| Kaposi's sarcoma (KS), a highly vascularized tumor of mesenchymal origin, is the most prevalent malignancy diagnosed among persons infected with the human immunodeficiency virus-1 (HIV-1). Mounting experimental evidence suggests that the HIV-1 TAT protein, following release from infected inflammatory cells, may initiate a localized biological cascade of molecular events resulting in the subsequent production of growth factors and cytokines by responsive target cells, relevant to the initiation and perpetuation of KS. The fibroblast growth factor family of polypeptides has gained general acceptance as initiators of angiogenesis and function as potent mitogens for mesoderm-derived cells and, therefore, are relevant to studies of KS pathogenesis.;To evaluate a potential biological relationship between HIV-1 TAT and FGF-1, primary murine embryonic fibroblasts were transfected/transduced with vectors designed to express either TAT, wild-type human FGF-1, or a secreted, chimeric form of this human polypeptide growth factor. Genetically modified cells were analyzed utilizing reverse transcriptase-polymerase chain reaction, in situ immunohistochemical, heparin affinity, DNA synthesis and Western blotting techniques. Measurements of oxidative status were performed by chromatographic and spectrophotometric analyses. Following in vivo transplantation, recovered tissue specimens were evaluated by in situ immunohistochemical and hybridization methods. Experimental evidence derived from the in vitro models presented herein serves to demonstrate that: (i) under steady state conditions intracellularly sequestered FGF-1 does not demonstrate biological activity; (ii) fibroblasts genetically engineered to secrete FGF-1 or express HIV-1 TAT elicit established FGF-mediated responses including cellular transformation; (iii) biological stress associated with either serum starvation, HIV-1 TAT expression, or pharmacologic depletion of cellular reducing equivalents, results in the release of FGF-1 as latent, high molecular mass complexes; and (iv) TAT expression induces alterations in cellular redox potential. In addition, in vivo experimental evidence suggests that embryonic fibroblasts expressing the HIV-1 TAT protein are capable of orchestrating the development of KS-like lesions following transplantation into normal syngeneic adult recipients; a process which appears to involve the inopportune expression of FGF-1. Collectively, these data not only provide a mechanism by which oxidative stress mediates the cellular release of FGF-1, but also support a role for this TAT-induced process in the initiation and perpetuation of AIDS-associated Kaposi's sarcoma. |
