Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany.
Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China.
Neuro Oncol. 2024 Nov 4;26(11):2084-2099. doi: 10.1093/neuonc/noae094.
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).
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.
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.
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.
脑转移（BM）由于其对神经功能的影响、有限的治疗选择和不良预后，构成了肿瘤学领域日益严峻的挑战。BM 通过循环肿瘤细胞穿过血脑屏障而发生。然而，转移过程仍知之甚少。我们在此提出了一个模拟类似梗塞的微环境反应的脑定植过程，该过程依赖于血管生成素-2（Ang-2）和血管内皮生长因子（VEGF）。
本研究使用了心脏内 BM 模型，并通过颅窗通过双光子显微镜监测脑内血液微循环。通过颅磁共振成像、生物发光成像和死后尸检观察 BM 的形成。采用 Ang-2/VEGF 靶向策略和 Ang-2 功能获得（GOF）小鼠来干扰 BM 的形成。此外，还分析了 BM 患者的血管和基质因素以及临床结果。
检测到癌细胞引起的血管闭塞，同时伴有显著的脑血液微循环紊乱和局灶性中风样组织学特征。在小鼠和人类 BM 中，脑内皮细胞均表现出明显的 Ang-2 表达上调。Ang-2 GOF 导致 BM 负担增加。联合抗 Ang-2/抗 VEGF 治疗可减少脑转移瘤的大小和数量。已建立的人类 BM 中肿瘤血管的 Ang-2 表达与生存呈负相关。
我们的观察结果揭示了脑血液微循环紊乱与脑转移形成之间的关系。这表明肿瘤细胞引起的血管闭塞促进了脑转移的渗出和定植，而联合抑制 Ang-2 和 VEGF 的微环境效应可防止大转移瘤的生长。
