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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3305-3311.
Prepublished online as a Blood First Edition Paper on August 3, 2004; DOI 10.1182/blood-2004-01-0266.
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NEOPLASIA
Enhanced tumorigenesis in HTLV-1 Tax-transgenic mice deficient in interferon-gamma
Shibani Mitra-Kaushik,
John Harding,
Jay Hess,
Robert Schreiber, and
Lee Ratner
From the Departments of Internal Medicine, Molecular Microbiobology, and Pathology, Washington University School of Medicine, St Louis, MO; and the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon- (IFN-) in HTLV-1-infected CD4+ cells and Tax-transgenic tumors. We examined the role of IFN- in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-. IFN--/- Tax+-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-+/- or IFN-+/+ Tax+ mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor- (IL-2R) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN--/- Tax+ transgenic mice. IFN--/- tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-+/- or IFN-+/+ Tax+ mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax+IFN--/- mice compared with Tax+IFN-+/+ littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN- results in down-regulation of tumor necrosis factor- (TNF-) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN- contributes to host resistance against HTLV-induced tumors through an angiostatic effect. (Blood. 2004;104:3305-3311)
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