Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-11-04 DOI:10.1093/neuonc/noae094
Jenny Roesler, Daniel Spitzer, Xiaoxiong Jia, Synnøve Nymark Aasen, Kathleen Sommer, Bastian Roller, Niels Olshausen, Nils R Hebach, Nawid Albinger, Evelyn Ullrich, Ling Zhu, Fan Wang, Jadranka Macas, Marie-Therese Forster, Joachim P Steinbach, Lisa Sevenich, Kavi Devraj, Frits Thorsen, Matthia A Karreman, Karl H Plate, Yvonne Reiss, Patrick N Harter
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Abstract

Background: Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF).

Methods: In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients.

Results: Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival.

Conclusions: Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.

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脑血液微循环紊乱和缺氧缺血微环境与脑转移的发生有关。
脑转移瘤(BM)对神经功能的影响、有限的治疗方案和较差的预后,构成了肿瘤学领域日益严峻的挑战。脑转移瘤是通过循环肿瘤细胞外渗穿过血脑屏障而发生的。然而,人们对肿瘤细胞的外渗过程仍然知之甚少。我们在此提出了一种脑定植过程,该过程模仿脑梗塞样微环境反应,依赖于血管生成素(Ang-2)和血管内皮生长因子(VEGF)。在这项研究中,使用了心内BM模型,并通过颅窗使用双光子显微镜监测脑血液微循环。利用头颅磁共振、生物发光成像和尸体解剖观察了BM的形成。采用 Ang-2/VEGF 靶向策略和 Ang-2 功能增益(GOF)小鼠来干扰 BM 的形成。此外,还对BM患者的血管和基质因素以及临床结果进行了分析。研究发现,癌细胞导致血管闭塞,并伴有明显的脑血液微循环障碍和局灶性卒中样组织学征象。在小鼠和人的骨髓瘤中,脑内皮细胞的 Ang-2 表达均升高。Ang-2 GOF会导致脑组织负担加重。抗Ang-2/抗VEGF联合疗法可减少脑转移瘤的大小和数量。已确诊的人类脑转移瘤的肿瘤血管中的 Ang-2 表达与存活率呈负相关。我们的观察结果表明,脑血液微循环紊乱与脑转移瘤的形成之间存在关系。这表明,肿瘤细胞堵塞血管有利于脑转移瘤的外渗和播种,而联合抑制 Ang-2 和血管内皮生长因子的微环境效应可防止大转移瘤的生长。
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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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