title: A microscale mathematical model for metabolic symbiosis: Investigating the effects of metabolic inhibition on ATP turnover in tumors.
abstract: Cancer cells are notorious for their metabolic adaptations to hypoxic and acidic conditions, and especially for highly elevated glycolytic rates in tumor tissues. An end product of glycolysis is lactate, a molecule that cells can utilize instead of glucose to fuel respiration in the presence of oxygen. This could be beneficial to those cells that do not have sufficient oxygen as it conserves glucose for glycolysis. To better quantify this phenomenon we develop a diffusion-reaction mathematical model for nutrient concentrations in cancerous tissue surrounding a single cylindrical microvessel. We use our model to analyze the interdependence between cell populations' metabolic behaviors on a microscopic scale, specifically the emerging paradigm of metabolic symbiosis that exists between aerobic and glycolytic cells. The ATP turnover rates are calculated as a function of distance from the blood vessel, which exhibit a lactate-consuming population at intermediate distances from the vessel. We also consider the ramifications of the Warburg effect where cells utilize aerobic glycolysis along with this lactate-consuming respiration. We also investigate the effect of inhibiting metabolic pathways on cancer cells since insufficient ATP can trigger cell apoptosis. Effects that could be induced by metabolic inhibitors are analyzed by calculating the total ATP turnover in a unit tissue annulus in various parameter regimes that correspond to treatment conditions where specific metabolic pathways are knocked out. We conclude that therapies that target glycolysis, e.g. lactate dehydrogenase inhibitors or glycolytic enzyme inhibition, are the keys to successful metabolic repression.
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1. Electronic address: cphipps@uwaterloo.ca.
authors.forename: Colin
authors.initials: C
authors.lastname: Phipps
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
authors.forename: Hamid
authors.initials: H
authors.lastname: Molavian
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1; Center for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, Ontario, Canada M5T 3J1.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kohandel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D003198:Computer Simulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010101:Oxygen Consumption; D013559:Symbiosis
chemical_list: D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose
keywords: Cancer cell metabolism; Glycolytic inhibition; Lactate dehydrogenase inhibitor; Tumor hypoxia; Warburg effect