title: Glucose-lactate metabolic cooperation in cancer: insights from a spatial mathematical model and implications for targeted therapy.
abstract: A recent study has hypothesised a glucose-lactate metabolic symbiosis between adjacent hypoxic and oxygenated regions of a developing tumour, and proposed a treatment strategy to target this symbiosis. However, in vivo experimental support remains inconclusive. Here we develop a minimal spatial mathematical model of glucose-lactate metabolism to examine, in principle, whether metabolic symbiosis is plausible in human tumours, and to assess the potential impact of inhibiting it. We find that symbiosis is a robust feature of our model system-although on the length scale at which oxygen supply is diffusion-limited, its occurrence requires very high cellular metabolic activity-and that necrosis in the tumour core is reduced in the presence of symbiosis. Upon simulating therapeutic inhibition of lactate uptake, we predict that targeted treatment increases the extent of tissue oxygenation without increasing core necrosis. The oxygenation effect is correlated strongly with the extent of wild-type hypoxia and only weakly with wild-type symbiotic behaviour, and therefore may be promising for radiosensitisation of hypoxic, lactate-consuming tumours even if they do not exhibit a spatially well-defined symbiosis. Finally, we conduct in vitro experiments on the U87 glioblastoma cell line to facilitate preliminary speculation as to where highly malignant tumours might fall in our parameter space, and find that these experiments suggest a weakly symbiotic regime for U87 cells, thus raising the new question of what relationship might exist between symbiosis and tumour malignancy.
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, United Kingdom. Electronic address: jessica.mcgillen@maths.ox.ac.uk.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: McGillen
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Kelly
authors.affiliation: Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Avda. Camilo José Cela, 13071 Ciudad Real, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martínez-González
authors.affiliation: School of Social and Community Medicine, Bristol University, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, United Kingdom.
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Martin
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, United Kingdom.
authors.forename: Eamonn A
authors.initials: EA
authors.lastname: Gaffney
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, United Kingdom.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
authors.affiliation: Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Avda. Camilo José Cela, 13071 Ciudad Real, Spain.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Pérez-García
mesh_terms: D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D019344:Lactic Acid; D005947:Glucose
keywords: Cancer metabolism; Multidimensional sensitivity analysis; Partial differential equations