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Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

Oncogene volume 24, pages 5897–5904 (2005)Cite this article

Abstract

Chemokine receptor 7 (CCR7) upregulation, which mediates immune cell survival and migration to lymph nodes, has recently been associated with nodal metastasis of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of CCR7 in tumor progression, its downstream signaling mediators, and interactions with other pathways contributing to metastasis of SCCHN have not been determined. We hypothesized that inflammatory chemokine-mediated signals could also promote tumor proliferation and mitogenic effects. Functional assays showed that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospholipase Cγ-1. In addition, treatment of CCR7+ metastatic SCCHN cells with CCL19 (MIP-3β) showed rapid activation of the prosurvival, PI3K/Akt pathway. Transactivation of EGFR-mediated and mitogen-activated protein kinase signaling pathways, which can promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Thus, proinflammatory chemokine signals that mediate activation, trafficking and survival of tumor-infiltrating immune cells in the tumor microenvironment actually appear to induce signals for progression of cancer cells. The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis.

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Acknowledgements

This work was funded by the American Head and Neck Society/American Academy of Otolaryngology (to RLF), and by the University of Pittsburgh Cancer Institute and the Eye and Ear Foundation, through the Stout Family Fund for Head and Neck Cancer Research.

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Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, 15213, PA, USA

    Jun Wang & Robert L Ferris

  2. Department of Immunology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, 15213, PA, USA

    Jun Wang & Robert L Ferris

  3. University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, 15213, PA, USA

    Jun Wang, Jennifer R Grandis & Robert L Ferris

  4. Department of Hematology & Oncology, Winship Cancer Institute, Emory University, Suite C3068, 1365-C Clifton Road, Atlanta, 30322, GA, USA

    Xin Zhang & Zhuo (Georgia) Chen

  5. Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, 15213, PA, USA

    Alan Wells

  6. Department of Pharmacology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, 15213, PA, USA

    Sufi M Thomas & Jennifer R Grandis

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  1. Jun Wang
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Correspondence to Robert L Ferris.

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Wang, J., Zhang, X., Thomas, S. et al. Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR. Oncogene 24, 5897–5904 (2005). https://doi.org/10.1038/sj.onc.1208740

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