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Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo

Abstract

Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of β1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking β1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.

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Figure 1: Immunohistochemical staining of ECM proteins around SCLC cells in vivo.
Figure 2: β1-integrin-mediated adhesion to ECM proteins protects SCLC cells from chemotherapy-induced apoptosis.
Figure 3: ECM proteins stimulate SCLC cell growth and tumorigenicity.
Figure 4: Chemotherapy-induced caspase-3 activation is blocked by β1 integrin-stimulated tyrosine kinase activation.

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Acknowledgements

We thank G. Boyd and J. Cummings (ICRF, Western General Hospital, Edinburgh, UK) for help with topoisomerase II alpha experiments, and J. Lauder and B. Simpson (Department of Pathology, University of Edinburgh) for assistance with immunohistochemistry. We also thank P. Hughes (Scripps Research Institute) for comments on the manuscript. This work was supported by the Medical Research Council UK (Clinical Training Fellowship to RCR) and the Scottish Hospital Endowment Research Trust.

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Correspondence to Tariq Sethi.

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Sethi, T., Rintoul, R., Moore, S. et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 5, 662–668 (1999). https://doi.org/10.1038/9511

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