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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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Submitted January 23, 2004
Accepted May 25, 2004
Enhanced tumorigenesis in HTLV-1 Tax transgenic mice deficient in interferon gamma
Shibani Mitra-Kaushik, John Harding, Jay Hess, Robert Schreiber, and Lee Ratner*
Departments of Internal Medicine and Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA
Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Department of Pathology, Washington University School of Medicine, St Louis, MO, USA
Departments of Internal Medicine and Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA; Department of Pathology, Washington University School of Medicine, St Louis, MO, USA
* Corresponding author; email: lratner{at}im.wustl.edu.
The oncoprotein Tax of 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 gamma (IFN- ) in HTLV-1 infected CD4 T 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 vs. 6 months), dissemination (median 5 vs. 7 months) and death (median 7 vs. 10 months), compared to IFN-+/- or IFN-+/+ Tax+ mice. Pathological and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced IL-2R and suppressed ICAM-1 expression on tumors from IFN--/- Tax+ transgenic mice. IFN--/- tumors demonstrate enhanced CD31 (PECAM-1) staining compared to those from IFN-+/- or IFN-+/+ Tax+ mice. Angiogenesis specific cDNA micro array analysis identified four mediators of angiogenic growth differentially expressed in tumors from Tax+IFN--/- compared to Tax+IFN-+/+ littermates. As confirmed by RT-PCR, loss of IFN- results in down-regulation of TNF- and TIMP-1 while up-regulating expression of 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.
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