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CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells

Oncogene volume 24, pages 4462–4471 (2005)Cite this article

Abstract

Small cell lung cancer (SCLC) is an aggressive, rapidly metastazising neoplasm with a high propensity for marrow involvement. SCLC cells express high levels of functional CXCR4 receptors for the chemokine stromal-cell-derived factor-1 (SDF-1/CXCL12). Adhesion of SCLC cells to extracellular matrix or accessory cells within the tumor microenvironment confers resistance to chemotherapy via integrin signaling and thus may be responsible for residual disease and relapses commonly seen in SCLC. We examined the signaling mechanisms that regulate CXCL12-induced adhesion of SCLC cells to fibronectin, collagen and stromal cells and the effects on SCLC cell chemoresistance. We found that CXCL12-induced integrin activation which resulted in an increased adhesion of SCLC cells to fibronectin and collagen. This was mediated by α2, α4, α5 and β1 integrins along with CXCR4 activation, which could be inhibited by CXCR4 antagonists. Stromal cells protected SCLC cells from chemotherapy-induced apoptosis and this protection could also be antagonized by CXCR4 inhibitors. We conclude that activation of integrins and CXCR4 chemokine receptors co-operate in mediating adhesion and survival signals from the tumor microenvironment to SCLC cells. Therefore, CXCR4 antagonists in combination with cytotoxic drugs should be explored in SCLC to overcome CXCL12-mediated adhesion and survival signals in the tumor microenvironment.

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Acknowledgements

The authors are grateful to Myriam Krome and Barbara Rogalsky for excellent technical assistance. Supported by the Deutsche Forschungsgemeinschaft (DFG) grant no. BU/1159/3-2 (to MB) and Deutsche Krebshilfe grant no. 10-1688-Bu (to JAB).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, Freiburg University Hospital, Hugstetterstr. 55, D-79106, Freiburg, Germany

    Tanja N Hartmann, Jan A Burger & Meike Burger

  2. Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA

    Aleksandra Glodek

  3. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Nobutaka Fujii

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Hartmann, T., Burger, J., Glodek, A. et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 24, 4462–4471 (2005). https://doi.org/10.1038/sj.onc.1208621

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