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As the current therapies of NF\u2010PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin\u20102 (ANGPT2) is elevated in patients with NF\u2010PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2\/TIE2 axis in NF\u2010PitNETs in the GH3 PitNET cell line, primary human NF\u2010PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF\u2010PitNET 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).\n                    <jats:italic>Tie2<\/jats:italic>\n                    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\u2010PitNETs and possibly in other tumors expressing ANGPT2\/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC\u2010specific expands our view on the microenvironmental cues that are essential for tumor progression.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202114364","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T06:01:10Z","timestamp":1646892070000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Angpt2\/Tie2 autostimulatory loop controls tumorigenesis"],"prefix":"10.1038","volume":"14","author":[{"given":"Ninelia Minaskan","family":"Karabid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-7407","authenticated-orcid":false,"given":"Tobias","family":"Wiedemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-010X","authenticated-orcid":false,"given":"Sebastian","family":"Gulde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-1166","authenticated-orcid":false,"given":"Hermine","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu Chandra","family":"Segaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Geppert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3926-1534","authenticated-orcid":false,"given":"Maria","family":"Rohm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Vitale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germano","family":"Gaudenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Dicitore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna Pauler","family":"Ankerst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rickmer","family":"Braren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8382-8062","authenticated-orcid":false,"given":"Georg","family":"Kaissis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Schillmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8601-9903","authenticated-orcid":false,"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3950-3652","authenticated-orcid":false,"given":"Stephan","family":"Herzig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Roncaroli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen B","family":"Honegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-7784","authenticated-orcid":false,"given":"Natalia S","family":"Pellegata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,10]]},"reference":[{"key":"BFEMMM202114364_CR1","doi-asserted-by":"crossref","first-page":"C5","DOI":"10.1530\/ERC-17-0004","volume":"24","author":"SL Asa","year":"2017","unstructured":"Asa SL, Casar\u2010Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N, Karavitaki N et\u00a0al (2017) From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. 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