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Minaskan Karabid, N. ; Wiedemann, T. ; Gulde, S. ; Mohr, H. ; Segaran Renu, C. ; Geppert, J. ; Rohm, M. ; Vitale, G.* ; Gaudenzi, G.* ; Dicitore, A.* ; Ankerst, D.P.* ; Chen, Y.* ; Braren, R.* ; Kaissis, G.* ; Schilling, F.* ; Schillmaier, M.* ; Eisenhofer, G.* ; Herzig, S. ; Roncaroli, F.* ; Honegger, J.B.* ; Pellegata, N.S.

Angpt2/Tie2 autostimulatory loop controls tumorigenesis.

EMBO Mol. Med.:e14364 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF-PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on the microenvironmental cues that are essential for tumor progression.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Angiopoietin 2 ; Anti-angiopoietin Biologicals ; Pitnets ; Tumor-bound Tie2 ; Tumor/endothelial Cell Crosstalk; Endothelial-cell Survival; Focal Adhesion Kinase; Disease Progression; Messenger-rna; Angiopoietin-2; Tie2; Expression; Adenomas; Cancer; Invasion
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: , Issue: , Pages: , Article Number: e14364 Supplement: ,
Publisher Wiley
Publishing Place Chichester
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
POF-Topic(s) 30201 - Metabolic Health
90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502590-001
G-501900-257
G-501900-251
Grants Deutsche Krebshilfe
German Research Foundation (Deutsche Forschungsgemeinschaft-DFG)
Wilhelm Sander Stiftung foundation
DOI 10.15252/emmm.202114364
WOS ID WOS:000766598000001
Scopus ID 85126009171
PubMed ID 35266635
Erfassungsdatum 2022-05-04
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