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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

(a) A HCT 116 control spheroid stained for proliferating cells using Ki-67 (green) and for hypoxia using EF5 (red) (b) a HCT 116 spheroid treated with 50 nM of gemcitabine showing markedly smaller hypoxic centre than untreated spheroid. (c) OCR estimated from stained cross-sections by previously outlined method [26] for 4 control spheroids and 7 spheroids treated with 50nM gemcitabine.Average OCR for treated spheroids is 6.18 ×10−7 m3 kg−1 s−1 (18.75 mmHg / s) versus 9.05 ×10−7 m3 kg−1 s−1 (27.43 mmHg / s) for untreated spheroids (P-Value < 0.01 using a two-tailed Welch’s correction t-test,α = 0.05). This suggests a marked decrease in OCR for treated spheroids.
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pone.0153692.g005: (a) A HCT 116 control spheroid stained for proliferating cells using Ki-67 (green) and for hypoxia using EF5 (red) (b) a HCT 116 spheroid treated with 50 nM of gemcitabine showing markedly smaller hypoxic centre than untreated spheroid. (c) OCR estimated from stained cross-sections by previously outlined method [26] for 4 control spheroids and 7 spheroids treated with 50nM gemcitabine.Average OCR for treated spheroids is 6.18 ×10−7 m3 kg−1 s−1 (18.75 mmHg / s) versus 9.05 ×10−7 m3 kg−1 s−1 (27.43 mmHg / s) for untreated spheroids (P-Value < 0.01 using a two-tailed Welch’s correction t-test,α = 0.05). This suggests a marked decrease in OCR for treated spheroids.

Mentions: Using the model, the effects of gemcitabine on OCR could also be ascertained. This is illustrated in Fig 5, for untreated HCT-116 spheroids and HCT-116 spheroids treated with 50nM of gemcitabine. Untreated HCT 116 spheroids were estimated to have an average OCR of 27.43 mmHg/s, in high agreement with estimated consumption rate experimentally derived in this work (mean value 27.92 mmHg / s)through the confocal mass estimation method. A Welch’s correction two-tailed T-test was performed between the two groups, with highly significant result of P < 0.01. These results are shown in Fig 5.


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)

(a) A HCT 116 control spheroid stained for proliferating cells using Ki-67 (green) and for hypoxia using EF5 (red) (b) a HCT 116 spheroid treated with 50 nM of gemcitabine showing markedly smaller hypoxic centre than untreated spheroid. (c) OCR estimated from stained cross-sections by previously outlined method [26] for 4 control spheroids and 7 spheroids treated with 50nM gemcitabine.Average OCR for treated spheroids is 6.18 ×10−7 m3 kg−1 s−1 (18.75 mmHg / s) versus 9.05 ×10−7 m3 kg−1 s−1 (27.43 mmHg / s) for untreated spheroids (P-Value < 0.01 using a two-tailed Welch’s correction t-test,α = 0.05). This suggests a marked decrease in OCR for treated spheroids.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835055&req=5

pone.0153692.g005: (a) A HCT 116 control spheroid stained for proliferating cells using Ki-67 (green) and for hypoxia using EF5 (red) (b) a HCT 116 spheroid treated with 50 nM of gemcitabine showing markedly smaller hypoxic centre than untreated spheroid. (c) OCR estimated from stained cross-sections by previously outlined method [26] for 4 control spheroids and 7 spheroids treated with 50nM gemcitabine.Average OCR for treated spheroids is 6.18 ×10−7 m3 kg−1 s−1 (18.75 mmHg / s) versus 9.05 ×10−7 m3 kg−1 s−1 (27.43 mmHg / s) for untreated spheroids (P-Value < 0.01 using a two-tailed Welch’s correction t-test,α = 0.05). This suggests a marked decrease in OCR for treated spheroids.
Mentions: Using the model, the effects of gemcitabine on OCR could also be ascertained. This is illustrated in Fig 5, for untreated HCT-116 spheroids and HCT-116 spheroids treated with 50nM of gemcitabine. Untreated HCT 116 spheroids were estimated to have an average OCR of 27.43 mmHg/s, in high agreement with estimated consumption rate experimentally derived in this work (mean value 27.92 mmHg / s)through the confocal mass estimation method. A Welch’s correction two-tailed T-test was performed between the two groups, with highly significant result of P < 0.01. These results are shown in Fig 5.

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