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PlGF-induced VEGFR1...
PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors
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- Iwamoto, Hideki (författare)
- Karolinska Inst, Sweden
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- Zhang, Yin (författare)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Seki, Takahiro (författare)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Yang, Yunlong (författare)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Nakamura, Masaki (författare)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Wang, Jian (författare)
- Karolinska Inst, Sweden
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- Yang, Xiaojuan (författare)
- Karolinska Inst, Sweden; Tongji Univ, Peoples R China
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- Torimura, Takuji (författare)
- Kurume Univ, Japan
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- Cao, Yihai (författare)
- Linköpings universitet,Institutionen för medicin och hälsa,Medicinska fakulteten,Karolinska Inst, Sweden; Univ Leicester, England; Glenfield Hosp, England
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(creator_code:org_t)
- AMER ASSOC ADVANCEMENT SCIENCE, 2015
- 2015
- Engelska.
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Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 1:3
- Relaterad länk:
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https://liu.diva-por... (primary) (Raw object)
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http://advances.scie...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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- art (ämneskategori)
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