenby RA, Gawlinski ET. A reaction-diffusion model of cancer invasion. Cancer Res 1996; 56: 5745–53.
Gatenby RA. Altered glucose metabolism and the invasive tumour phenotype: Insights provided through mathematical models (Review). Int J Oncol 1996; 8: 597–601.
Webb SD, Sherratt JA, Fish RG. Mathematical modelling of tumour acidity: regulation of intracellular pH. J Theor Biol 1999; 196: 237–50.
Hochachka PW, Mommsen TP. Protons and Anaerobiosis. Science 1983; 219: 1391–7.
Busa WB, Nucatelli R. Metabolic regulation via intracellular pH. Am J Physiol 1984; 246: R409–38.
Roos A, Boron WF. Intracellular pH. Physiol Rev 1981; 61: 296–434.
Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumours in vivo: High-resolution reveal a lack of correlation. Nature Med 1997; 3: 177–81.
Casciari JJ, Otirchos SV, Sutherland RM. Variations in tumour growth rates and metabolism with oxygen concentration, glucose concentration, and extracellular pH. J Cell Physiol 1992; 151: 386–94.
Vassalli J, Pepper S. Membrane proteases in focus. Nature 1994; 370: 14–5.
Davis GE, Martin BM. A latent MR 94,000 gelatin-degrading metalloproteinase induced during differentiation of HL-60 promyelocytic leukemia cells – a member of the collagenase family of enzymes. Cancer Res 1990; 50: 1113–20.
Kramer MD, Robinson P, Vlodavsky I et al. Characterization of an extracellular matrix-degrading protease derived from a highly metastatic tumour cell line. Eur J Cancer Clin Oncol 1985; 21: 307–16.
Turner GA. Increased release of tumour cells by collagenase at acid pH: a possible mechanism for metastasis. Experimentia 1979; 35: 1657–8.
Jang A, Hill RP. An examination of the effect of hypoxia acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. Clin Exp Metastasis 1997; 15: 469–83.
Briozzo P, Morisset M, Capony F et al. In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. Cancer Res 1988; 48: 3688–92.
Van der Stappen JWJ, Williams AC, Maciewicz RA, Paraskeva C. Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D. Int J Cancer 1996; 67: 547–54.
Chambers AF, Colella R, Denhardt DT, Wilson SM. Increased expression of cathepsins L and B and decreased activity of their inhibitors 407 in metastatic, ras-transformed NIH 3T3 cells. Mol Carcin 1992; 5: 238–45.
Qian F, Bajkowski AS, Steiner DF et al. Expression of five cathepsins in murine melanomas of varying metastatic potential and normal tissues. Cancer Res 1989; 49: 4870–5.
Sartorelli AC. Therpeutic attack of hypoxic cells of solid tumors: Presidential address. Cancer Res 1988; 48: 775–8.
Frelin C, Vigne P, Ladoux A, Lazdunski M. The regulation of the intracellular pH in cells from vertebrates. Eur J Biochem 1988; 174: 3–14.
Strazzabosco M, Boyer MJ. Regulation of intracellular pH in the hepatocyte. J Hepatol 1996; 24: 631–4.
Martinez-Zaguilan R, Lynch RM, Martinez GM, Gillies RJ. Vacuolartype H+-ATPases are functionally expressed in plasma membranes of human tumor-cells. Am J Physiol 1993; 265: C1015–29.
Vaananen HK, Karhukorpi EK, Sundquist K et al. Evidence for the presence of a proton pump of the vacuolar H+-ATPase type in the ruffled borders of osteoclasts. J Cell Biol 1990; 111: 1305–11.
Tapper H, Sundler R. Cytosolic pH regulation in mouse macrophages – proton extrusion by plasma-membrane-localized H+-ATPase. Biochem 1992; 281: 245–50.
Grinstein S, Rotin D, Mason MJ. Na+/H+ exchange and growth factor induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta 1989; 988: 73–97.
Madshus IH. Regulation of intracellular pH in eukaryotic cells. Biochem J 1988; 250: 1–8.
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Webb, S.D., Sherratt, J.A. & Fish, R.G. Alterations in proteolytic activity at low pH and its association with invasion: A theoretical model. Clin Exp Metastasis 17, 397–407 (1999). https://doi.org/10.1023/A:1006667303583
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DOI: https://doi.org/10.1023/A:1006667303583