Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.
Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.
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DOI：
10.1016/j.biomaterials.2018.01.053
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发表时间：
2018-04
期刊：
影响因子：
14
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Cui X;Morales RT;Qian W;Wang H;Gagner JP;Dolgalev I;Placantonakis D;Zagzag D;Cimmino L;Snuderl M;Lam RHW;Chen W
胶质母细胞瘤（GBM）是最致命的原发性成人脑肿瘤，其病理特征是扭曲的新生血管形成，弥漫性肿瘤相关的巨噬细胞浸润和有效的免疫抑制。构建具有仿生细胞异质性和相互作用、促/抗炎环境和细胞外基质（ECM）力学的器官型肿瘤血管生成模型对于临床前抗血管生成治疗筛选至关重要。然而，目前的体外系统不能准确反映体内人脑肿瘤微环境。在这里，我们设计了一个三维（3D），微流体血管生成模型，具有可控和仿生免疫抑制条件，免疫血管和细胞基质相互作用。我们在体外证明，GL 261和CT-2A GBM样肿瘤引导巨噬细胞极化向M2样表型，以促进免疫抑制和促血管生成的生态位，这与人脑肿瘤一致。我们区分出GBM和M2样免疫抑制性巨噬细胞促进血管生成，而M1样促炎性巨噬细胞抑制血管生成，我们称之为“炎症驱动的血管生成”。我们观察到可溶性免疫抑制细胞因子，主要是TGF-β1和表面整合素（αvβ3）内皮-巨噬细胞相互作用是炎症驱动的血管生成所必需的。我们证明了使用整合素（αvβ3）特异性胶原水凝胶调节细胞粘附受体，通过Src-PI 3 K-YAP信号传导调节炎症驱动的血管生成，突出了改变细胞-ECM相互作用在炎症中的重要性。为了验证我们的3D类器官模型的临床前应用和炎症驱动的血管生成的机制发现，我们筛选了一种新型的双重整合素（αvβ3）和细胞因子受体（TGFβ-R1）阻断剂，通过同时靶向巨噬细胞相关的免疫抑制、内皮-巨噬细胞相互作用和改变的ECM来抑制GBM肿瘤新生血管形成。因此，我们提供了一个互动和可控的GBM肿瘤微环境，并强调了巨噬细胞相关的免疫抑制在GBM血管生成中的重要性，为筛选新型抗血管生成疗法开辟了新的方向。
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-β1, and surface integrin (αvβ3) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (αvβ3)-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 (αvβ3) and cytokine receptor (TGFβ-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.
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影响因子：
4.8
作者：
Bayin, N. Sumru;Ma, Lin;Thomas, Cheddhi;Baitalmal, Rabaa;Sure, Akhila;Fansiwala, Kush;Bustoros, Mark;Golfinos, John G.;Pacione, Donato;Snuderl, Matija;Zagzag, David;Barcellos-Hoff, Mary Helen;Placantonakis, Dimitris
通讯作者：
Placantonakis, Dimitris
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
影响因子：
5.6
作者：
Ferrari, Giovanni;Cook, Brandoch D.;Terushkin, Vitaly;Pintucci, Giuseppe;Mignatti, Paolo
通讯作者：
Mignatti, Paolo
影响因子：
--
作者：
Jackson C;Ruzevick J;Phallen J;Belcaid Z;Lim M
通讯作者：
Lim M
DOI：
10.1097/ppo.0b013e3182431c6f
发表时间：
2012-01
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Gerstner ER;Batchelor TT
通讯作者：
Batchelor TT