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Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Oncogene volume 29, pages 3758–3769 (2010)Cite this article

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Abstract

ADAMs (a disintegrin and metalloprotease) are transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. However, its contribution to tumorigenesis in the context of lung cancer metastasis remains unknown. Native ADAM8 expression levels were lower in lung cancer cell lines. In contrast, we identified and characterized two novel spliced isoforms encoding truncated proteins, Δ18a and Δ14′, which were present in several tumor cell lines and not in normal cells. Overexpression of Δ18a protein resulted in enhanced invasive activity in vitro. ADAM8 and its Δ14′ isoform expression levels were markedly increased in lung cancer cells, in conditions mimicking tumor microenvironment. Moreover, addition of supernatants from Δ14′-overexpressing cells resulted in a significant increase in tartrate-resistant acid phosphatase+ cells in osteoclast cultures in vitro. These findings were associated with increased pro-osteoclastogenic cytokines interleukin (IL)-8 and IL-6 protein levels. Furthermore, lung cancer cells overexpressing Δ14′ increased prometastatic activity with a high tumor burden and increased osteolysis in a murine model of bone metastasis. Thus, the expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.

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Abbreviations

MMP:

metalloprotease

NSCLC:

nonsmall cell lung cancer

SCLC:

small cell lung cancer

TRAP:

tartrate-resistant acid phosphatase

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Acknowledgements

We thank especially S Martínez and the members of the Morphology and Animal Core Facilities. C Berasain for critical reading of the article. This work was supported by ‘UTE project FIMA’ agreement, and RTICCC C03/10, FIT-090100-2005-46, PI042284, PI070031 and SAF-2009-11280 (to FL). FL is also supported by funds from the I3 Program, ‘La Caixa Foundation’, and is a recipient of the ‘Ortiz de Landázuri’ award (67/2005, Government of Navarra).

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Authors and Affiliations

  1. Division of Oncology, Adhesion and Metastasis Laboratory, University of Navarra, Pamplona, Spain

    I Hernández, C Zandueta & F Lecanda

  2. Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA

    J L Moreno

  3. Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain

    L Montuenga

  4. Biomarkers Laboratory, Center for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain

    L Montuenga

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  1. I Hernández
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Correspondence to F Lecanda.

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Hernández, I., Moreno, J., Zandueta, C. et al. Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer. Oncogene 29, 3758–3769 (2010). https://doi.org/10.1038/onc.2010.130

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