Kaposi's sarcoma cells of different etiologic origins respond to HIV-Tat through the Flk-1/KDR (VEGFR-2): relevance in AIDS-KS pathology.

Kaposi's sarcoma (KS) is an hyperplastic lesion whose main histological features are typical spindle shaped cells with a mixed endothelial-mesenchymal-macrophage phenotype, an intense vascularization and an inflammatory infiltrate. The etiology of KS appears to be linked to activation of a latent HHV8 infection. Sporadic and iatrogenic KS are slow progressing lesions that can undergo spontaneous regression. In contrast, KS, which is frequently associated with HIV infection, is found in a highly aggressive form in AIDS patients. The HIV-1 Tat has been shown to activate the VEGF receptor KDR in endothelial and KS spindle cells, suggesting this HIV protein could contribute to KS pathogenesis. We used primary 'reactive' KS cell culture from sporadic and epidemic KS, and an immortal KS-line (KS-Imm) isolated in our laboratory from a iatrogenic KS lesion, to verify if Tat-induced cell signaling is able to mediate cellular responses. We demonstrate that KS cells migrated in response to Tat and that VEGF is able to compete with the Tat chemotactic activity towards these cells. A function-blocking anti-KDR antibody was able to abrogate both VEGF and Tat-induced KS chemotactic response, indicating a direct involvement of this receptor. Our data show that HIV-Tat can also activate KS cells derived from sporadic or iatrogenic lesions, suggesting that in AIDS patients Tat could cooperate with VEGF in activation of KDS on KS precursor spindle and endothelial cells, and contribute to the aggressiveness of AIDS-KS lesions.

Morini M ，Benelli R ，Giunciuglio D ，Carlone S ，Arena G ，Noonan DM ，Albini A ... -  《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》

Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development.

Samaniego F ，Markham PD ，Gendelman R ，Watanabe Y ，Kao V ，Kowalski K ，Sonnabend JA ，Pintus A ，Gallo RC ，Ensoli B ... -  《-》

IFN-gamma induces endothelial cells to proliferate and to invade the extracellular matrix in response to the HIV-1 Tat protein: implications for AIDS-Kaposi's sarcoma pathogenesis.

Fiorelli V ，Barillari G ，Toschi E ，Sgadari C ，Monini P ，Stürzl M ，Ensoli B ... -  《JOURNAL OF IMMUNOLOGY》

Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells.

Fiorelli V ，Gendelman R ，Samaniego F ，Markham PD ，Ensoli B ... -  《JOURNAL OF CLINICAL INVESTIGATION》

The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells.

Albini A ，Soldi R ，Giunciuglio D ，Giraudo E ，Benelli R ，Primo L ，Noonan D ，Salio M ，Camussi G ，Rockl W ，Bussolino F ... -  《NATURE MEDICINE》