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Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells

Oncogene volume 22, pages 8093–8101 (2003)Cite this article

Abstract

Small-cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm. The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is constitutively secreted by marrow stromal cells and plays a key role for homing of hematopoietic cells to the marrow. Here, we report that tumor cells from patients with SCLC express high levels of functional CXCR4 receptors for the chemokine CXCL12. Reverse transcriptase–polymerase chain reaction and flow cytometry demonstrated CXCR4 mRNA and CXCR4 surface expression in SCLC cell lines. Immunohistochemistry of primary tumor samples from SCLC patients revealed high expression of CXCR4. CXCL12 elicited CXCR4 receptor endocytosis, actin polymerization, and a robust activation of phospho-p44/42 mitogen-activated protein kinase in SCLC cells. Furthermore, CXCL12 induced SCLC cell invasion into extracellular matrix and firm adhesion to marrow stromal cells. Stromal cell adhesion of SCLC cells was significantly inhibited by the specific CXCR4 antagonist T140, pertussis toxin, antivascular cell adhesion molecule-1(VCAM-1) antibodies, and CS-1 peptide, demonstrating the importance of CXCR4 chemokine receptor activation and α4β1 integrin binding, respectively. In addition, CXCL12 enhanced the adhesion of SCLC cells to immobilized VCAM-1, demonstrating that CXCR4 chemokine receptors can induce integrin activation on SCLC cells. As SCLC has a high propensity for bone marrow involvement, our findings suggest that CXCR4 chemokine receptors and α4β1 integrins play a critical role in the interaction of SCLC cells with stromal cells in the tumor microenvironment.

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Acknowledgements

The authors are grateful to Barbara Rogalsky and B Weinhold for excellent technical asssistance. This work was supported by Deutsche Forschungsgemeinschaft (DFG) Grant No. BU/1159/3-1 (to MB), and Deutsche Krebshilfe Grant No. 10-1688-Bu I (to JAB).

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Authors and Affiliations

  1. Department of Internal Medicine, Freiburg University Hospital, Freiburg, Germany

    Meike Burger, Tanja Hartmann & Jan A Burger

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

    Aleksandra Glodek & Leslie E Silberstein

  3. Department of Pathology, Freiburg University Hospital, Freiburg, Germany

    Anette Schmitt-Gräff

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

    Nobutaka Fujii

  5. Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, USA

    Thomas J Kipps

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  1. Meike Burger
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Correspondence to Jan A Burger.

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Burger, M., Glodek, A., Hartmann, T. et al. Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. Oncogene 22, 8093–8101 (2003). https://doi.org/10.1038/sj.onc.1207097

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