MATHEMATICAL-MODELING OF MICROENVIRONMENT AND GROWTH IN EMT6/RO MULTICELLULAR TUMOR SPHEROIDS
MATHEMATICAL-MODELING OF MICROENVIRONMENT AND GROWTH IN EMT6/RO MULTICELLULAR TUMOR SPHEROIDS
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DOI：
10.1111/j.1365-2184.1992.tb01433.x
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发表时间：
1992-01-01
影响因子：
8.5
通讯作者：
SUTHERLAND, RM
中科院分区：
文献类型：
--
作者：
CASCIARI, JJ;SOTIRCHOS, SV;SUTHERLAND, RM
为了确定微环境在肿瘤球体生长中的作用，开发了一个数学模型来预测EMT6/Ro球体生长和微环境，该模型基于氧、葡萄糖、乳酸根离子、二氧化碳、碳酸氢根离子、氯离子和氢离子的扩散/反应方程的数值解以及电中性方程。该模型考虑了氧浓度、葡萄糖浓度和胞外pH对细胞生长和代谢的影响。由于EMT6/Ro单细胞生长和代谢速率，球状体扩散常数和转瓶传质系数的独立测量是可用的，使用这些参数的模型预测与EMT6/Ro球状体生长和微环境的已发表数据进行了比较。由于细胞生长速率降低和细胞脱落而导致的球状体生长降低的模型预测拟合了低于700 μ m的球状体生长实验数据，但高估了较大直径处的球状体生长速率。基于预测的接近零的葡萄糖浓度的预测的可存活边缘厚度适合于在5.5mM或更低的中等葡萄糖浓度下生长的1000 μ m球状体的已发表的可存活边缘厚度数据。此外，该模型不能预测观察到的球体中氧和葡萄糖代谢随时间的降低，也不能预测观察到的生长平台期。这表明，其他未知因素，如抑制剂或细胞-细胞接触效应，也必须是重要的影响球体的生长和细胞代谢。
In order to determine the role of micromilieu in tumour spheroid growth, a mathematical model was developed to predict EMT6/Ro spheroid growth and microenvironment based upon numerical solution of the diffusion/reaction equation for oxygen, glucose, lactate ion, carbon dioxide, bicarbonate ion, chlorine ion and hydrogen ion along with the equation of electroneutrality. This model takes into account the effects of oxygen concentration, glucose concentration and extracellular pH on cell growth and metabolism. Since independent measurements of EMT6/Ro single cell growth and metabolic rates, spheroid diffusion constants, and spinner flask mass transfer coefficients are available, model predictions using these parameters were compared with published data on EMT6/Ro spheroid growth and microenvironment. The model predictions of reduced spheroid growth due to reduced cell growth rates and cell shedding fit experimental spheroid growth data below 700-mu-m, but overestimated the spheroid growth rate at larger diameters. Predicted viable rim thicknesses based on predicted near zero glucose concentrations fit published viable rim thickness data for 1000-mu-m spheroids grown at medium glucose concentrations of 5.5 mM or less. However, the model did not accurately predict the onset of necrosis. Moreover, the model could not predict the observed decreases in oxygen and glucose metabolism seen in spheroids with time, nor could it predict the observed growth plateau. This suggests that other unknown factors, such as inhibitors or cell-cell contact effects, must also be important in affecting spheroid growth and cellular metabolism.