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HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment

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Abstract

Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors—a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFRβ. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.

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Acknowledgments

We acknowledge Kristian Pietras and Sara Cunha, Karolinska Institute, for their valuable help in setting up the RIP1-Tag2 tumor model. We also thank Lars Hellman, Uppsala University for help with Fig. 7. This study was supported by the Swedish Cancer Society #11 0653 and The Swedish Research Council #2010-6903-75363-44 to AKO and #K2012-77PK-22157-01-2 to JC.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments comply with current Swedish laws.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Husargatan 3, 751 23, Uppsala, Sweden

    Jessica Cedervall, Yanyu Zhang, Maria Ringvall, Aristidis Moustakas & Anna-Karin Olsson

  2. Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden

    Åsa Thulin & Agneta Siegbahn

  3. Ludwig Institute for Cancer Research Ltd, Box 595, 751 24, Uppsala, Sweden

    Aristidis Moustakas

  4. Biointerface Laboratory, Department of Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

    Willi Jahnen-Dechent

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  1. Jessica Cedervall
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Correspondence to Anna-Karin Olsson.

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Cedervall, J., Zhang, Y., Ringvall, M. et al. HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment. Angiogenesis 16, 889–902 (2013). https://doi.org/10.1007/s10456-013-9363-8

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