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Enhanced tumorigenicity of fibroblasts transformed with human herpesvirus 8 chemokine receptor vGPCR by successive passage in nude and immunocompetent mice

Oncogene volume 26, pages 5702–5712 (2007)Cite this article

Abstract

The human herpes virus 8 (HHV-8)-encoded G protein-coupled chemokine receptor (vGPCR) has been implicated in the pathogenesis of Kaposi's sarcoma (KS), particularly because of its high constitutive signaling activity. Here, we used retroviral transduction to generate vGPCR-expressing 3T3 fibroblasts that are tumorigenic in nude mice, but as expected fail to induce tumors in their immunocompetent counterparts. However, tumor fragments obtained from nude mice grow progressively in immunocompetent BALB/c mice. Unexpectedly, vGPCR-expressing cells established from grafted tumor fragments gave rise to tumors in immunocompetent mice. These tumors exhibit a striking histological resemblance to KS including plump spindle cell morphology, a high degree of vascularization and brisk mitotic activity. High expression of vGPCR was confirmed in the cell lines and tumors using a newly developed vGPCR-specific monoclonal antibody. Finally, short interfering RNA directed at vGPCR abrogated or significantly delayed tumorigenesis in mice, demonstrating that the tumor development is specifically driven by vGPCR. This novel model for vGPCR-mediated oncogenesis will contribute to our understanding of the role of vGPCR in the pathogenesis of HHV-8 and may even be important in identifying critical molecular and epigenetic changes during tumor progression in vivo.

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Acknowledgements

We thank Heike Schwede and Monika Becker for excellent technical assistance. This work was supported by grants from the Federal Government, BMBF (01SF9804) and from the German Research Foundation, DFG (Research Training Group GRK 426).

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Author notes

  1. N Thirunarayanan and F Cifire: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Tumor Genetics and Immunogenetics, Max-Delbriick-Centre for Molecular Medicine, MDC, Berlin, Germany

    N Thirunarayanan, F Cifire, S Posner, J Benga, P Reiterer & M Lipp

  2. Department of Experimental Pharmacology, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany

    I Fichtner

  3. Institute of Molecular Immunology, GSF Research Center, Munich, Germany

    E Kremmer

  4. Institute for Pathology, Universitätsklinikum Charité, Campus Charité-Mitte, Berlin, Germany

    K Kölble

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  1. N Thirunarayanan
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  2. F Cifire
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  3. I Fichtner
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  8. K Kölble
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  9. M Lipp
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Correspondence to M Lipp.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Thirunarayanan, N., Cifire, F., Fichtner, I. et al. Enhanced tumorigenicity of fibroblasts transformed with human herpesvirus 8 chemokine receptor vGPCR by successive passage in nude and immunocompetent mice. Oncogene 26, 5702–5712 (2007). https://doi.org/10.1038/sj.onc.1210357

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