Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas
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Nahir Cortes-Santiago1,6, Mohammad B. Hossain1, Konrad Gabrusiewicz1, Xuejun Fan1, Joy Gumin2, Frank C. Marini3, Marta M. Alonso4, Frederick Lang2, W.K. Yung1, Juan Fueyo1,2, Candelaria Gomez-Manzano1,5,6
1Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, USA
4Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain
5Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
Candelaria Gomez-Manzano, e-mail: firstname.lastname@example.org
Keywords: anti-angiogenesis, glioma, invasion, angiopoietin 2, Tie2-expressing monocytes
Received: November 10, 2015 Accepted: January 29, 2016 Published: February 21, 2016
Glioblastoma recurrence after treatment with the anti–vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.
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