Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3129
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Funding
- 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]
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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.
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