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  • Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis.

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis.

Nature communications (2013-07-09)
Kayoko Hosaka, Yunlong Yang, Takahiro Seki, Masaki Nakamura, Patrik Andersson, Pegah Rouhi, Xiaojuan Yang, Lasse Jensen, Sharon Lim, Ninghan Feng, Yuan Xue, Xuri Li, Ola Larsson, Toshio Ohhashi, Yihai Cao
ABSTRACT

Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-β signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-β and inactivation of the PDGF-β signalling decreases integrin α1β1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Goat Anti-Rabbit IgG Antibody, Cy3 conjugate, Species Adsorbed, 1.5 mg/mL, Chemicon®
Sigma-Aldrich
Anti-NG2 Chondroitin Sulfate Proteoglycan Antibody, Chemicon®, from rabbit