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

AIDS. 1994 Sep;8(9):1237-44. doi: 10.1097/00002030-199409000-00004.


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.

Design and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Tissue Inhibitor of Metalloproteinase-2
  • tat Gene Products, Human Immunodeficiency Virus


  • Gene Products, tat
  • Proteins
  • tat Gene Products, Human Immunodeficiency Virus
  • Fibroblast Growth Factor 2
  • Tissue Inhibitor of Metalloproteinase-2
  • Metalloendopeptidases