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Platelets govern pre-metastatic tumor communication to bone

Oncogene volume 32, pages 4319–4324 (2013)Cite this article

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Abstract

Although the survival rate for early detected cancers is high, once a cancer metastasizes to bone, it is incurable. Interestingly, patients without visible metastases display abnormal bone formation and resorption, suggesting a link between primary cancers and the bone microenvironment prior to metastasis, and this link likely facilitates preparation of the pre-metastatic niche. We hypothesized that communication with the primary tumor would result in bone remodeling alterations, and that platelets could facilitate this communication. By using three tumor models, we demonstrate that primary tumor growth stimulates bone formation measured by microcomputed tomography. Further, platelet depletion prevented tumor-induced bone formation, highlighting the importance of platelets in the communication between tumors and the bone microenvironment. Finally, we determine that platelets sequester a variety of tumor-derived proteins, TGF-β1 and MMP-1 in particular, which regulate bone formation. Thus, our data reveal that platelets function as mediators of tumor–bone communication prior to metastasis.

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Abbreviations

BV/TV:

ratio of bone volume to total volume

microCT:

microcomputed tomography

Tb.N:

trabecular number

TIMP:

tissue inhibitor of metalloproteinase

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Acknowledgements

We thank Miroslava Tischenko, Steven Maximuk and Richard Rozic for their technical assistance. Dr Amit Vasanji developed the software and techniques for the microCT analysis. Cleveland Clinic Biomedical Imaging and Analysis Core Center was funded, in part by NIAMS Core Center, grant no. 1P30 AR050953. BAK was supported by a Ruth L Kirschstein NRSA award (F32 CA142133) from the NIH/NCI. NPM was supported by a Ruth L Kirstein NRSA award (F32 CA117262). This study was supported by research funding from the NIH/NCI (grant no. CA126847) to TVB.

Author contributions: BAK designed and performed the research, analyzed the data and wrote the paper; NPM and WF performed the research and analyzed the data; TVB designed the research, analyzed the data and wrote the paper.

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Author notes

  1. N P McCabe

    Present address: 4Current address: Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA.,

Authors and Affiliations

  1. Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA

    B A Kerr, N P McCabe, W Feng & T V Byzova

  2. The First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    W Feng

  3. Taussig Cancer Center, The Cleveland Clinic, Cleveland, OH, USA

    T V Byzova

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  1. B A Kerr
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Correspondence to T V Byzova.

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Competing interests

Dr Byzova’s work has been funded by the NIH. Dr Kerr and Dr McCabe have been awarded fellowships from the NIH. Dr W Feng declares no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Kerr, B., McCabe, N., Feng, W. et al. Platelets govern pre-metastatic tumor communication to bone. Oncogene 32, 4319–4324 (2013). https://doi.org/10.1038/onc.2012.447

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