Baker Gregory J, Yadav Viveka Nand, Motsch Sebastien, Koschmann Carl, Calinescu Anda-Alexandra, Mineharu Yohei, Camelo-Piragua Sandra Ines, Orringer Daniel, Bannykh Serguei, Nichols Wesley S, deCarvalho Ana C, Mikkelsen Tom, Castro Maria G, Lowenstein Pedro R
Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Neoplasia. 2014 Jul;16(7):543-61. doi: 10.1016/j.neo.2014.06.003.
As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.
当胶质瘤细胞浸润大脑时，它们会与各种脑微解剖结构相关联，如血管、白质束和脑实质。这些不同的侵袭模式如何协调肿瘤生长并影响临床结果仍知之甚少。我们研究了在血管高度丰富的大脑中，血管周围生长如何影响胶质瘤的生长模式以及对抗血管生成治疗的反应。原位植入的啮齿动物和人类胶质瘤细胞通常在脑血管周围空间内侵袭和增殖。这种脑肿瘤生长和侵袭形式也被证明是新生的内源性小鼠脑肿瘤、原发性人类胶质母细胞瘤（GBM）活检以及外周癌转移至人脑的特征。当单个胶质瘤细胞将血管周围空间用作肿瘤侵袭的通道时，血管周围侵袭性脑肿瘤会由正常脑微血管形成血管。基于主体的计算模型再现了血管周围胶质瘤的生物学生长，而无需新生血管生成。我们通过用血管生成抑制剂贝伐单抗和DC101治疗动物，测试了血管周围胶质瘤中新生血管生成的必要性。这些抑制剂诱导了预期的血管正常化，但未能减少肿瘤生长或提高原位或内源性胶质瘤小鼠的生存率，同时加剧了脑肿瘤的侵袭。我们的结果提供了令人信服的实验证据，支持最近描述的临床使用的抗血管生成药物未能延长人类GBM患者总生存期的观点。
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