Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis

被引：207

作者：

Cui, Xin ^{[1
]}

Morales, Renee-Tyler Tan ^{[1
]}

Qian, Weiyi ^{[1
]}

Wang, Haoyu ^{[1
]}

Gagner, Jean-Pierre ^{[2
]}

Dolgalev, Igor ^{[2
]}

Placantonakis, Dimitris ^{[3
]}

Zagzag, David ^{[2
,3
]}

Cimmino, Luisa ^{[2
]}

Snuderl, Matija ^{[2
]}

Lam, Raymond H. W. ^{[4
]}

Chen, Weiqiang ^{[1
]}

机构：

[1] NYU, Dept Mech & Aerosp Engn, Brooklyn, NY 11201 USA

[2] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[3] NYU, Dept Neurosurg, Sch Med, 550 1St Ave, New York, NY 10016 USA

[4] City Univ Hong Kong, Dept Mech & Biomed Engn, Hong Kong, Hong Kong, Peoples R China

来源：

BIOMATERIALS | 2018年 / 161卷

基金：

美国国家卫生研究院;

关键词：

Glioblastoma; Angiogenesis; Endothelial-macrophage interaction; ECM; TUMOR-ASSOCIATED MACROPHAGES; ANTIANGIOGENIC THERAPY; STEM-CELLS; PATHWAY; CANCER; POLARIZATION; MATRIGEL; GRADE; MODEL;

D O I：

10.1016/j.biomaterials.2018.01.053

中图分类号：

R318 [生物医学工程];

学科分类号：

100103 [病原生物学];

摘要：

Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-beta 1, and surface integrin (alpha(v)beta(3)) endothelial macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (4133)-specific collagen hydrogel regulated inflammation driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (alpha(v)beta(3)) and cytokine receptor (TGF beta-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：164 / 178

页数：15

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