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The Role of Oxygen in Avascular Tumor Growth.

Grimes DR, Kannan P, McIntyre A, Kavanagh A, Siddiky A, Wigfield S, Harris A, Partridge M - PLoS ONE (2016)

Bottom Line: These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.

ABSTRACT
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, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. 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.

No MeSH data available.


Related in: MedlinePlus

Cross-section of a tumor spheroid of radius ro.The anoxic radius is denoted by rn. The radius rp depicts the radial extent of pm, the minimal oxygen level required for mitosis. The orange part of the image is the region rp ≤ r ≤ ro, the purple part corresponds to rn ≤ r ≤ rp and the central anoxic core (r ≤ rn) is shown in gray.
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pone.0153692.g001: Cross-section of a tumor spheroid of radius ro.The anoxic radius is denoted by rn. The radius rp depicts the radial extent of pm, the minimal oxygen level required for mitosis. The orange part of the image is the region rp ≤ r ≤ ro, the purple part corresponds to rn ≤ r ≤ rp and the central anoxic core (r ≤ rn) is shown in gray.

Mentions: In this investigation, we confine our investigation to a simple case to allow us reduce the number of parameters. Specifically, we shall model the effects of oxygen on spheroid growth whilst controlling for other potentially confounding factors. Spheroids provide insight into how avascular tumors propagate; as spheroids increase in size, their central core becomes anoxic and leads to the formation of two distinct zones—a necrotic core and a viable rim, as depicted in Fig 1. We have recently derived an explicit analytical model for oxygen distribution in spheroids, which accurately predicts properties such as the extent of the anoxic, hypoxic and viable regions and allows determination of the oxygen consumption rate from first principles for a spheroid at a given time point [26]. It can further be shown from this analysis that the oxygen consumption rate (OCR) of a spheroid drives both its oxygen distribution and the physical extent of the anoxic core rn. Indeed, oxygen distribution in situ has serious ramifications for therapy too, as radiotherapy is up to a factor of 3 more effective in well-oxygenated regions [27]. In this work, we derive a time-dependent discrete growth model for tumor spheroids, linking their relative rates of oxygen consumption to their growth curves. The model used in this work has only has free parameters of oxygen diffusion and oxygen consumption rate, and average cellular doubling time so that local oxygen partial pressure determines cell behaviour. We do not model other nutrients such as glucose, which are assumed to be present in excess in the media. The model is limited to spheroids from a single cell line. This model can be directly contrasted to experimental data and is validated across a range of cell lines. We further show how this method might be used to infer the effect of different clinical compounds on oxygen consumption rate, using gemcitabine as an illustration.


The Role of Oxygen in Avascular Tumor Growth.

Grimes DR, Kannan P, McIntyre A, Kavanagh A, Siddiky A, Wigfield S, Harris A, Partridge M - PLoS ONE (2016)

Cross-section of a tumor spheroid of radius ro.The anoxic radius is denoted by rn. The radius rp depicts the radial extent of pm, the minimal oxygen level required for mitosis. The orange part of the image is the region rp ≤ r ≤ ro, the purple part corresponds to rn ≤ r ≤ rp and the central anoxic core (r ≤ rn) is shown in gray.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835055&req=5

pone.0153692.g001: Cross-section of a tumor spheroid of radius ro.The anoxic radius is denoted by rn. The radius rp depicts the radial extent of pm, the minimal oxygen level required for mitosis. The orange part of the image is the region rp ≤ r ≤ ro, the purple part corresponds to rn ≤ r ≤ rp and the central anoxic core (r ≤ rn) is shown in gray.
Mentions: In this investigation, we confine our investigation to a simple case to allow us reduce the number of parameters. Specifically, we shall model the effects of oxygen on spheroid growth whilst controlling for other potentially confounding factors. Spheroids provide insight into how avascular tumors propagate; as spheroids increase in size, their central core becomes anoxic and leads to the formation of two distinct zones—a necrotic core and a viable rim, as depicted in Fig 1. We have recently derived an explicit analytical model for oxygen distribution in spheroids, which accurately predicts properties such as the extent of the anoxic, hypoxic and viable regions and allows determination of the oxygen consumption rate from first principles for a spheroid at a given time point [26]. It can further be shown from this analysis that the oxygen consumption rate (OCR) of a spheroid drives both its oxygen distribution and the physical extent of the anoxic core rn. Indeed, oxygen distribution in situ has serious ramifications for therapy too, as radiotherapy is up to a factor of 3 more effective in well-oxygenated regions [27]. In this work, we derive a time-dependent discrete growth model for tumor spheroids, linking their relative rates of oxygen consumption to their growth curves. The model used in this work has only has free parameters of oxygen diffusion and oxygen consumption rate, and average cellular doubling time so that local oxygen partial pressure determines cell behaviour. We do not model other nutrients such as glucose, which are assumed to be present in excess in the media. The model is limited to spheroids from a single cell line. This model can be directly contrasted to experimental data and is validated across a range of cell lines. We further show how this method might be used to infer the effect of different clinical compounds on oxygen consumption rate, using gemcitabine as an illustration.

Bottom Line: These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.

ABSTRACT
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, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. 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.

No MeSH data available.


Related in: MedlinePlus