Enokida Y, Tsuruno Y, Okubo K, Yamaoka Y, Takahashi E
Advanced Technology Fusion, Graduate School of Science and Engineering, Saga University, Saga, Japan.
Adv Exp Med Biol. 2017;977:169-174. doi: 10.1007/978-3-319-55231-6_23.
We hypothesized that cancer cells actively migrate toward intratumor microvessels, guided by tissue gradients of metabolic substrates (such as O) and/or metabolites (such as CO/H). To test this hypothesis, we developed an in vitro model in which cellular energy metabolism establishes gradients of O/nutrient/metabolite in monolayer cells cultured in a conventional culture dish. When gradients of O ranging from 3% to ~0% were produced, MDA-MB-231 cells located at 300, 500 and 1500 μm downstream in the gradient demonstrated significant directional migrations (Rayleigh z test). We also found a similar directionality in cell migration at the same location even when the initial O level in the O gradient was raised from 3% to 21%. Interestingly, such directionalities were no longer demonstrated when the cell density was lowered from 1.8 × 10 to 0.9 × 10 cells/ml. In the former, the magnitude of the extracellular pH gradient in regions 300 and 500 μm downstream in the gradient was significantly larger. Thus, the direction of cell migrations appeared to depend on the gradient of extracellular pH rather than on O.
我们假设癌细胞会在代谢底物（如氧气）和/或代谢产物（如二氧化碳/氢离子）的组织梯度引导下，朝着肿瘤内微血管积极迁移。为了验证这一假设，我们开发了一种体外模型，在传统培养皿中培养的单层细胞中，细胞能量代谢会建立氧气/营养物质/代谢产物的梯度。当产生3%至约0%的氧气梯度时，位于梯度下游300、500和1500μm处的MDA-MB-231细胞表现出显著的定向迁移（瑞利z检验）。我们还发现，即使氧气梯度中的初始氧气水平从3%提高到21%，同一位置的细胞迁移仍具有相似的方向性。有趣的是，当细胞密度从1.8×10降低到0.9×10个细胞/毫升时，这种方向性就不再表现出来。在前者中，梯度下游300和500μm区域的细胞外pH梯度幅度明显更大。因此，细胞迁移的方向似乎取决于细胞外pH梯度而非氧气。
