Mechanisms of blood flow and hypoxia production in rat 9L-epigastric tumors.
Mechanisms of blood flow and hypoxia production in rat 9L-epigastric tumors.
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DOI：
10.2478/tumor-2012-0001
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Evans SM
中科院分区：
文献类型：
--
作者：
Koch CJ;Jenkins WT;Jenkins KW;Yang XY;Shuman AL;Pickup S;Riehl CR;Paudyal R;Poptani H;Evans SM
对肿瘤生理学的经典描述表明，肿瘤缺氧有两个来源：稳态(扩散受限)缺氧和循环(血流调节)缺氧。这两种起源主要是在小鼠模型中研究和表征的，都预示着相对较小的孤立的缺氧灶或薄壳状低氧组织夹杂着对比的氧气组织。由于氧扩散距离(由透氧率和组织耗氧率决定)在不同肿瘤之间没有明显差异，因此这些病灶或外壳不会随着肿瘤的整体大小而增大。我们已经在大鼠胶质肉瘤肿瘤和较大的人类肿瘤(特别是肉瘤和高级别胶质肿瘤)中发现了更大(宏观)的缺氧区，缺氧标志物EF5的生化结合表明。因此，我们考虑了另一种肿瘤缺氧的原因，这与首次在窗腔式肿瘤模型中观察到的现象有关：即纵向小动脉梯度。虽然最初描述的纵向小动脉梯度在本质上也是微观的，但如果以适当的方式组织肿瘤血流，它们可能会随着肿瘤大小的变化而变化。在这个组织中，流入的血液将来自相对氧气充足的来源，然后分支并聚集到氧气含量较低的流出血液中，其距离远远超过常规小动脉的长度(数毫米尺度)。这一新概念不同于通常将肿瘤血流描述为无组织和/或混乱的特征。血流的组织产生延长的纵向梯度和宏观的局部缺氧对肿瘤的成像、治疗和生物学特性具有许多重要的意义。在这里，我们报告了第一个关于这种血流的实验证据，使用生长在上腹动/静脉对上的大鼠9L胶质肉瘤。
Classical descriptions of tumor physiology suggest two origins for tumor hypoxia; steady-state (diffusion-limited) hypoxia and cycling (perfusion-modulated) hypoxia. Both origins, primarily studied and characterized in murine models, predict relatively small, isolated foci or thin shells of hypoxic tissue interspersed with contrasting oxic tissue. These foci or shells would not be expected to scale with overall tumor size since the oxygen diffusion distance (determined by oxygen permeability and tissue oxygen consumption rate) is not known to vary dramatically from tumor to tumor. We have identified much larger (macroscopic) regions of hypoxia in rat gliosarcoma tumors and in larger human tumors (notably sarcomas and high-grade glial tumors), as indicated by biochemical binding of the hypoxia marker, EF5. Thus, we considered an alternative cause of tumor hypoxia related to a phenomenon first observed in window-chamber tumor models: namely longitudinal arteriole gradients. Although longitudinal arteriole gradients, as originally described, are also microscopic in nature, it is possible for them to scale with tumor size if tumor blood flow is organized in an appropriate manner. In this organization, inflowing blood would arise from relatively well-oxygenated sources and would branch and then coalesce to poorly-oxygenated outflowing blood over distances much larger than the length of conventional arterioles (multi-millimeter scale). This novel concept differs from the common characterization of tumor blood flow as disorganized and/or chaotic. The organization of blood flow to produce extended longitudinal gradients and macroscopic regional hypoxia has many important implications for the imaging, therapy and biological properties of tumors. Herein, we report the first experimental evidence for such blood flow, using rat 9L gliosarcoma tumors grown on the epigastric artery/vein pair.