Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
Morgridge Institute for Research, 330 N Orchard Street, Madison, WI 53715, USA.
Int J Mol Sci. 2020 Nov 28;21(23):9075. doi: 10.3390/ijms21239075.
Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death.
肿瘤特异性代谢适应性为选择性地破坏癌细胞提供了一个有趣的治疗机会。然而，实体瘤在肿瘤块内也存在营养物质和废物产物的梯度，迫使肿瘤细胞根据周围微环境中的营养物质可用性来适应其代谢。因此，实体瘤在整个肿瘤块中表现出异质的代谢表型，这使得设计针对所有存在的肿瘤群体的有效治疗方法变得复杂。在这项工作中，我们使用微流控装置来研究肿瘤对几种代谢抑制剂的代谢易感性。微装置包括一个中央腔室，用于在三维（3D）基质中培养肿瘤细胞，以及腔室一侧的一个管腔。这种设计在中央腔室中产生了不对称的营养物质分布，从而产生了细胞活力梯度。结果表明，位于营养丰富环境中的肿瘤细胞对靶向糖酵解、脂肪酸氧化或氧化磷酸化的代谢抑制剂的敏感性低至无。相反，当模型内部的细胞密度增加，营养物质供应受到限制时，添加这些代谢抑制剂会破坏细胞的氧化还原平衡，导致肿瘤细胞死亡。
