Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Biological mechanisms in the pathogenesis of AIDS-associated Kaposi's sarcoma (Meeting abstract).
Proc Annu Meet Am Assoc Cancer Res; 35:659 1994. Unique Identifier : AIDSLINE ICDB/95606241 Ensoli B; Barillari G; Fiorelli V; Albini A; Raffeld M; Markham P; Zon G; Gallo R; Lab. of Tumor Cell Biology, NCI, Bethesda, MD 20892
Abstract:
Kaposi's sarcoma (KS), a rare vascular tumor affecting elderly men of Mediterranean origin (classical KS), has become the most common form of cancer in HIV-I-infected individuals, mostly homosexual men (AIDS-KS). Establishment of long-term cultures of spindle cells of vascular origin from KS lesions of AIDS patients (AIDS-KS cells) by culturing them in the presence of conditioned media (CM) from HTLV-I or HTLV-II transformed CD4+ T cells, and the development of animal models have allowed studies on KS pathobiology which indicated that AIDS-KS cells constitutively express very high levels of bFGF, IL-1 beta and IL-6, and moderate levels of GM-CSF, TGF beta, PDGF-A and PDGF-B, VEGF and IL-8. As bFGF is highly expressed by KS spindle cells in vitro and in vivo, and since anti-bFGF antibodies blocked AIDS-KS cell growth and the growth of normal endothelial cells in response to CM from AIDS-KS cells, we focused on this cytokine. Determination of the pathogenetic role of bFGF and investigation of potential therapies for KS with bFGF injected sc in nude mice, and utilizing antisense oligonucleotides directed against bFGF mRNA to block the growth and angiogenic activity of AIDS-KS cells is described. The data indicated that bFGF is a key factor in KS histogenesis but did not explain the reasons for the increased frequency and aggressiveness of KS in HlV-I-infected homosexual men. Recent results indicating that the HIV-I Tat protein and inflammatory cytokines cooperate with bFGF in KS development are summarized. The results indicated that Tat may play a role in KS development, and they suggested that inflammatory cytokines are involved in the induction of KS. Clinical-epidemiological data and experimental results indicated that immune activation and consequent release of inflammatory cytokines participate in KS pathogenesis by multiple pathways. Homosexual men present evidence of immune activation including increased levels of the same inflammatory cytokines inducing vascular cell responsiveness to Tat that precede and accompany HIV-I infection. Treatment of AIDS-associated KS with recombinant TNF-alpha or gamma-IFN has been shown to increase the progression of KS. These cytokines induce normal vascular cells, potential precursor of KS cells, to acquire the features of the KS cell phenotype. These include the acquisition of a spindle-shaped morphology, the expression of adhesion molecule expression, the production of bFGF, the expression of receptors mediating the effects of extracellular Tat and the ability to induce KS-like lesions in nude mice. As both bFGF and Tat induce vascular cell growth, experiments were addressed to determine whether when present at the same time, as in HIV-I-infected individuals, they could synergize in inducing angiogenic effects. When bFGF and Tat were added simultaneously to endothelial cells, the growth effect increased in a synergistic manner. Similarly, when suboptimal concentration of bFGF and Tat (unable to induce macroscopic lesions) were injected simultaneously in nude mice, macroscopic vascular lesions closely resembling KS in humans developed in 40% of the animals. These data suggest that, at least in early stage, KS is a hyperplastic/proliferative disease mediated by the cooperation of inflammatory cytokines, Tat, and bFGF and may explain the biological mechanisms underlying the predominance of KS in HIV-I-infected homosexual men. (10 Refs)
Keywords: Acquired Immunodeficiency Syndrome/*COMPLICATIONS/METABOLISM Animal Cytokines/METABOLISM/PHARMACOLOGY/THERAPEUTIC USE Fibroblast Growth Factor, Basic/METABOLISM Gene Products, tat/METABOLISM Human HIV Infections/COMPLICATIONS/METABOLISM/PATHOLOGY HIV-1 Male Mice Sarcoma, Kaposi's/*ETIOLOGY/METABOLISM/PATHOLOGY/THERAPY ABSTRACT 950430
M9541147
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
