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 () represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (k p) deals with cell line specific factors to promote growth. The K H,K N 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 and lower k p, indicating that tumours are poorly perfused and slow growing. >Group 2 share the value of the oxygen uptake rate () and vary greatly in k p, 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.
展开▼
机译:与临床肿瘤相比,异种移植物(作为癌症的简化动物模型)在脉管系统和基质结构上有很大不同。这使得基于数学模型的临床结果预测具有挑战性。我们的目的是进一步了解动物模型与临床之间在肿瘤进展和生理上的差异。为此,我们提出了一种基于肿瘤病理生理学的数学模型,其中氧气(作为内分泌传递的替代物)是我们的主要研究重点。使用氧气扩散方程的氧气驱动模型(ODM)描述了肿瘤的生长,缺氧和坏死。 ODM描述了两个关键的生理参数。表观吸氧率(<数学xmlns:mml =“ http://www.w3.org/1998/Math/MathML” id =“ M1” overflow =“ scroll”> <种植> k < / mi> R mi> ' mo> msubsup> mrow> math>)代表似乎需要增殖的氧气细胞数量。他们似乎需要更多的氧气,更多的氧气传输。 展开▼