Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity
Peter J. Holst, Mette M. Rosenkilde, Denise Manfra, Shu-Cheng Chen, Maria T. Wiekowski, Birgitte Holst, Felix Cifire, Martin Lipp, Thue W. Schwartz, Sergio A. Lira
Peter J. Holst, Mette M. Rosenkilde, Denise Manfra, Shu-Cheng Chen, Maria T. Wiekowski, Birgitte Holst, Felix Cifire, Martin Lipp, Thue W. Schwartz, Sergio A. Lira
View: Text | PDF
Article

Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

Abstract

ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein–coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines.

Authors

Peter J. Holst, Mette M. Rosenkilde, Denise Manfra, Shu-Cheng Chen, Maria T. Wiekowski, Birgitte Holst, Felix Cifire, Martin Lipp, Thue W. Schwartz, Sergio A. Lira

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Angiogenic and inflammatory lesions in CDVG, R2H and Δ22 transgenic mice...
Angiogenic and inflammatory lesions in CDVG, R2H and Δ22 transgenic mice. (a) Angiogenic lesions in the ear of a CDVG (line 19) mouse. (b) Angiogenic lesions in the ear of a R2H (line 24) mouse. (c) Erythematous, swollen, ulcerated ear lesions in a Δ22 (line 1) mouse. (d) Tail tumor in a CDVG (line 19) mouse. (e) Tail tumor in a R2H line 24 mouse. (f) Ulcerations and scales in the tail of a Δ22 (line 1) animal. (g) H&E-stained section of the tumor from the CDVG mouse shown in d. The tumor is moderately pleomorphic, and many spindle-shaped cells arranged in interlacing fascicles are present. Several slitlike vascular spaces often containing erythrocytes are observed. (h) H&E-stained section of the tumor from the R2H mouse shown in e. The cellular composition and the arrangement of spindle cells in fascicles is indistinguishable from that found in CDVG mice (e). (i) H&E-stained section of the ear of the Δ22 animal shown in c. The cellular infiltrate in inflamed ears consists mostly of granulocytes (eosinophils and neutrophils) and mononuclear cells.