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

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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
    Linköping University)

  • 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
    Linköping University)

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.

Suggested Citation

  • 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 O, 2013. "Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis," Nature Communications, Nature, vol. 4(1), pages 1-14, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3129
    DOI: 10.1038/ncomms3129
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