Human Kaposi's sarcoma cell-mediated tumorigenesis in human immunodeficiency type 1 Tat-expressing transgenic mice

Background: The human immunodeficiency virus type 1 (HIV-1) transactivator (Tat) protein has been linked to the development and course of Kaposi's sar coma (KS) associated with acquired immunodeficiency disease syndrome (AIDS- KS), Tat is an 86-101 amino-acid protein encoded by two exons, To evaluate the growth-promoting effects of Tat in AIDS-KS in vivo, we developed transg enic mice expressing the one-exon-encoded 72 amino-acid protein (Tat(72)) a nd the two-exon-encoded 86 amino-acid protein (Tat(86)). Methods: Human KS SLK cells were injected subcutaneously into CD4(+) T-cell-depleted male mic e, and the tumors that formed after 3-4 weeks were recovered and analyzed f or the expression of Tat protein(s), different cytokine messenger RNAs (mRN As), and matrix metalloproteinases (MMPs), All statistical tests were two-s ided. Results: The average tumor weight was maximum in Tat(86) mice (simila r to 600 mg) compared with Tat(72) (similar to 200 mg) and nontransgenic (s imilar to 100 mg) mice (P<.005). Histologic examination of tumors showed sp indle-shaped SLK cells with prominent infiltrates of inflammatory cells. Al l of the tumors from Tat mice expressed abundant Tat mRNA, suggesting that the infiltrating mouse cells actively expressed Tat. A comparison of the gr owth-promoting cytokines in the tumors from Tat(86)-transgenic and nontrans genic mice showed that the expression of the following cytokines was substa ntially increased in the tumors of the Tat,, mice: tumor necrosis factor-al pha, interleukin 6, interleukin 8, granulocyte-macrophage colony-stimulatin g factor, and basic fibroblast growth factor. Furthermore, these tumors sho wed abundant expression of a 105-kd MMP activity associated with infiltrate s of host leukocytes in the lesions. Conclusion: Our in vivo data clearly s uggest that extracellular Tat can contribute to the growth and tumorigenesi s of human KS cells.