title: Leaky vessels as a potential source of stromal acidification in tumours.
abstract: Malignant tumours are characterised by higher rates of acid production and a lower extracellular pH than normal tissues. Previous mathematical modelling has indicated that the tumour-derived production of acid leads to a gradient of low pH in the interior of the tumour extending to a normal pH in the peritumoural tissue. This paper uses mathematical modelling to examine the potential of leaky vessels as an additional source of stromal acidification in tumours. We explore whether and to what extent increasing vascular permeability in vessels can lead to the breakdown of the acid gradient from the core of the tumour to the normal tissue, and a progressive acidification of the peritumoural stroma. We compare our mathematical simulations to experimental results found in vivo with a tumour implanted in the mammary fat pad of a mouse in a window chamber construct. We find that leaky vasculature can cause a net acidification of the normal tissue away from the tumour boundary, though not a progressive acidification over time as seen in the experiments. Only through progressively increasing the leakiness can the model qualitatively reproduce the experimental results. Furthermore, the extent of the acidification predicted by the mathematical model is less than as seen in the window chamber, indicating that although vessel leakiness might be acting as a source of acid, it is not the only factor contributing to this phenomenon. Nevertheless, tumour destruction of vasculature could result in enhanced stromal acidification and invasion, hence current therapies aimed at buffering tumour pH should also examine the possibility of preventing vessel disruption.
authors.affiliation: Centre for Mathematical Biology, Mathematical Institute, Oxford University, 24-29 St Giles', Oxford OX1 3LB, UK. natasha.martin@bristol.ac.uk
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Martin
authors.forename: Eamonn A
authors.initials: EA
authors.lastname: Gaffney
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D003198:Computer Simulation; D003238:Connective Tissue / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology