Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
2013 (English)In: Nature Communications, ISSN 2041-1723, Vol. 4, no 2129Article in journal (Refereed) Published
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-beta signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-beta and inactivation of the PDGF-beta signalling decreases integrin alpha 1 beta 1 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.
Place, publisher, year, edition, pages
Nature Publishing Group: Nature Communications , 2013. Vol. 4, no 2129
Engineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-97672DOI: 10.1038/ncomms3129ISI: 000323715900009OAI: oai:DiVA.org:liu-97672DiVA: diva2:649973
Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Karolinska Institute||Tianjin Natural Science Foundation (CMM-Tianjin)|09ZCZDSF04400|Torsten Soderbergs foundation||European Union Integrated Project of Metoxia|222741|European Research Council (ERC)|250021|2013-09-192013-09-192013-09-19