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PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2015 (English)In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 1, no 3, article id e1400244Article in journal (Refereed) Published
Abstract [en]

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE , 2015. Vol. 1, no 3, article id e1400244
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Cell and Molecular Biology
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URN: urn:nbn:se:liu:diva-145073DOI: 10.1126/sciadv.1400244ISI: 000216592400006PubMedID: 26601163OAI: oai:DiVA.org:liu-145073DiVA, id: diva2:1181255
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni

Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-03-09

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Cao, Yihai
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