Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature.
Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy.
Hedlund
Eva-Maria
EM
Department of Microbiology and Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Hosaka
Kayoko
K
Zhong
Zhaodong
Z
Cao
Renhai
R
Cao
Yihai
Y
D000818:Animals; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology; D020286:Pericytes / Q000166:cytology / Q000473:pathology / Q000502:physiology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000627:therapeutic use
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2