Angiogenic potential in vivo by Kaposi's sarcoma cell-free supernatants and HIV-1 tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2

• Published in: AIDS (London) Vol. 8; no. 9; p. 1237
• Main Authors: Albini, A, Fontanini, G, Masiello, L, Tacchetti, C, Bigini, D, Luzzi, P, Noonan, D M, Stetler-Stevenson, W G
• Format: Journal Article
• Language: English
• Published: England 01-09-1994
• Subjects: Animals; Cell-Free System; Disease Models, Animal; Fibroblast Growth Factor 2 - pharmacology; Gene Products, tat - pharmacology; HIV-1 - pathogenicity; Humans; Male; Metalloendopeptidases - antagonists & inhibitors; Mice; Mice, Inbred C57BL; Mice, Nude; Microscopy, Electron; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - pathology; Proteins - pharmacology; Sarcoma, Kaposi - etiology; Sarcoma, Kaposi - pathology; Sarcoma, Kaposi - prevention & control; tat Gene Products, Human Immunodeficiency Virus; Tissue Inhibitor of Metalloproteinase-2
• ISSN: 0269-9370
• DOI: 10.1097/00002030-199409000-00004

To determine the neoplastic nature of Kaposi's sarcoma (KS). A highly vascularized lesion, KS is frequently associated with AIDS, indicating HIV products may be involved.
We determined the angiogenic properties of KS cell-secreted products and the HIV-1-tat gene product in vivo. Cell-free secreted products (KS-CM) from cultured epidemic and sporadic KS spindle cells or recombinant (r) HIV-1 tat protein were injected into mice with a matrix support (Matrigel).
KS-CM produced lesions carrying all the phenotypic hallmarks of KS, as observed by light and electron microscopy: spindle-shaped cells, haemorrhages and an inflammatory infiltrate, as well as Factor VIII-positive endothelial cells lining new blood vessels. Electron microscopy indicated an initial granulocyte invasion, with spindle-cell migration and neocapillary formation in the centre of the matrix. These lesions required the cofactor heparin; KS-CM or heparin alone were poorly angiogenic. A less intense angiogenesis, with lower cellularity and few granulocytes, was observed in basic fibroblast growth factor (bFGF)/heparin lesions, indicating that factors other than bFGF are present in the KS spindle-cell products. When the collagenase inhibitor tissue inhibitor of metalloproteinases (TIMP)-2 was added to the sponges, KS-CM-induced angiogenesis was reduced by approximately 65% and bFGF-induced angiogenesis inhibited completely. Recombinant HIV-1 tat protein, a growth factor for KS cells, induced vascularization that was also enhanced by heparin, implying that HIV-1 tat could contribute to the aetiology of HIV-associated KS.
KS-like lesions were obtained by injecting cell-free secreted products, suggesting that KS is a 'self-propagating' proliferative lesion caused by a cytokine imbalance and not a true neoplasm. Heparin-binding factors appear to be involved, and HIV-1 tat angiogenic properties implicate this molecule in AIDS-associated KS. Inhibition of KS-CM-induced KS-like lesions by TIMP-2 suggests that metalloproteinase inhibitors could be potential therapeutic agents for KS.