Pathogenesis and vascular integrity of breast cancer brain metastasis
Pathogenesis and vascular integrity of breast cancer brain metastasis
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DOI：
10.1002/ijc.22388
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发表时间：
2007-03-01
影响因子：
6.4
通讯作者：
Schroit, Alan J.
中科院分区：
文献类型：
--
作者：
Lu, Weixin;Bucana, Corazon D.;Schroit, Alan J.
理论认为脑转移起源于肿瘤细胞的增殖，血脑屏障（BBB）阻止了化疗药物向肿瘤的输送。本研究的目的是阐明在小鼠乳腺癌脑转移模型中肿瘤定位和进展与BBB功能的参与之间的关系。将表达绿色荧光蛋白的MDA-MB 435乳腺癌细胞注射到左心室或裸鼠中。在不同的时间点，用罗丹明缀合的白蛋白标记整个脉管系统。然后通过激光扫描共聚焦和立体荧光显微镜对肿瘤和脉管系统进行成像。大约75%到达大脑的细胞外渗并在血管周围生长。然而，25%的细胞在血管内增殖，最终导致脑实质血栓样梗死。致瘤性“栓子”充当持续释放源或肿瘤细胞至下游部位。持续的血管内肿瘤扩张导致BBB破坏和细胞溢出，这些细胞沿血管周围沿着血管进展到远处部位，重新获得BBB的保护。乳腺癌脑转移涉及血管外和血管内生长或肿瘤细胞。这些不同的途径导致不同的病理表型，产生促进或抑制化疗药物递送至肿瘤的异质性BBB。(c)2000 Wiley-Liss，Inc.
Dogma dictates that brain metastasis originate from the prolireration of extravasated tumor cells and that the blood-brain barrier (BBB) prevents the delivery of chemotherapeutic drugs to the tumors. The purpose of this study was to clarify the relationship between tumor localization and progression and the involvement of BBB function in a murine model of breast cancer brain metastasis. Green fluorescent protein expressing MDA-MB435 breast cancer cells were injected into the left ventricle or nude mice. At various time points, the entire vasculature was labeled with rhodamine-conjugated albumin. The tumors and vasculature were then imaged by laser-scanning confocal and stereo fluorescence microscopy. About 75% of the cells that reached the brain extravasated and grew perivascularly. Twenty five percent of the cells, however, proliferated within the vasculature and ultimately led to thrombosis-like infarction of the brain parenchyma. The tumorigenic "embolus" served as a sustained release source or tumor cells to downstream sites. Continuing intravascular tumor expansion led to disruption of the BBB and to overflow of cells that progressed along the vessels perivascularly to distant sites that regained protection of the BBB. Breast cancer brain metastases involve both extravascular and intravascular growth or tumor cells. These distinct pathways contribute to different pathological phenotypes that generate a heterogeneous BBB that facilitates or inhibits the delivery of chemotherapeutic drugs to the tumor. (c) 2000 Wiley-Liss, Inc.