Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions.
Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released by both KS and host cells, as well as HHV-8 and HIV viral products, have been implicated in the pathogenesis of this lesion. Angiogenesis is the result of imbalance among angiogenesis promoters and inhibitors, which disrupts homeostasis. The aim of this study was to investigate the expression and mechanism of KS control of thrombospondin-1 (TSP), a physiological inhibitor of angiogenesis. Immunohistochemical analysis of four KS lesions showed only spotty reactivity for TSP in the stroma and in less than 10 per cent of lesional blood vessels. In addition, the typical KS spindle cells were not stained. In agreement with these findings, decreased levels of TSP were measured with an ELISA assay in the supernatants of cultured KS cells, compared with endothelial cells. In vitro, TSP inhibited the endothelial cell proliferation and motility induced by KS cell supernatants. TSP also prevented endothelial cell motility induced by Tat, a product of HIV-1 endowed with angiogenic potential and implicated in the pathogenesis of AIDS-KS. In vivo, TSP inhibited the angiogenic activity exerted by Tat in the Matrigel sponge model. These results suggest that TSP down-regulation might be permissive for the development of KS-associated angiogenesis.
Department of Oncology, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy. taraboletti@irfmn.mnegri.it
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G
Taraboletti
R
R
Benelli
P
P
Borsotti
M
M
Rusnati
M
M
Presta
R
R
Giavazzi
L
L
Ruco
A
A
Albini
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000032:analysis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015696:Gene Products, tat; D019700:Thrombospondin 1