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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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References

  1. Ihde, D., Pass, H., & Glastein, E. in Cancer: Principles and Practice of Oncology 4th edn. (eds. De Vita, V.T.Jr., Hellman, S. and Rosenberg, S.A.) 591–687 (J.B. Lippincott, Philadelphia, 1993).

    Google Scholar 

  2. Smyth, J.F. et al. The impact of chemotherapy on small cell carcinoma of the bronchus. Q. J. Med. 61, 969– 976 (1986).

    CAS  PubMed  Google Scholar 

  3. Meredith, J.E. Jr., Fazeli, B. & Schwartz, M.A. The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4, 953–961 (1993).

    Article  CAS  Google Scholar 

  4. Frisch, S.M. & Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994).

    Article  CAS  Google Scholar 

  5. Meredith, J.E. Jr. & Schwartz, M.A. Integrins adhesion and apoptosis. Trends Cell Biol. 7, 146–150 (1997).

    Article  CAS  Google Scholar 

  6. Boudreau, N., Sympson, C.J., Werb, Z. & Bissell, M.J. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267, 891–893 (1995).

    Article  CAS  Google Scholar 

  7. Freedman, V.H. & Shin, S. Cellular tumorigenicity in nude mice, correlation with cell growth in semi-solid medium. Cell 3, 355–359 (1974).

    Article  CAS  Google Scholar 

  8. Smith, P.J. et al. Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small cell lung cancer cells. Br. J. Cancer 70, 914–921 ( 1994).

    Article  CAS  Google Scholar 

  9. Aas, T. et al. Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med. 2, 811–814 (1996).

    Article  CAS  Google Scholar 

  10. Tallet, A. et al. Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. Cancer Res. 56, 4255– 4263 (1996).

    Google Scholar 

  11. Sethi, T., Langdon, S., Smyth, J. & Rozengurt, E. Growth of small cell lung cancer cells: stimulation by multiple neuropeptides and inhibition by broad spectrum antagonists in vitro and in vivo. Cancer Res. 52, 2737s–2742s (1992).

    CAS  PubMed  Google Scholar 

  12. Langdon, S.P., Cummings, J. & Smyth, J.F. Antagonists of mitogenic peptides. Cancer Topics 9, 10–13 ( 1994).

    Google Scholar 

  13. Kelly, M.J. et al. Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer. Chest 112, 256–261 ( 1997).

    Article  Google Scholar 

  14. Haynes, R.O. Integrins: Versatility and signaling in cell adhesion. Cell 69, 11–25 (1992).

    Article  Google Scholar 

  15. Elices, M.J., Urry, L.A. & Hemler, M.E. Receptor functions for the integrin VLA-3: Fibronectin, collagen and laminin binding are differentially influenced by ARG-GLY-ASP peptide and by divalent cations. J. Cell Biol. 112, 169–181 (1991).

    Article  CAS  Google Scholar 

  16. Vogel, B.E., Tarone, G., Giancotti, F.G., Gailit, J. & Ruoslahti, E. A novel fibronectin receptor with an unexpected subunit composition (αvβ1). J. Biol. Chem. 265, 5934–5937 ( 1990).

    CAS  PubMed  Google Scholar 

  17. Falcioni, R. et al. Expression of β1, β3, β4 and β5 integrins by Human Lung Carcinoma cells of different histotypes. Exp. Cell Res. 210, 113–122 ( 1994).

    Article  CAS  Google Scholar 

  18. Carney, D.N., Gazdar, A.F. & Minna, J.D. Positive correlation between histological tumor involvement and generation of tumor cell colonies in agarose in specimens taken directly from patients with small-cell carcinoma of the lung. Cancer Res . 40, 1820–1823 ( 1980).

    CAS  PubMed  Google Scholar 

  19. Giaccone, G. Small cell lung cancer and topoisomerases. Anticancer Res. 14, 269–276 (1994).

    CAS  PubMed  Google Scholar 

  20. Sakahira, H., Enari, M. & Nagata, S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391, 96– 99 (1998).

    Article  CAS  Google Scholar 

  21. Enari, M. et al. A caspase-activated DNAase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43– 50 (1998).

    Article  CAS  Google Scholar 

  22. Sentman, C.L., Shutter, J.R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S.J. Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).

    Article  CAS  Google Scholar 

  23. Chinnaiyan, A.M. et al. Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. J. Biol. Chem. 271, 4573–4576 ( 1996).

    Article  CAS  Google Scholar 

  24. Sethi, T & Rozengurt, E. Multiple neuropeptides stimulate clonal growth of small cell lung cancer: effects of bradykinin, vasopressin, cholecystokinin, galanin, and neurotensin. Cancer Res. 51, 3621–3623 ( 1991).

    CAS  PubMed  Google Scholar 

  25. Bepler, G. et al. Peptides and growth factors in small cell lung cancer: production, binding sites, and growth effects. Cancer Res. Clin. Oncol. 114, 235–244 (1988).

    Article  CAS  Google Scholar 

  26. Rozengurt, E. Neuropeptides as cellular growth factors: role of multiple signaling pathways. Eur. J. Clin. Invest. 21, 123– 134 (1991).

    Article  CAS  Google Scholar 

  27. Arenberg, D.A. et al. Inhibition of interleukin-8 reduces tumourigenesis of human non-small cell lung cancer in SCID mice. J. Clin. Invest. 97, 2792–2802 (1996).

    Article  CAS  Google Scholar 

  28. Borsi, L., Castellani, P., Risso, A.M., Leprini, A. & Zardi, L. Transforming growth factor-β regulates the splicing pattern of fibronectin messenger RNA precursor. FEBS Lett. 261, 175–178 (1990).

    Article  CAS  Google Scholar 

  29. Sieweke, M.H., Thompson, N.L., Sporn, M.B. & Bissell, M.J. Mediation of wound-related Rous Sarcoma virus tumourigenesis by TGF-β. Science 48, 1656–1660 (1990).

    Article  Google Scholar 

  30. Bloch, W. et al. β1 integrin is essential for teratoma growth and angiogenesis. J. Cell Biol. 139, 265– 278 (1997).

    Article  CAS  Google Scholar 

  31. Nicolò, G. et al. Expression of tenascin and of the ED-B containing oncofetal fibronectin isoform in human cancer. Cell Diff. Dev. 32, 401–408 (1990).

    Article  Google Scholar 

  32. Hedin, U., Holm, J. & Hansson, G.K. Induction of tenascin in rat arterial injury: relationship to altered smooth muscle cell phenotype. Am. J. Pathol. 139, 649–656 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jones, P.L., Crack, J. & Rabinovitch, M. Regulation of Tenascin-C, a vascular smooth muscle cell survival factor that interacts with the αvβ3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J. Cell Biol. 139, 279– 293 (1997).

    Article  CAS  Google Scholar 

  34. Lai, S.L. et al. MDR1 gene expression in lung cancer. J. Natl. Cancer Inst. 81, 1144–1150 ( 1989).

    Article  CAS  Google Scholar 

  35. Fridman, R. et al. Reconstituted basement membrane (matrigel) and laminin can enhance the tumorgenicity and the drug resistance of small cell lung cancer cell lines. Proc. Natl. Acad. Sci. USA 87, 6698–6702 (1990).

    Article  CAS  Google Scholar 

  36. McCarthy, J.B., Barara, M.L., Palm, S.L., Sas, D.F. & Furcht. L.T. The role of cell adhesion proteins-laminin and fibronectin-in the movement of malignant and metastatic cells. Cancer Metastasis Rev. 4, 125–152 ( 1985).

    Article  CAS  Google Scholar 

  37. Suzuki, J., Kaziro, Y., & Koide, H. Synergistic action of R-Ras and IGF-1 on Bcl-xL expression and caspase-3 inhibition in BaF3 cells: R-Ras and IGF-1 control distinct anti-apoptotic kinase pathways. FEBS Lett. 437, 112– 116 (1998).

    Article  CAS  Google Scholar 

  38. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P.H., & Downward, J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16, 2783– 2793 (1997).

    Article  CAS  Google Scholar 

  39. Duke R.C. & Cohen. J.J. in Current Protocols in Immunology (eds. Coligan, J.E. et al.) 3.17.1– 3.17.16 (John Wiley & Sons, New York, 1992).

    Google Scholar 

  40. Staal, F.J.T., Roederer, M., Herzenberg L.A. & Herzenberg L.A. Intracellular thiols regulate activation of nuclear kB and transcription of human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 87, 9943–9947 (1990).

    Article  CAS  Google Scholar 

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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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