Angpt2/Tie2 autostimulatory loop controls tumorigenesis

Ninelia Minaskan Karabid, Tobias Wiedemann, Sebastian Gulde, Hermine Mohr, Renu Chandra Segaran, Julia Geppert, Maria Rohm, Giovanni Vitale, Germano Gaudenzi, Alessandra Dicitore, Donna Pauler Ankerst, Yiyao Chen, Rickmer Braren, Georg Kaissis, Franz Schilling, Mathias Schillmaier, Graeme Eisenhofer, Stephan Herzig, Federico Roncaroli, Jürgen B. HoneggerNatalia S. Pellegata

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere14364
JournalEMBO Molecular Medicine
Volume14
Issue number5
DOIs
StatePublished - 9 May 2022

Keywords

  • PitNETs
  • angiopoietin 2
  • anti-angiopoietin biologicals
  • tumor-bound Tie2
  • tumor/endothelial cell crosstalk

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