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

Abstract

BACKGROUND:

The human immunodeficiency virus type 1 (HIV-1) transactivator (Tat) protein has been linked to the development and course of Kaposi's sarcoma (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 transgenic mice expressing the one-exon-encoded 72 amino-acid protein (Tat(72)) and the two-exon-encoded 86 amino-acid protein (Tat(86)).

METHODS:

Human KS SLK cells were injected subcutaneously into CD4(+) T-cell-depleted male mice, and the tumors that formed after 3-4 weeks were recovered and analyzed for the expression of Tat protein(s), different cytokine messenger RNAs (mRNAs), and matrix metalloproteinases (MMPs). All statistical tests were two-sided.

RESULTS:

The average tumor weight was maximum in Tat(86) mice ( approximately 600 mg) compared with Tat(72) ( approximately 200 mg) and nontransgenic ( approximately 100 mg) mice (P<.005). Histologic examination of tumors showed spindle-shaped SLK cells with prominent infiltrates of inflammatory cells. All of the tumors from Tat mice expressed abundant Tat mRNA, suggesting that the infiltrating mouse cells actively expressed Tat. A comparison of the growth-promoting cytokines in the tumors from Tat(86)-transgenic and nontransgenic mice showed that the expression of the following cytokines was substantially increased in the tumors of the Tat(86) mice: tumor necrosis factor-alpha, interleukin 6, interleukin 8, granulocyte-macrophage colony-stimulating factor, and basic fibroblast growth factor. Furthermore, these tumors showed abundant expression of a 105-kd MMP activity associated with infiltrates of host leukocytes in the lesions.

CONCLUSION:

Our in vivo data clearly suggest that extracellular Tat can contribute to the growth and tumorigenesis of human KS cells.

• Authors: O Prakash, Z Y Tang, Y E He, M S Ali, R Coleman, J Gill, G Farr, F Samaniego
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 92 Issue 9 Pg. 721-8 (May 03 2000) ISSN: 0027-8874 [Print] United States
• PMID: 10793108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gene Products, tat
• NF-kappa B
• RNA, Messenger
• tat Gene Products, Human Immunodeficiency Virus
• Metalloendopeptidases

Topics

• Animals
• Extravasation of Diagnostic and Therapeutic Materials
• Gene Expression
• Gene Products, tat (genetics)
• Genes, Viral (genetics)
• HIV-1 (genetics)
• Humans
• Male
• Metalloendopeptidases (metabolism)
• Mice
• Mice, Nude
• Mice, Transgenic
• NF-kappa B (genetics)
• Neoplasms, Experimental (etiology, genetics, metabolism)
• Neutrophil Infiltration
• Neutrophils (enzymology, metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• Sarcoma, Kaposi (pathology)
• Tissue Distribution
• Tumor Cells, Cultured
• tat Gene Products, Human Immunodeficiency Virus