Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma

Publication

Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma

Journal Paper/Review - Dec 14, 2015

Scholz Alexander, Meinhardt Matthias, Weyerbrock Astrid, Timmer Marco, Goldbrunner Roland, Deckert Martina, Braun Christian, Schittenhelm Jens, Frueh Jochen T, Ullrich Evelyn, Mittelbronn Michel, Plate Karl H, Krex Dietmar, Herrlinger Ulrich, Glas Martin, Harter Patrick N, Cremer Sebastian, Yalcin Burak H, Gurnik Stefanie, Yamaji Maiko, Di Tacchio Mariangela, Sommer Kathleen, Baumgarten Peter, Bähr Oliver, Steinbach Joachim P, Trojan Jörg, Reiss Yvonne

Citation

Scholz A, Meinhardt M, Weyerbrock A, Timmer M, Goldbrunner R, Deckert M, Braun C, Schittenhelm J, Frueh J, Ullrich E, Mittelbronn M, Plate K, Krex D, Herrlinger U, Glas M, Harter P, Cremer S, Yalcin B, Gurnik S, Yamaji M, Di Tacchio M, Sommer K, Baumgarten P, Bähr O, Steinbach J, Trojan J, Reiss Y. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol Med 2015; 8:39-57.

Type

Journal Paper/Review (English)

Journal

EMBO Mol Med 2015; 8

Publication Date

Dec 14, 2015

Issn Electronic

1757-4684

Pages

39-57

Brief description/objective

Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy.