Casciari J J, Sotirchos S V, Sutherland R M
Cancer Center, University of Rochester, New York 14627.
J Cell Physiol. 1992 May;151(2):386-94. doi: 10.1002/jcp.1041510220.
Tumors and multicellular tumor spheroids can develop gradients in oxygen concentration, glucose concentration, and extracellular pH as they grow. In order to calculate these gradients and assess their impact on tumor growth, it is necessary to quantify the effect of these variables on tumor cell metabolism and growth. In this work, the oxygen consumption rates, glucose consumption rates, and growth rates of EMT6/Ro mouse mammary tumor cells were measured at a variety of oxygen concentrations, glucose concentrations, and extracellular pH levels. At an extracellular pH of 7.25, the oxygen consumption rate of EMT6/Ro cells increased by nearly a factor of 2 as the glucose concentration was decreased from 5.5 mM to 0.4 mM. This effect of glucose concentration on oxygen consumption rate, however, was slight at an extracellular pH of 6.95 and disappeared completely at an extracellular pH of 6.60. The glucose consumption rate of EMT6/Ro cells increased by roughly 40% when the oxygen concentration was reduced from 0.21 mM to 0.023 mM and decreased by roughly 60% when the extracellular pH was decreased from 7.25 to 6.95. The growth rate of EMT6/Ro cells decreased with decreasing oxygen concentration and extracellular pH; however, severe conditions were required to stop cell growth (0.0082 mM oxygen and an extracellular pH of 6.60). Empirical correlations were developed from these data to express EMT6/Ro cell growth rates, oxygen consumption rates, and glucose consumption rates, as functions of oxygen concentration, glucose concentration, and extracellular pH. These empirical correlations make it possible to mathematically model the gradients in oxygen concentration, glucose concentration, and extracellular pH in EMT6/Ro multicellular spheroids by solution of the diffusion/reaction equations. Computations such as these, along with oxygen and pH microelectrode measurements in EMT6/Ro multicellular spheroids, indicated that nutrient concentration and pH levels in the inner regions of spheroids were low enough to cause significant changes in nutrient consumption rates and cell growth rates. However, pH and oxygen concentrations measured or calculated in EMT6/Ro spheroids where quiescent cells have been observed were not low enough to cause the cessation of cell growth, indicating that the observed quiescence must have been due to factors other than acidic pH, oxygen depletion, or glucose depletion.
肿瘤和多细胞肿瘤球体在生长过程中会形成氧浓度、葡萄糖浓度和细胞外pH值的梯度。为了计算这些梯度并评估它们对肿瘤生长的影响，有必要量化这些变量对肿瘤细胞代谢和生长的作用。在这项工作中，在多种氧浓度、葡萄糖浓度和细胞外pH水平下测量了EMT6/Ro小鼠乳腺肿瘤细胞的氧消耗率、葡萄糖消耗率和生长率。在细胞外pH为7.25时，随着葡萄糖浓度从5.5 mM降至0.4 mM，EMT6/Ro细胞的氧消耗率增加了近2倍。然而，在细胞外pH为6.95时，葡萄糖浓度对氧消耗率的这种影响很小，而在细胞外pH为6.60时则完全消失。当氧浓度从0.21 mM降至0.023 mM时，EMT6/Ro细胞的葡萄糖消耗率大约增加了40%，而当细胞外pH从7.25降至6.95时，葡萄糖消耗率大约降低了60%。EMT6/Ro细胞的生长率随着氧浓度和细胞外pH的降低而下降；然而，需要极端条件才能停止细胞生长（0.0082 mM氧和细胞外pH为6.60）。根据这些数据建立了经验关联式，以将EMT6/Ro细胞的生长率、氧消耗率和葡萄糖消耗率表示为氧浓度、葡萄糖浓度和细胞外pH的函数。这些经验关联式使得通过求解扩散/反应方程来对EMT6/Ro多细胞球体中的氧浓度、葡萄糖浓度和细胞外pH梯度进行数学建模成为可能。诸如此类的计算，以及对EMT6/Ro多细胞球体中的氧和pH微电极测量，表明球体内部区域的营养物质浓度和pH水平低到足以导致营养物质消耗率和细胞生长率发生显著变化。然而，在观察到静止细胞的EMT6/Ro球体中测量或计算得到的pH和氧浓度并不低到足以导致细胞生长停止，这表明观察到的静止状态必定是由酸性pH、氧耗竭或葡萄糖耗竭以外的因素引起的。
