The Vascular Basement Membrane as “Soil” in Brain Metastasis

Brain-specific homing and direct interactions with the neural substance are prominent hypotheses for brain metastasis formation and a modern manifestation of Paget's “seed and soil” concept. However, there is little direct evidence for this “neurotropic” growth in vivo. In contrast, many experimental studies have anecdotally noted the propensity of metastatic cells to grow along the exterior of pre-existing vessels of the CNS, a process termed vascular cooption. These observations suggest the “soil” for malignant cells in the CNS may well be vascular, rather than neuronal. We used in vivo experimental models of brain metastasis and analysis of human clinical specimens to test this hypothesis. Indeed, over 95% of early micrometastases examined demonstrated vascular cooption with little evidence for isolated neurotropic growth. This vessel interaction was adhesive in nature implicating the vascular basement membrane (VBM) as the active substrate for tumor cell growth in the brain. Accordingly, VBM promoted adhesion and invasion of malignant cells and was sufficient for tumor growth prior to any evidence of angiogenesis. Blockade or loss of the β1 integrin subunit in tumor cells prevented adhesion to VBM and attenuated metastasis establishment and growth in vivo. Our data establishes a new understanding of CNS metastasis formation and identifies the neurovasculature as the critical partner for such growth. Further, we have elucidated the mechanism of vascular cooption for the first time. These findings may help inform the design of effective molecular therapies for patients with fatal CNS malignancies.

脑特异性归巢与神经组织直接相互作用，是脑转移形成的核心假说，亦是佩吉特“种子与土壤”学说（Paget's “seed and soil” concept）的现代体现。然而，目前针对这种“嗜神经性”生长的体内（in vivo）直接证据仍极为匮乏。与之相对，诸多实验研究曾偶然观察到，转移细胞倾向于沿中枢神经系统（Central Nervous System, CNS）已存在血管的外壁生长，这一过程被称为血管共选择（vascular cooption）。上述观察结果提示，中枢神经系统内适配恶性细胞生长的“土壤”或许是血管结构，而非神经元组织。为此，我们采用脑转移体内实验模型，并对人类临床标本展开分析，以验证该假说。研究证实，在被检测的早期微转移灶中，超过95%均呈现血管共选择现象，几乎未发现孤立性嗜神经性生长的证据。这种与血管的相互作用具有黏附特性，表明血管基底膜（vascular basement membrane, VBM）是脑内肿瘤细胞生长的活性底物。相应地，血管基底膜可促进恶性细胞的黏附与侵袭，且在尚未出现血管生成（angiogenesis）的阶段，即可支持肿瘤生长。阻断肿瘤细胞的β1整合素亚基或使其缺失，可阻止其与血管基底膜的黏附，并削弱体内转移灶的建立与生长能力。本研究数据为中枢神经系统转移的形成机制提供了全新认知，并明确神经血管系统是此类肿瘤生长的关键伙伴。此外，我们首次阐明了血管共选择的作用机制。上述发现可为针对致命性中枢神经系统恶性肿瘤患者的有效分子治疗方案设计提供参考依据。