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The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

Oncogene volume 28, pages 412–421 (2009)Cite this article

Abstract

Bone resorption by osteoclasts is thought to promote the proliferation of prostate cancer cells disseminated to the skeleton (Mundy, 2002). Using a mouse model of experimental metastasis, we found that although late-stage metastatic tumors were indeed surrounded by osteoclasts, these cells were spatially unrelated to the small foci of cancer cells in early-stage metastases. This is the first evidence that survival and growth of disseminated prostate cancer cells immediately after their extravasation may not depend on osteoclast involvement. Interestingly, prostate cancer cells expressing the α-receptor for platelet-derived growth factor (PDGFRα) progress during early-stages of skeletal dissemination, whereas cells expressing lower levels or lacking this receptor fail to survive after extravasation in the bone marrow. However, non-metastatic cells acquire bone-metastatic potential upon ectopic overexpression of PDGFRα. Finally, functional blockade of human PDGFRα on prostate cancer cells utilizing a novel humanized monoclonal antibody—soon to undergo phase-II clinical trials—significantly impairs the establishment of early skeletal metastases. In conclusion, our results strongly implicate PDGFRα in prostate cancer bone tropism through its promotion of survival and progression of early-metastatic foci, providing ground for therapeutic strategies aimed at preventing or containing the initial progression of skeletal metastases in patients affected by prostate adenocarcinoma.

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Acknowledgements

The cDNA for human PDGFRα was a kind gift of Dr Carl-Henrik Heldin (Ludwig Institute for Cancer Research, Uppsala, Sweden). We thank Dr Olimpia Meucci (Department of Pharmacology and Physiology) for critically reading the manuscript and helpful discussion, Dr Mark Stearns (Department of Pathology and Laboratory Medicine) for helpful discussion, Dr Gregg Johannes (Department of Pathology and Laboratory Medicine) for help with the PDGFRα-expressing vector, Mr Michael Amatangelo for his contribution to the immuno-detection of PDGFRα in human tissues and Dr Nick Loizos (ImClone Systems Inc., New York, NY, USA) for kindly providing the IMC-3G3 antibody. This study was supported in part by the NIH Grant GM067892 to AF.

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Author notes

  1. N G Dolloff

    Present address: 3Current address: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,

  2. M R Russell and W L Jamieson: MR Russell and WL Jamieson contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA

    M R Russell, W L Jamieson, N G Dolloff & A Fatatis

  2. Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, USA

    A Fatatis

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  1. M R Russell
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  2. W L Jamieson
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  4. A Fatatis
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Correspondence to A Fatatis.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Russell, M., Jamieson, W., Dolloff, N. et al. The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells. Oncogene 28, 412–421 (2009). https://doi.org/10.1038/onc.2008.390

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