Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis
Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis
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DOI：
10.2353/ajpath.2010.090838
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Felding-Habermann, Brunhilde
中科院分区：
文献类型：
--
作者：
Lorger, Mihaela;Felding-Habermann, Brunhilde
脑转移瘤难以治疗，并且大多在进行性转移性疾病的晚期发展。有风险的患者将从预防和改进治疗的发展中受益。这需要了解导致脑转移的初始事件。本研究揭示了乳腺癌细胞脑转移启动过程中的细胞事件，并记录了免疫缺陷和免疫活性小鼠模型颈动脉注射后对传入癌细胞的最早宿主反应。我们的研究结果捕获和表征了异质性星形胶质细胞和小胶质细胞对脑中癌细胞的逮捕和外渗的反应，显示了个体癌细胞到达时脑微环境的立即和剧烈变化。我们确定反应性星形胶质细胞作为最活跃的宿主细胞群，其立即定位于个体侵入的肿瘤细胞并持续与生长的转移性病变相关联。在外渗癌细胞附近与星形胶质细胞活化相关的基质金属蛋白酶-9的上调可能支持其进展。不同宿主细胞类型的早期参与表明环境线索，可能编码确定单个癌细胞是否进展为大转移或保持休眠。因此，脑归巢肿瘤细胞和反应性宿主细胞之间的初始相互作用的信息可能有助于制定预防和治疗症状性乳腺癌脑转移的策略。(Am J Pathol 2010，176：2958-2971; DOI：10.2353/ajpath.2010.090838）
Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Upregulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might code-termine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases. (Am J Pathol 2010, 176:2958-2971; DOI: 10.2353/ajpath.2010.090838)