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Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma.

Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SA - J. Exp. Med. (2000)

Bottom Line: Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells.These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor.We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.

ABSTRACT
Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein-coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.

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Microscopic changes in CDVG mice. (A) Tail. Multiple nodular angioproliferative tumors located in the dermal compartment of the skin. (B) Tail. Large numbers of spindle-shaped cells arranged in interlacing fascicles. Blood vessels are lined by plump endothelial cells and surrounded by oval to spindle-shaped cells. (C) Ear. Border between interlacing fascicles of spindle-shaped cells. There are irregular vascular clefts between cells that contain erythrocytes. (D) Immunohistochemical staining of a typical angioproliferative lesion with anti-CD34. Numerous positively stained cells are present.
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Figure 3: Microscopic changes in CDVG mice. (A) Tail. Multiple nodular angioproliferative tumors located in the dermal compartment of the skin. (B) Tail. Large numbers of spindle-shaped cells arranged in interlacing fascicles. Blood vessels are lined by plump endothelial cells and surrounded by oval to spindle-shaped cells. (C) Ear. Border between interlacing fascicles of spindle-shaped cells. There are irregular vascular clefts between cells that contain erythrocytes. (D) Immunohistochemical staining of a typical angioproliferative lesion with anti-CD34. Numerous positively stained cells are present.

Mentions: Mice expressing vGPCR were normal at birth. However, within the first 30–90 d of life, all transgenic mice from three independent lines (9, 19, and 122) developed lesions that initially consisted of erythematous to purplish maculae and plaques that subsequently progressed to purple nodules and eventually to overt tumors on the ears, tail, nose, and paws (Fig. 2A–E). Erythematous nodules were also seen in skeletal muscle and in the walls of the small and large intestine (Fig. 2 F). Microscopically, the CDVG tumors were multicentric angioproliferative lesions that were nodular and grew between or invested normal structures of skin (Fig. 3 A). Similar lesions were detected occasionally in heart, skeletal muscle, and the submucosa and muscularis propria of the small and large intestine. They were characterized by sarcomatoid appearing sheets and fascicles of spindled cells forming slit-like and round vascular spaces that contained erythrocytes (Fig. 3B and Fig. C). Mitotic figures were uncommon, and necrotic cells were rare. In addition, the CDVG lesions showed strong expression of CD34, an endothelial cell marker present in angiogenic tumors, including KS tumors (Fig. 3 D; reference 16).


Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma.

Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SA - J. Exp. Med. (2000)

Microscopic changes in CDVG mice. (A) Tail. Multiple nodular angioproliferative tumors located in the dermal compartment of the skin. (B) Tail. Large numbers of spindle-shaped cells arranged in interlacing fascicles. Blood vessels are lined by plump endothelial cells and surrounded by oval to spindle-shaped cells. (C) Ear. Border between interlacing fascicles of spindle-shaped cells. There are irregular vascular clefts between cells that contain erythrocytes. (D) Immunohistochemical staining of a typical angioproliferative lesion with anti-CD34. Numerous positively stained cells are present.
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Related In: Results  -  Collection

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Figure 3: Microscopic changes in CDVG mice. (A) Tail. Multiple nodular angioproliferative tumors located in the dermal compartment of the skin. (B) Tail. Large numbers of spindle-shaped cells arranged in interlacing fascicles. Blood vessels are lined by plump endothelial cells and surrounded by oval to spindle-shaped cells. (C) Ear. Border between interlacing fascicles of spindle-shaped cells. There are irregular vascular clefts between cells that contain erythrocytes. (D) Immunohistochemical staining of a typical angioproliferative lesion with anti-CD34. Numerous positively stained cells are present.
Mentions: Mice expressing vGPCR were normal at birth. However, within the first 30–90 d of life, all transgenic mice from three independent lines (9, 19, and 122) developed lesions that initially consisted of erythematous to purplish maculae and plaques that subsequently progressed to purple nodules and eventually to overt tumors on the ears, tail, nose, and paws (Fig. 2A–E). Erythematous nodules were also seen in skeletal muscle and in the walls of the small and large intestine (Fig. 2 F). Microscopically, the CDVG tumors were multicentric angioproliferative lesions that were nodular and grew between or invested normal structures of skin (Fig. 3 A). Similar lesions were detected occasionally in heart, skeletal muscle, and the submucosa and muscularis propria of the small and large intestine. They were characterized by sarcomatoid appearing sheets and fascicles of spindled cells forming slit-like and round vascular spaces that contained erythrocytes (Fig. 3B and Fig. C). Mitotic figures were uncommon, and necrotic cells were rare. In addition, the CDVG lesions showed strong expression of CD34, an endothelial cell marker present in angiogenic tumors, including KS tumors (Fig. 3 D; reference 16).

Bottom Line: Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells.These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor.We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.

ABSTRACT
Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein-coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.

Show MeSH
Related in: MedlinePlus