TY - JOUR T1 - The role of oxygen in avascular tumor growth JF - bioRxiv DO - 10.1101/024562 SP - 024562 AU - David Robert Grimes AU - Pavitra Kannan AU - Alan McIntyre AU - Anthony Kavanagh AU - Abul Siddiky AU - Simon Wigfield AU - Adrian Harris AU - Mike Partridge Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/01/05/024562.abstract N2 - The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, where oxygen supply can be described by diffusion alone and are a much better approximation of realistic tumor dynamics than monolayers. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.Author Summary We derive a mechanistic growth model for avascular tumors, yielding a familiar sigmoidal growth curve with a minimum of assumptions. Specifically, it is assumed that only cells with requisite oxygen for mitosis can produce daughter cells. This work is validated on tumor spheroids, with well-understood oxygen dynamics and distributions and found to fit the measured data from several cell lines well. The importance of cellular mass in determining OCR is outlined, and a method for doing so alongside theoretical justification is outlined. Finally, the application of the model in determining the change in OCR due to clinical compounds is demonstrated using gemcitabine, a potent radio-sensitizer. ER -