title: A mathematical model of tumour and blood pHe regulation: The HCO3-/CO2 buffering system.
abstract: Malignant tumours are characterised by a low, acidic extracellular pH (pHe) which facilitates invasion and metastasis. Previous research has proposed the potential benefits of manipulating systemic pHe, and recent experiments have highlighted the potential for buffer therapy to raise tumour pHe, prevent metastases, and prolong survival in laboratory mice. To examine the physiological regulation of tumour buffering and investigate how perturbations of the buffering system (via metabolic/respiratory disorders or changes in parameters) can alter tumour and blood pHe, we develop a simple compartmentalised ordinary differential equation model of pHe regulation by the HCO3-/CO2 buffering system. An approximate analytical solution is constructed and used to carry out a sensitivity analysis, where we identify key parameters that regulate tumour pHe in both humans and mice. From this analysis, we suggest promising alternative and combination therapies, and identify specific patient groups which may show an enhanced response to buffer therapy. In addition, numerical simulations are performed, validating the model against well-known metabolic/respiratory disorders and predicting how these disorders could change tumour pHe.
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: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: Ian F
authors.initials: IF
authors.lastname: Robey
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology*; D000138:Acidosis / Q000097:blood / Q000150:complications / Q000378:metabolism; D000142:Acidosis, Respiratory / Q000097:blood / Q000150:complications / Q000378:metabolism; D000465:Algorithms; D000471:Alkalosis / Q000097:blood / Q000150:complications / Q000378:metabolism; D000472:Alkalosis, Respiratory / Q000097:blood / Q000150:complications / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000097:blood / Q000378:metabolism*; D001769:Blood / Q000378:metabolism; D002021:Buffers; D002245:Carbon Dioxide / Q000097:blood / Q000378:metabolism*; D003198:Computer Simulation; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000628:therapy
chemical_list: D001639:Bicarbonates; D002021:Buffers; D002245:Carbon Dioxide