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- Iwamoto, HidekiKarolinska Inst, Sweden (author)
PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors
- Article/chapterEnglish2015
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- AMER ASSOC ADVANCEMENT SCIENCE,2015
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- LIBRIS-ID:oai:DiVA.org:liu-145073
- https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-145073URI
- https://doi.org/10.1126/sciadv.1400244DOI
- http://kipublications.ki.se/Default.aspx?queryparsed=id:136560524URI
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- Language:English
- Summary in:English
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- 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
- 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.
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- Zhang, YinKarolinska Institutet,Karolinska Inst, Sweden (author)
- Seki, TakahiroKarolinska Institutet,Karolinska Inst, Sweden (author)
- Yang, YunlongKarolinska Institutet,Karolinska Inst, Sweden (author)
- Nakamura, MasakiKarolinska Institutet,Karolinska Inst, Sweden (author)
- Wang, JianKarolinska Inst, Sweden (author)
- Yang, XiaojuanKarolinska Inst, Sweden; Tongji Univ, Peoples R China (author)
- Torimura, TakujiKurume Univ, Japan (author)
- Cao, YihaiLinköpings universitet,Institutionen för medicin och hälsa,Medicinska fakulteten,Karolinska Inst, Sweden; Univ Leicester, England; Glenfield Hosp, England(Swepub:liu)yihca64 (author)
- Karolinska InstitutetKarolinska Inst, Sweden (creator_code:org_t)
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- In:Science Advances: AMER ASSOC ADVANCEMENT SCIENCE1:32375-2548
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- https://liu.diva-portal.org/smash/get/diva2:1181255/FULLTEXT01.pdffulltext:print
- http://advances.sciencemag.org/content/1/3/e1400244.full.pdf
- https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-145073
- https://doi.org/10.1126/sciadv.1400244
- http://kipublications.ki.se/Default.aspx?queryparsed=id:136560524
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- Yang, Xiaojuan
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