Immune modulatory and growth-inducing functions of viral chemokine receptors: A murine model for Kaposi ́s sarcoma

 (in cooperation with I. Anagnostopoulos, H. Stein, K. Kölble, Charité)

 

Infection with human herpes virus 8 (HHV-8) has been linked by epidemiological and molecular evidence to the pathogenesis of all forms of Kaposi’s sarcoma, a non- Hodgkin’s B cell lymphoma, and multicentric Castleman’s disease (MCD). The research project is aimed to establish whether the HHV-8-encoded chemokine receptor (vGPCR) plays a critical role in the development of HHV8-associated diseases and malignancies as an essential oncogenic and paracrine factor. The HHV-8-encoded G protein-coupled chemokine receptor (vGPCR) has been implicated in viral pathogenesis particularly because of its high constitutive signaling activity. 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.