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M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells.

ABSTRACT: Vasculogenic mimicry (VM) has offered a new horizon for understanding tumor angiogenesis, but the mechanisms of VM in glioma progression have not been studied explicitly until now. As a significant component of immune infiltration in tumor microenvironment, macrophages have been demonstrated to play an important role in tumor growth and angiogenesis. However, whether macrophages could play a potential key role in glioma VM is still poorly understood. Herein we reported that both VM and CD163+ cells were associated with WHO grade and reduced patient survival, and VM channel counting was correlated to the number of infiltrated CD163+ cells in glioma specimens. In vitro studies of glioma cell lines implicated that M2-like macrophages (M2) promoted glioma VM. We found that conditional medium derived from M2 amplified IL-6 expression in glioma cells. Furthermore, our data indicated that IL-6 could promote glioma VM, as blocking IL-6 with neutralizing antibodies abrogated M2-mediated VM enhancement. In addition, the potent PKC inhibitor bisindolylmaleimide I could prevent M2-induced IL-6 upregulation and further inhibited glioma VM facilitation. Taken together, our results suggested that M2-like macrophages drove glioma VM through amplifying IL-6 secretion in glioma cells via PKC pathway.

SUBMITTER: Zhang L

PROVIDER: S-EPMC5352199 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells.

Zhang Lin L Xu Yangyang Y Sun Jintang J Chen Weiliang W Zhao Lei L Ma Chao C Wang Qingjie Q Sun Jia J Huang Bin B Zhang Yun Y Li Xingang X Qu Xun X

Oncotarget 20170101 1

Vasculogenic mimicry (VM) has offered a new horizon for understanding tumor angiogenesis, but the mechanisms of VM in glioma progression have not been studied explicitly until now. As a significant component of immune infiltration in tumor microenvironment, macrophages have been demonstrated to play an important role in tumor growth and angiogenesis. However, whether macrophages could play a potential key role in glioma VM is still poorly understood. Herein we reported that both VM and CD163+ ce ...[more]

PMID: 27903982

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Project description:Vasculogenic mimicry (VM) has been identified as an important vasculogenic mechanism in malignant tumors, but little is known about its clinical meanings and mechanisms in oligodendroglioma. In this study, VM-positive cases were detected in 28 (20.6%) out of 136 oligodendroglioma samples, significantly associated with higher WHO grade, lower Karnofsky performance status (KPS) scores, and recurrent tumor (p < 0.001, p = 0.040, and p = 0.020 respectively). Patients with VM-positive oligodendroglioma had a shorter progress-free survival (PFS) compared with those with VM-negative tumor (p < 0.001), whereas no significant difference was detected in overall survival (OS) between these patients. High levels of phosphorylate serine/threonine kinases Ataxia-telangiectasia mutated (pATM) and phosphorylate Ataxia-telangiectasia and Rad3-Related (pATR) were detected in 31 (22.8%) and 34 (25.0%), respectively out of 136 oligodendroglioma samples. Higher expressions of pATM and pATR were both associated with a shorter PFS (p < 0.001 and p < 0.001). VM-positive oligodendroglioma specimens tended to exhibit higher pATM and pATR staining than VM-negative specimens (rs = 0.435, p < 0.001 and rs = 0.317, p < 0.001). Besides, Hypoxia-inducible factor-1α (HIF1α) expression was detected in 14(10.3%) samples, correlated with higher WHO grade and non-frontal lobe (p = 0.010 and p = 0.029). However, no obvious connection was detected between HIF1α expression and VM formation (p = 0.537). Finally, either univariate or multivariate analysis suggested that VM was an independent unfavorable predictor for oligodendroglioma patients (p < 0.001, HR = 7.928, 95%CI: 3.382-18.584, and p = 0.007, HR = 4.534, 95%CI: 1.504-13.675, respectively). VM is a potential prognosticator for tumor progression in oligodendroglioma patients. Phosphorylation of ATM and ATR linked to treatment-resistance may be associated with VM formation. The role of VM in tumor progression and the implication of pATM/pATR in VM formation may provide potential therapeutic targets for oligodendroglioma treatment.

Project description:Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.

Dataset Information

M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells.

Publications

M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells.

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