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Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis

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Abstract

Men who die of prostate cancer (PCa) do so because of systemic metastases, the most frequent of which are within the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced collagen I binding through increased expression of integrin α2β1 stimulated in vitro invasion and promoted the growth of PCa cells within the bone. Accordingly, we sought to determine whether α2β1 integrin is a potential mediator of skeletal metastasis. To examine whether α2β1 integrin mediates PCa metastasis, α2 integrin was over-expressed in low-tumorigenic LNCaP PCa cells or selectively knocked-down in highly metastatic LNCaPcol PCa cells. We document that the over-expression of α2 cDNA stimulated whereas α2 shRNA inhibited the ability of transduced cells to bind to or migrate towards collagen in vitro. Correspondingly, α2 integrin knock-down reduced the tumor burden of intra-osseous tumors compared to control-transduced cells. To investigate the clinical significance of α2β1 expression in PCa, α2β1 protein was measured in prostatic tissues and in soft tissue and bone metastases. The data demonstrate that α2β1 protein was elevated in PCa skeletal metastases compared to either PCa primary lesions or soft tissue metastases suggesting that α2β1 contributes to the selective metastasis to the bone. Taken together, these data support that α2β1 integrin is needed for the efficient metastasis of PCa cells to the skeleton.

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Acknowledgments

We would like to thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program at the University of Washington. We would also like to acknowledge Dr. Celestia Higano, Martine Roudier, Lawrence True, Paul Lange, Bruce Montgomery, Peter Nelson, and Robert Vessella. The Prostate Cancer Donor Program is supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1CA085859), and the Richard M. LUCAS Foundation. Supported in part by Grants from the Department of Defense (PC094375) to CLH and the National Institutes of Health (UL1RR024986).

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Authors and Affiliations

  1. Department of Urology, The University of Michigan, Ann Arbor, MI, 48109, USA

    Joseph L. Sottnik, Stephanie Daignault-Newton, Evan T. Keller & Christopher L. Hall

  2. The Department of Urology, The University of Washington, Seattle, WA, 98195, USA

    Xiaotun Zhang & Colm Morrissey

  3. Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, 48109, USA

    Maha H. Hussain

  4. Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, S3-221, Worcester, MA, 01655, USA

    Christopher L. Hall

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  1. Joseph L. Sottnik
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Correspondence to Christopher L. Hall.

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Sottnik, J.L., Daignault-Newton, S., Zhang, X. et al. Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis. Clin Exp Metastasis 30, 569–578 (2013). https://doi.org/10.1007/s10585-012-9561-6

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  • DOI: https://doi.org/10.1007/s10585-012-9561-6

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