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Tumor–stromal interactions of the bone microenvironment: in vitro findings and potential in vivo relevance in metastatic lung cancer models

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Abstract

Lung cancer comprises a large variety of histological subtypes with a frequent proclivity to form bone metastasis; a condition associated with dismal prognosis. To identify common mechanisms in the development of osteolytic metastasis, we systematically screened a battery of lung cancer cell lines and developed three models of non-small cell lung cancer (NSCLC) with a common proclivity to form osseous lesions, which represented different histological subtypes. Comparative analysis revealed different incidences and latency times. These differences were correlated with cell-type-specific secretion of osteoclastogenic factors, including macrophage inflammatory protein-1α, interleukin-8 and parathyroid hormone-related protein, some of which were exacerbated in conditions that mimicked tumor–stroma interactions. In addition, a distinct signature of matrix metalloproteinase (MMP) activity derived from reciprocal tumor–stroma interactions was detected for each tumor cell line. Thus, these results suggest subtle differences in the mechanisms of bone colonization for each lung cancer subtype, but share, although each to a different degree, dual MMP and osteoclastogenic activities that are differentially enhanced upon tumor–stromal interactions.

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Abbreviations

i.c.:

Intracardiac

SCDC:

Single cell derived colonies

TRAP:

Tartrate-resistant acid phosphatase

qPCR:

Real time quantitative RT-PCR

MMP:

Metalloprotease

CM:

Conditioned medium

NSCLC:

Non-small cell lung cancer

SCLC:

Small-cell lung cancer

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Acknowledgments

We are grateful to Dr. Pina for his valuable help assessing radiographs and the members of the Morphology Core facility and Animal Core Facilities. This work was supported by “UTE project FIMA” agreement, and RTICC C03/10, FIT-090100-2005-46, PI042284, PI070031, SAF-2009-11280 (to FL), Royo Foundation (SV), FPU (DL-R and KV), and Basque Government (IA). FL is also supported by funds from the I3 Program, “La Caixa Foundation”, and grants 67/2005, 09/2009 from the Government of Navarra. There are no conflicts of interest to disclose.

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Author notes

  1. Silvestre Vicent

    Present address: Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA

Authors and Affiliations

  1. Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, 31080, Pamplona, Spain

    Diego Luis-Ravelo, Iker Antón, Silvestre Vicent, Igor Hernández, Karmele Valencia, Carolina Zandueta, Susana Martínez-Canarias & Fernando Lecanda

  2. Department of Oncology, Clínica Universidad de Navarra (CUN), University of Navarra, Pamplona, Spain

    Alfonso Gúrpide

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  1. Diego Luis-Ravelo
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Corresponding author

Correspondence to Fernando Lecanda.

Additional information

D. Luis-Ravelo, I. Antón and S. Vicent have contributed equally to this work.

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Luis-Ravelo, D., Antón, I., Vicent, S. et al. Tumor–stromal interactions of the bone microenvironment: in vitro findings and potential in vivo relevance in metastatic lung cancer models. Clin Exp Metastasis 28, 779–791 (2011). https://doi.org/10.1007/s10585-011-9409-5

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  • DOI: https://doi.org/10.1007/s10585-011-9409-5

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