The HIV-1 Tat protein transactivates HIV, viral and some host cell genes. Tat can be released by infected cells and acts extracellularly in the microenvironment, regulating functions of immunocompetent and mesenchymal cells. One of the most striking effects of Tat is the induction of a functional program in vascular cells related to angiogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin). Tat induces growth of Kaposi's sarcoma (KS) spindle cells and is angiogenic in vivo and in transgenic mice10-12. We previously reported that Tat is a direct angiogenic factor and noted the Tat arginine- and lysine-rich sequence is similar to that of other potent angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). It is possible that Tat mimics one of these factors by interacting with its growth factor tyrosine kinase receptor. Here we demonstrate that Tat specifically binds and activates the Flk-1/kinase insert domain receptor (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in the absence of activation of FLT-1, another VEGF-A tyrosine kinase receptor.

The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat

Human immunodeficiency virus (HIV)Tat

Somatostatin and its analogs are active in the inhibition of SST receptor-positive endocrine neoplasms, but their activity and mechanism in nonendocrine tumors is not clear. Somatostatin potently inhibited growth of a Kaposi's sarcoma xenograft in nude mice, yet in vitro the tumor cells did not express any known somatostatin receptors and were not growth inhibited by somatostatin. Histological examination revealed limited vascularization in the somatostatin-treated tumors as compared with the controls. Somatostatin was a potent inhibitor of angiogenesis in an in vivo assay. In vitro, somatostatin inhibited endothelial cell growth and invasion. Migration of monocytes, important mediators of the angiogenic cascade, was also inhibited by somatostatin. Both cells types expressed somatostatin receptor mRNAs. These data demonstrate that somatostatin is a potent antitumor angiogenesis compound directly affecting both endothelial and monocytic cells. The debated function of somatostatin in tumor treatment and the design of therapeutic protocols should be reexamined considering these data.