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|
gratis
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.
Yang, YunlongKarolinska Institute, Sweden
(författare)
Seki, TakahiroKarolinska Institute, Sweden
(författare)
Nakamura, MasakiKarolinska Institute, Sweden
(författare)
Andersson, PatrikKarolinska Institute, Sweden
(författare)
Rouhi, PegahKarolinska Institute, Sweden
(författare)
Yang, XiaojuanKarolinska Institute, Sweden
(författare)
Jensen, LasseLinköpings universitet,Avdelningen för kardiovaskulär medicin,Hälsouniversitetet,Karolinska Institute, Sweden(Swepub:liu)larje86
(författare)
Lim, SharonKarolinska Institute, Sweden
(författare)
Feng, NinghanKarolinska Institute, Sweden
(författare)
Xue, YuanKarolinska Institute, Sweden
(författare)
Li, XuriSun Yat Sen University, Peoples R China
(författare)
Larsson, OlaKarolinska Institute, Sweden
(författare)
Ohhashi, ToshioShinshu University, Japan
(författare)
Cao, YihaiLinköpings universitet,Avdelningen för kardiovaskulär medicin,Hälsouniversitetet,Karolinska Institute, Sweden(Swepub:liu)yihca64
(författare)