Research Papers:

Tumor-associated macrophages induce vasculogenic mimicry of glioblastoma multiforme through cyclooxygenase-2 activation

Xiaoming Rong, Bo Huang, Shuwei Qiu, Xiangpen Li, Lei He and Ying Peng _

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Oncotarget. 2016; 7:83976-83986. https://doi.org/10.18632/oncotarget.6930

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Xiaoming Rong1,*, Bo Huang1,*, Shuwei Qiu1,2, Xiangpen Li1, Lei He1, Ying Peng1

1Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China

2Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China

*These authors have contributed equally to this work

Correspondence to:

Ying Peng, e-mail: [email protected]

Keywords: M2 macrophages, glioblastoma multiforme, vasculogenic mimicry, COX-2

Received: June 03, 2015   Accepted: December 29, 2015   Published: January 18, 2016


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.

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