Authors' Affiliations: Center of Functionally Integrative Neuroscience and MINDLab, Department of Clinical Medicine, Aarhus University, Aarhus Denmark; Department of Neuroradiology, and Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
Cancer Res. 2013 Sep 15;73(18):5618-24. doi: 10.1158/0008-5472.CAN-13-0964. Epub 2013 Jun 13.
Antiangiogenic therapies are being pursued as a means of starving tumors of their energy supply. Although numerous studies show that such therapies render tumors hypoxic, just as many studies have, surprisingly, shown improved tumor oxygenation. These contradicting findings challenge both the original rationale for antiangiogenic therapy and our understanding of the physiology of tissue oxygenation. The flow-diffusion equation, which describes the relation between blood flow and the extraction of freely diffusible molecules in tissue, was recently extended to take the heterogeneity of capillary transit times (CTH) into account. CTH is likely to be high in the chaotic microvasculature of a tumor, increasing the effective shunting of blood through its capillary bed. We review the properties of the extended flow-diffusion equation in tumor tissue. Elevated CTH reduces the extraction of oxygen, glucose, and cytotoxic molecules. The extent to which their net extraction is improved by antiangiogenic therapy, in turn, depends on the extent to which CTH is normalized by the treatment. The extraction of oxygen and glucose are affected to different extents by elevated CTH, and the degree of aerobic glycolysis-known as the Warburg effect-is thus predicted to represent an adaptation to the CTH of the local microvasculature.
抗血管生成治疗正被作为一种剥夺肿瘤能量供应的手段来进行研究。尽管大量研究表明此类治疗会使肿瘤缺氧，但同样多的研究令人惊讶地表明肿瘤的氧合作用得到了改善。这些相互矛盾的发现既挑战了抗血管生成治疗的最初原理，也挑战了我们对组织氧合生理学的理解。描述血流与组织中自由扩散分子提取之间关系的流动-扩散方程最近被扩展到考虑毛细血管通过时间（CTH）的异质性。CTH 在肿瘤的混沌微血管中很可能很高，从而增加了血液通过其毛细血管床的有效分流。我们回顾了肿瘤组织中扩展的流动-扩散方程的特性。升高的 CTH 会降低氧气、葡萄糖和细胞毒性分子的提取。抗血管生成治疗对其净提取的改善程度反过来又取决于治疗对 CTH 的归一化程度。氧气和葡萄糖的提取受到 CTH 的不同程度影响，因此有氧糖酵解的程度——即所谓的沃伯格效应——被预测代表了对局部微血管 CTH 的适应。
