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.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Albini
A
A
National Institute of Research on Cancer, Genoa, Italy.
Fontanini
G
G
Masiello
L
L
Tacchetti
C
C
Bigini
D
D
Luzzi
P
P
Noonan
D M
DM
Stetler-Stevenson
W G
WG
D000818:Animals; D002474:Cell-Free System; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008854:Microscopy, Electron; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000473:pathology; D011506:Proteins / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D019716:Tissue Inhibitor of Metalloproteinase-2; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D011506:Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases