title: Oxygen-Driven Tumour Growth Model: A Pathology-Relevant Mathematical Approach.
abstract: Xenografts--as simplified animal models of cancer-differ substantially in vasculature and stromal architecture when compared to clinical tumours. This makes mathematical model-based predictions of clinical outcome challenging. Our objective is to further understand differences in tumour progression and physiology between animal models and the clinic. To achieve that, we propose a mathematical model based upon tumour pathophysiology, where oxygen--as a surrogate for endocrine delivery--is our main focus. The Oxygen-Driven Model (ODM), using oxygen diffusion equations, describes tumour growth, hypoxia and necrosis. The ODM describes two key physiological parameters. Apparent oxygen uptake rate (k'R) represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. k'R gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (kp) deals with cell line specific factors to promote growth. The KH,KN describe the switch of hypoxia and necrosis. Retrospectively, using archived data, we looked at longitudinal tumour volume datasets for 38 xenografted cell lines and 5 patient-derived xenograft-like models. Exploration of the parameter space allows us to distinguish 2 groups of parameters. Group 1 of cell lines shows a spread in values of k'R and lower kp, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate (k'R) and vary greatly in kp, which we interpret as having similar oxygen transport, but more tumour intrinsic variability in growth. However, the ODM has some limitations when tested in explant-like animal models, whose complex tumour-stromal morphology may not be captured in the current version of the model. Incorporation of stroma in the ODM will help explain these discrepancies. We have provided an example. The ODM is a very simple -and versatile- model suitable for the design of preclinical experiments, which can be modified and enhanced whilst maintaining confidence in its predictions.
authors.affiliation: Modelling & Simulation Oncology DMPK, AstraZeneca, Cambridge, United Kingdom; Physics Department, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Delgado-SanMartin
authors.affiliation: In vivo bioscience, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Hare
authors.affiliation: Physics Department, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Alessandro P S
authors.initials: AP
authors.lastname: de Moura
authors.affiliation: Modelling & Simulation Oncology DMPK, AstraZeneca, Cambridge, United Kingdom.
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption
chemical_list: D010100:Oxygen