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

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 and Yihai Cao ()
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Kayoko Hosaka: Tumor and Cell Biology, Karolinska Institute
Yunlong Yang: Tumor and Cell Biology, Karolinska Institute
Takahiro Seki: Tumor and Cell Biology, Karolinska Institute
Masaki Nakamura: Tumor and Cell Biology, Karolinska Institute
Patrik Andersson: Tumor and Cell Biology, Karolinska Institute
Pegah Rouhi: Tumor and Cell Biology, Karolinska Institute
Xiaojuan Yang: Tumor and Cell Biology, Karolinska Institute
Lasse Jensen: Tumor and Cell Biology, Karolinska Institute
Sharon Lim: Tumor and Cell Biology, Karolinska Institute
Ninghan Feng: Tumor and Cell Biology, Karolinska Institute
Yuan Xue: Tumor and Cell Biology, Karolinska Institute
Xuri Li: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University
Ola Larsson: Karolinska Institute
Toshio Ohhashi: Shinshu University School of Medicine
Yihai Cao: Tumor and Cell Biology, Karolinska Institute

Nature Communications, 2013, vol. 4, issue 1, 1-14

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3129

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