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Endocrine Abstracts (2022) 81 OC7.6 | DOI: 10.1530/endoabs.81.OC7.6

1Helmholtz Zentrum München, Institute for Diabetes and Cancer, Munich, Germany; 2Istituto Auxologico Italiano IRCCS, Milan, Italy; 3Technical University Munich, Munich, Germany; 4Technical University Dresden, Dresden, Germany; 5University of Manchester, Manchester, United Kingdom; 6Eberhard Karls University Tübingen, Tübingen, Germany

Background: Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated to frequent relapse and significant comorbidities. As current treatments often fail against NF-PitNETs, identifying actionable therapeutic targets is essential. We focused on the angiopoietin-2 (Angpt2)/Tie2 axis, usually active in endothelial cells (ECs).

Methods: ANGPT2 plasma levels in NF-PitNET patients and healthy controls were measured by ELISA. qRT-PCR and immunohistochemistry assessed Angpt2 and Tie2 expression in rat and human NF-PitNETs. The role of endogenous Angpt2 in PitNET cells was investigated by gene knockdown (siRNA, shRNA) followed by proliferation/apoptosis assays. Xenografts of shAngpt2 PitNET cells in zebrafish embryos demonstrated that tumor cell-borne Angpt2 is pro-angiogenic. Proximity ligation assay (PLA) showed Angpt2/Tie2 interaction on primary NF-PitNET cells. Downstream targets activation upon Angpt2-mediated receptor stimulation was assessed by western blotting. Mouse xenografts of CRISPR/Cas9-generated Tie2-knockout PitNET cells proved the role of Tie-2 in pituitary tumorigenesis in vivo. Drugs inhibiting Angpt2/Tie2 signaling were tested against primary rat/human NF-PitNET cultures. Treatment of mouse xenografts of PitNET cells with an angiopoietin-neutralizing peptibody (AMG386), followed by MRI imaging, determined the effects of Angpt2/Tie2 inhibition on tumor growth in vivo. The efficacy of Angpt/Tie2 inhibition was also assessed in MENX rats, the only spontaneous and autochthonous NF-PitNET model. MENX rats were treated with AMG386 and longitudinally monitored using anatomical and functional (diffusion weighted) MRI.

Results: In NF-PitNET patients, circulating Angpt2 levels are elevated and correlate with tumor aggressiveness. PitNET cells express and secrete bioactive Angpt2, which stimulates tumor cell proliferation in vitro, and angiogenesis in zebrafish xenografts in vivo. Noteworthy, NF-PitNET cells possess a functional Tie2 receptor, which is activated by Angpt2 and stimulates downstream mitogenic signals. This establishes an autocrine/paracrine stimulatory loop in NF-PitNET cells, as so far only demonstrated in ECs. Tie2 knockout blunts PitNETs growth in vivo. Proof-of-principle pharmacological inhibition of Angpt2/Tie2 signaling antagonizes NF-PitNETs ex vivo (primary cultures of human/rat tumors) and in vivo (mouse xenografts, MENX rats).

Conclusion: The Angpt2/Tie2 axis emerges as exploitable therapeutic target in NF-PitNETs, hence addressing an unmet clinical need. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on microenvironmental cues essential for tumor progression. Tumor-targeted Angpt2/Tie2 inhibition is a novel concept in anti-cancer strategies applicable to tumors expressing Angpt2/Tie2.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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