The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells
Marcos G. Grisotto, Alexandre Garin, Andrea P. Martin, Kristian K. Jensen, PokMan Chan, Stuart C. Sealfon, Sergio A. Lira
Marcos G. Grisotto, Alexandre Garin, Andrea P. Martin, Kristian K. Jensen, PokMan Chan, Stuart C. Sealfon, Sergio A. Lira
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Research Article Oncology

The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

Abstract

We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein–coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Upon treatment with doxycycline (DOX), cells expressing vGPCR and LacZ (vGPCR/LacZ+ cells) progressively accumulated in areas where angioproliferation was observed. Sorted vGPCR/LacZ+ cells from angiogenic lesions expressed markers characteristic of endothelial progenitor cells, produced angiogenic factors, and proliferated in vitro. Prolonged treatment of transgenic mice with DOX led to development of tumors in the skin of ears, tail, nose, and paws. vGPCR/LacZ+ cells were frequent in early lesions but scarce within these tumors. Finally, transfer of vGPCR/LacZ+ cells into Rag1–/– mice treated with DOX led to angioproliferation and, with time, to development of tumors containing both vGPCR/LacZ+ and vGPCR/LacZ– cells. Taken together, these results indicate that vGPCR triggers angioproliferation directly and suggest a novel role for this molecule in the pathogenesis of Kaposi sarcoma.

Authors

Marcos G. Grisotto, Alexandre Garin, Andrea P. Martin, Kristian K. Jensen, PokMan Chan, Stuart C. Sealfon, Sergio A. Lira

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Figure 7

Adoptive transfer of vGPCR/LacZ+ cells promotes development of tumors.

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Adoptive transfer of vGPCR/LacZ+ ce...
Sorted vGPCR/LacZ+ cells (3 × 104) from the ears of DOX-treated iORF74/LacZ mice were transplanted into tail skin of Rag1–/– mice. Tumors in the tails of recipient mice were observed after 200 days of DOX treatment. (A) β-gal histochemistry of the tail tumor. (B) Tail tumors were mainly composed of CD31+ cells. (C) Higher magnification of the tail tumor seen in A shows the presence of both LacZ+ and LacZ– cells. (D–I) Quantum dot FISH of sections of WT, iORF74/LacZ, and Rag1–/– recipient mice. (D and G) FISH in tail sections of WT mice for LacZ (D) and vGPCR (G) probes, respectively. (E and H) FISH in adjacent tail sections of iORF74/LacZ mice treated for 60 days with DOX, LacZ (E), and vGPCR (H) probes, respectively. (F and I) FISH in adjacent tail sections of Rag1–/– recipient mice treated for 200 days with DOX, LacZ (F), and vGPCR (I) probes, respectively. Scale bars: 400 μm (A and B); 100 μm (C); 40 μm (D–I).