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Related Experiment Videos

Modelling tumour acidity and invasion.

S D Webb1, J A Sherratt, R G Fish

  • 1Department of Mathematics, Heriot-Watt University, Edinburgh, UK.

Novartis Foundation Symposium
|December 1, 2001
PubMed
Summary
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Solid tumors exhibit a reversed pH gradient, promoting cancer cell invasion. Mathematical models suggest that altered activity and redistribution of proteinases, like cathepsin B, at low extracellular pH contribute to increased tumor metastasis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Mammalian cells tightly regulate intracellular pH (pHi).
  • Solid tumors often display a neutral or alkaline pHi despite an acidic extracellular environment (pHe), creating a reversed pH gradient compared to normal tissues.
  • This reversed pH gradient is linked to tumor progression, including enhanced invasion.

Purpose of the Study:

  • To investigate whether altered proteolytic activity at low extracellular pH contributes to the enhanced metastatic phenotype of tumor cells.
  • To examine the effect of culture pH on the secretion and activity of matrix metalloproteinases (MMPs) and cysteine proteinases (e.g., cathepsin B).

Main Methods:

  • Utilized mathematical modeling to simulate cellular processes.
  • Analyzed the impact of varying extracellular pH on proteinase secretion and activity.

Related Experiment Videos

  • Focused on matrix metalloproteinases (MMPs) and cathepsin B.

    • Main Results:

    • Mathematical modeling predicted that altered activity of matrix metalloproteinases (MMPs) at low pH could influence tumor invasion.
    • The study's modeling indicated that a pH-induced peripheral redistribution of cathepsin B is a significant factor in promoting a more metastatic phenotype.
    • These findings suggest a dual role for proteinases in pH-mediated tumor cell invasiveness.

    Conclusions:

    • Altered proteolytic activity, particularly the redistribution of cathepsin B, at low extracellular pH is a key mechanism driving tumor cell metastasis.
    • The reversed pH gradient in tumors may actively promote invasion through modulation of specific proteinases.
    • Targeting these pH-dependent proteinase activities could offer novel therapeutic strategies for inhibiting cancer metastasis.