Tumor-associated macrophages induce vasculogenic mimicry of glioblastoma multiforme through cyclooxygenase-2 activation.
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.
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Xiaoming
X
Rong
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Bo
B
Huang
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.|Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Shuwei
S
Qiu
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Xiangpen
X
Li
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Lei
L
He
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Ying
Y
Peng
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D018572:Disease-Free Survival; D004789:Enzyme Activation; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; C545635:PTGER1 protein, human; D058306:Receptors, Prostaglandin E, EP1 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011493:Protein Kinase C; D015232:Dinoprostone
COX-2; M2 macrophages; glioblastoma multiforme; vasculogenic mimicry