Research ArticleANGIOGENESIS

PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors

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Science Advances  10 Apr 2015:
Vol. 1, no. 3, e1400244
DOI: 10.1126/sciadv.1400244

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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.

  • Angiogenesis
  • Notch signaling
  • tumor growth
  • PlGF
  • vascular
  • remodeling

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