Research Papers:

Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma

Yuji Piao, Verlene Henry, Ningyi Tiao, Soon Young Park, Juan Martinez-Ledesma, Jian Wen Dong, Veerakumar Balasubramaniyan and John F. de Groot _

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Oncotarget. 2017; 8:96970-96983. https://doi.org/10.18632/oncotarget.18859

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Yuji Piao1, Verlene Henry2, Ningyi Tiao1, Soon Young Park1, Juan Martinez-Ledesma1, Jian Wen Dong1, Veerakumar Balasubramaniyan1 and John F. de Groot1

1Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Neuro-Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

John F. de Groot, email: [email protected]

Keywords: intercellular cell adhesion molecule-1, bevacizumab, signal transducer and activator of transcription 3, macrophage

Received: November 10, 2016     Accepted: June 10, 2017     Published: June 29, 2017


Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma’s resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. We also detected ICAM1 expression in most glioma stem cells (GSCs). We investigated the mechanism of ICAM-1 overexpression after bevacizumab treatment and found that ICAM-1 protein expression was markedly increased in a time-dependent manner in GSC11 and GSC17 cells under hypoxic conditions in vitro. We also found that hypoxia induced ICAM-1 overexpression through the up-regulation of phosphorylated signal transducer and activator of transcription (p-STAT3). Hypoxia-induced p-STAT3 increased the mRNA transcription of ICAM-1, which we could inhibit with the STAT3 inhibitor AZD1480. Next, we used GFP-tagged ICAM-1 shRNA lentivirus to knock down ICAM-1 in GSC11 and GSC17 glioma cell lines. Then, we injected shICAM-1 GSC11 and scramble glioma stem cells into the brains of nude mice. Mice bearing tumors from shICAM-1 GSC11 cells survived significantly longer than mice injected with control cells did. The tumor sizes was significantly decreased in mice bearing tumors from shICAM-1 cells than that in mice bearing tumors from GFP-tagged GSC11 control cells. Knocking down ICAM-1 suppressed tumor invasion in vitro and in vivo and inhibited macrophage infiltration to the tumor site in bevacizumab-treated mice. Our findings suggest that ICAM-1 is a potentially important mediator of tumor migration and invasion in bevacizumab-resistant glioblastoma. Targeting ICAM-1 may provide a new strategy for enhancing the efficacy of antiangiogenic therapy against glioblastoma and preventing the invasive phenotype of the disease.

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