Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma
Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma
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DOI：
10.1002/path.5569
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发表时间：
2020-11-24
影响因子：
7.3
通讯作者：
Brandenburg, Susan
中科院分区：
文献类型：
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作者：
Blank, Anne;Kremenetskaia, Irina;Brandenburg, Susan
骨髓细胞是多形性胶质母细胞瘤（GBM）微环境的固有部分。越来越多的证据表明它们参与了肿瘤逃逸的机制，特别是在最初有希望的抗VEGF/VEGFR治疗后产生耐药性。因此，我们试图确定髓样细胞促进人GBM中促血管生成分子表达的能力。我们研究了GBM标本与间变性星形细胞瘤（WHO III级）和癫痫患者新鲜手术标本的比较。流式细胞术分析显示GBM组织中存在两种不同的CD 11b（+）CD 45（+）细胞群，它们被鉴定为小胶质细胞/巨噬细胞和粒细胞。由于不同的粒细胞流入，GBM样品被细分为具有低（GBM-hPMNL）和高（GBM-hPMNL）数量的粒细胞（多形核白细胞; PMNL）的组，这与小胶质细胞/巨噬细胞群体的活化有关。GBM-hPMNL组的小胶质细胞/巨噬细胞与星形细胞瘤样本的那些相似，但是GBM-hPMNL组织的那些通过表达高水平的CD 163、TIE 2、HIF 1 α、VEGF、CXCL 2和CD 13而揭示改变的表型。虽然小胶质细胞/巨噬细胞代表了替代促血管生成因子的主要来源，但粒细胞还参与了IL 8和CD 13的产生。此外，GBM-hPMNL标本中的小胶质细胞/巨噬细胞与肿瘤血管高度相关，伴随着血管结构的重塑。我们的数据强调，肿瘤浸润髓样细胞可能发挥关键作用的抗血管生成治疗的疗效有限，绕过VEGF介导的途径，通过表达替代促血管生成因子。(c)2020大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Myeloid cells are an inherent part of the microenvironment of glioblastoma multiforme (GBM). There is growing evidence for their participation in mechanisms of tumor escape, especially in the development of resistance following initially promising anti-VEGF/VEGFR treatment. Thus, we sought to define the capability of myeloid cells to contribute to the expression of proangiogenic molecules in human GBM. We investigated GBM specimens in comparison with anaplastic astrocytoma (WHO grade III) and epilepsy patient samples freshly obtained from surgery. Flow cytometric analyses revealed two distinct CD11b(+)CD45(+) cell populations in GBM tissues, which were identified as microglia/macrophages and granulocytes. Due to varied granulocyte influx, GBM samples were subdivided into groups with low (GBM-lPMNL) and high (GBM-hPMNL) numbers of granulocytes (polymorphonuclear leukocytes; PMNL), which were related to activation of the microglia/macrophage population. Microglia/macrophages of the GBM-lPMNL group were similar to those of astrocytoma specimens, but those of GBM-hPMNL tissues revealed an altered phenotype by expressing high levels of CD163, TIE2, HIF1 alpha, VEGF, CXCL2 and CD13. Although microglia/macrophages represented the main source of alternative proangiogenic factors, additionally granulocytes participated by production of IL8 and CD13. Moreover, microglia/macrophages of the GBM-hPMNL specimens were highly associated with tumor blood vessels, accompanied by remodeling of the vascular structure. Our data emphasize that tumor-infiltrating myeloid cells might play a crucial role for limited efficacy of anti-angiogenic therapy bypassing VEGF-mediated pathways through expression of alternative proangiogenic factors. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.