title: Quiescence as a mechanism for cyclical hypoxia and acidosis.
abstract: Tumour tissue characteristically experiences fluctuations in substrate supply. This unstable microenvironment drives constitutive metabolic changes within cellular populations and, ultimately, leads to a more aggressive phenotype. Previously, variations in substrate levels were assumed to occur through oscillations in the haemodynamics of nearby and distant blood vessels. In this paper we examine an alternative hypothesis, that cycles of metabolite concentrations are also driven by cycles of cellular quiescence and proliferation. Using a mathematical modelling approach, we show that the interdependence between cell cycle and the microenvironment will induce typical cycles with the period of order hours in tumour acidity and oxygenation. As a corollary, this means that the standard assumption of metabolites entering diffusive equilibrium around the tumour is not valid; instead temporal dynamics must be considered.
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK. kieran.smallbone@manchester.ac.uk
authors.forename: Kieran
authors.initials: K
authors.lastname: Smallbone
authors.forename: David J
authors.initials: DJ
authors.lastname: Gavaghan
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
authors.forename: J Michael
authors.initials: JM
authors.lastname: Brady
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008433:Mathematics; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016192:Resting Phase, Cell Cycle