Targeted inhibition of angiogenic factors in AIDS-related disorders.
Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposi's sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDS-related KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposi's sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting pro-angiogenic factors.
Aoki
Yoshiyasu
Y
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive 12N226 MSC1907, Bethesda, MD 20892, USA. aokiy@mail.nih.gov
Tosato
Giovanna
G
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D005871:Castleman Disease / Q000150:complications / Q000473:pathology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D006566:Herpesviridae Infections / Q000150:complications / Q000473:pathology; D019288:Herpesvirus 8, Human / Q000254:growth & development; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000150:complications / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000628:therapy*; D012514:Sarcoma, Kaposi / Q000098:blood supply* / Q000628:therapy* / Q000821:virology; D042461:Vascular Endothelial Growth Factor A
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2