title: PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.
abstract: 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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden. ; Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai, People's Republic of China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 831 0011 Kurume, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden. ; Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden. ; Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
keywords: Angiogenesis; Notch signaling; PlGF; remodeling; tumor growth; vascular