Alterations in proteolytic activity at low pH and its association with invasion: A theoretical model

The extracellular pH (pH(e)) 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 (pH(i)) have shown that the phi of solid tumours is neutral or slightly alkaline compared to normal tissue (pH(i) 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 turnout 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.