Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels.
Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels.
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发表时间：
1992-11
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通讯作者：
S. Kohn;J. Nagy;Harold F. Dvorak;Ann M. Dvorak
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作者：
S. Kohn;J. Nagy;Harold F. Dvorak;Ann M. Dvorak
背景供应肿瘤的血管对大分子具有高通透性，但其机制尚不清楚。实验设计为探讨肿瘤血管渗漏的结构基础，我们对三种同基因可移植癌(小鼠卵巢癌和豚鼠胆管癌细胞系1、10)静脉注射几种大分子示踪剂后早期进行了透射电子显微镜观察。研究了物理性质差异很大的示踪剂：辣根过氧化物酶、铁蛋白、150千吨荧光素异硫氰酸酯-葡聚糖和金牛血清白蛋白。结果所有示踪剂主要从肿瘤-宿主界面的小静脉和小静脉泄漏，大部分血管内有连续的内皮。在所有三种肿瘤中，所有四种示踪剂离开小静脉的主要途径是通过一个光滑的膜结合的、相互连接的小泡和空泡的系统；这些小泡和空泡往往以不规则的间隔聚集在内皮细胞胞浆中，形成细胞器样结构，即囊泡-空泡细胞器(VVO)。在良好的切片上，VVO与内皮细胞的管腔表面和腔面接触。单独的HRP通过相对的内皮细胞间连接穿过小静脉和小静脉。示踪剂也通过内皮窗离开血管，这些血管在小鼠卵巢肿瘤相关小静脉中(很少)出现。VVO以相似的频率和复杂性出现在连续的内皮排列的小静脉和小静脉中，这些小静脉和小静脉供应荷瘤动物或对照动物的正常皮下组织。与肿瘤相关血管一样，VVO提供了所有四种示踪剂离开正常血管的主要途径，但肿瘤的VVO标记和外渗都比对照血管大得多(铁蛋白P<；0.001)。结论VVO是肿瘤供血血管内皮细胞和控制血管内皮细胞的重要结构，是大分子外渗的主要途径。肿瘤血管通透性特征的大幅增加可能是由于VVO功能上调所致。
BACKGROUND Blood vessels supplying tumors are hyperpermeable to macromolecules, but the mechanisms responsible are poorly understood. EXPERIMENTAL DESIGN To investigate the structural basis for the leakiness of tumor blood vessels, we performed a transmission electron microscopic study of three syngeneic transplantable carcinomas (mouse ovarian carcinoma and the line 1 and line 10 bile duct guinea pig carcinomas) at early intervals after intravenous injection of several macromolecular tracers. Tracers with widely differing physical properties were studied: horseradish peroxidase, ferritin, 150 kilodalton fluorescein isothiocyanate-dextran and gold-bovine serum albumin. RESULTS All tracers leaked primarily from venules and small veins at the tumor-host interface, for the most part vessels lined by a continuous endothelium. The predominant pathway by which all four tracers exited venules in all three tumors was by way of a system of smooth membrane-bound, interconnecting vesicles and vacuoles; these tended to cluster together at irregular intervals in the endothelial cell cytoplasm to form organelle-like structures, vesiculo-vacuolar organelles (VVO). In favorable sections, VVO interfaced with both the luminal and abluminal surfaces of endothelial cells. HRP alone crossed venules and small veins through apposed inter-endothelial cell junctions. Tracers also exited vessels by way of endothelial fenestrae where these occurred (rarely) in mouse ovarian tumor-associated venules. VVO occurred with similar frequency and complexity in the continuous endothelium-lined venules and small veins that supplied the normal subcutis of either tumor-bearing or control animals. As in tumor-associated vessels, VVO provided the predominant pathway by which all four tracers exited normal vessels, but VVO labeling and extravasation were both much greater in tumor than in control vessels (p < 0.001 for ferritin). CONCLUSIONS VVO are prominent structures in both tumor-supplying and control vessel endothelial cells and provide the primary pathway for macromolecular extravasation. The large increase in permeability characteristic of tumor vessels is likely attributable to upregulation of VVO function.