Openings between defective endothelial cells explain tumor vessel leakiness
Openings between defective endothelial cells explain tumor vessel leakiness
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DOI：
10.1016/s0002-9440(10)65006-7
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发表时间：
2000-04-01
影响因子：
6
通讯作者：
McDonald, DM
中科院分区：
文献类型：
--
作者：
Hashizume, H;Baluk, P;McDonald, DM
血管在肿瘤中的泄漏可能导致疾病进展，并且是某些形式的癌症治疗的关键，但是泄漏的结构基础尚不清楚。我们试图确定内皮间隙或跨细胞孔（类似于炎症中泄漏血管中的孔）是否可以解释肿瘤血管的泄漏。将MCA-IV小鼠乳腺癌中的血管与三种较小的漏水肿瘤和正常乳腺的血管进行了比较，这些癌被称为异常漏水（功能性孔径1.2-2 mu M）。通过结合血管内注射的荧光阳离子脂质体和Lycopersicon esculentum凝集素以及CD31（PECAM）免疫反应性，可以鉴定血管，所有四种肿瘤中血管的腔表面的腔表面都有一个有缺陷的Endophelial单层单层，如MCA-MCA-MCA-MICARORS所示， ，14％的血管表面被连接不良的重叠细胞衬砌。最浅层的衬里细胞，例如内皮细胞，具有CD31免疫反应性和fenestrae，带有隔膜，但它们具有带有细胞质投影的分支表型，长达50 mU m。通过细胞间开口（平均直径1.7 mu m;范围为0.3-4.7 MU M）将一些分支细胞分离。还存在跨细胞孔（平均直径0.6 MU M），但仅与细胞间开口一样多8％。一些CD31阳性细胞伸入血管腔；其他人则发芽到血管周围肿瘤组织中。另外，RIP-TAG2小鼠中的肿瘤还具有肿瘤细胞的肿瘤细胞衬里湖泊。我们得出的结论是，某些肿瘤血管的细胞内膜有缺陷，由混乱，松散连接，分支，重叠或发芽的内皮细胞组成。这些细胞之间的开口有助于肿瘤血管泄漏，并可能允许将大分子治疗剂进入肿瘤细胞。
Leakiness of blood vessels in tumors may contribute to disease progression and is key to certain forms of cancer therapy, but the structural basis of the leakiness is unclear. We sought to determine whether endothelial gaps or transcellular holes, similar to those found in leaky vessels in inflammation, could explain the leakiness of tumor vessels. Blood vessels in MCa-IV mouse mammary carcinomas, which are known to be unusually leaky (functional pore size 1.2-2 mu m), were compared to vessels in three less leaky tumors and normal mammary glands. Vessels were identified by their binding of intravascularly injected fluorescent cationic liposomes and Lycopersicon esculentum lectin and by CD31 (PECAM) immunoreactivity, The luminal surface of vessels in all four tumors had a defective endothelial monolayer as revealed by scanning electron microscopy, In MCa-IV tumors, 14% of the vessel surface was lined by poorly connected, overlapping cells. The most superficial lining cells, like endothelial cells, had CD31 immunoreactivity and fenestrae with diaphragms, but they had a branched phenotype with cytoplasmic projections as long as 50 mu m. Some branched cells were separated by intercellular openings (mean diameter 1.7 mu m; range, 0.3-4.7 mu m). Transcellular holes (mean diameter 0.6 mu m) were also present but mere only 8% as numerous as intercellular openings. Some CD31-positive cells protruded into the vessel lumen; others sprouted into perivascular tumor tissue. Tumors in RIP-Tag2 mice had, in addition, tumor cell-lined lakes of extravasated erythrocytes. We conclude that some tumor vessels have a defective cellular lining composed of disorganized, loosely connected, branched, overlapping or sprouting endothelial cells. Openings between these cells contribute to tumor vessel leakiness and may permit access of macromolecular therapeutic agents to tumor cells.