Abstract
Glioblastoma multiforme (GBM) is a malignant brain tumor with characteristics of strong aggressiveness which depend on vigorous microvascular supply. Vasculogenic mimicry (VM), a new microvascular circulation not involving endothelial cells, is reported as one part of the vascularization of GBM. Tumor-associated macrophages (TAMs), mostly present as immunosuppressive M2 phenotype in GBM, are well known as a promoter for tumor angiogenesis. However, whether TAMs can induce VM in GBM remains uncertain. In the present study, immunohistochemistry showed that higher numbers of macrophages infiltrating in the VM-positive area where tumor cells also highly express COX-2. By using the coculture model of U87 cell line and Interleukin-4-activated M2 macrophages, we found that the capability of VM formation was increased and COX-2 expression was up-regulated in U87 cells. Moreover, knockdown of COX-2 by siRNA Oligonucleotides or abrogating activity of COX-2 by specific inhibitors resulted in impairment of VM formation. Besides, in the process of VM formation, PGE2/EP1/PKC pathway was activated in U87 cells and inhibition of COX-2 led to down-regulation of PGE2 and PKC. In in vivo experiment, we found that COX-2 loss of function in the U87 xenograft model lead to less vascular mimicry. Collectively, our study demonstrates that M2 macrophages are capable of promoting generation of VM in GBM with COX-2 dependent, providing potential mechanisms of the interaction between inflammatory microenvironment and perivascular microenvironment.
Highlights
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults, with characteristics of extreme aggressiveness and high proliferation[1]
Our study showed the infiltration of macrophages in Vasculogenic mimicry (VM)-positive areas and the role and underlying mechanism of M2 macrophages in inducing VM formation in GBM cells
In order to investigate whether M2 macrophages promote VM formation in GBM cells, we compared the capability of channel formation in U87 cells with or without coculture with M2 macrophages
Summary
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults, with characteristics of extreme aggressiveness and high proliferation[1]. The aggressiveness of GBM depends on the invasion of tumor cells and extracellular matrix remodeling, and on the strong vascular and nutrition supply to the tumor cells. Anti-angiogenic monotherapy, for example bevacizumab (a monoclonal antibody of vascular endothelial growth factor), did not show anticipated benefit for improving the overall survival[3, 4]. For those suffered from GBM recurrence, bevacizumab revealed little therapeutic effect[5, 6]. The above results remind us that there may be another vascular supply system which is different from the classic blood vessels dependent on vascular endothelial cells
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