title: Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas.
abstract: 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.
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Nahir
authors.initials: N
authors.lastname: Cortes-Santiago
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mohammad B
authors.initials: MB
authors.lastname: Hossain
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Gabrusiewicz
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.affiliation: Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Alonso
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Yung
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D042787:Receptor, TIE-2
keywords: Tie2-expressing monocytes; angiopoietin 2; anti-angiogenesis; glioma; invasion