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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1493-1500.
Prepublished online as a Blood First Edition Paper on October 29, 2008; DOI 10.1182/blood-2008-07-166462.
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Submitted July 2, 2008
Accepted October 9, 2008
Imaging spontaneous tumorigenesis:
Inflammation precedes development of peripheral NK tumors
Dan Rauch, Shimon Gross, John Harding, Stefan Niewiesk, Michael Lairmore, David Piwnica-Worms, and Lee Ratner*
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO, United States
Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
College of Veterinary Medicine, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO, United States
* Corresponding author; email: lratner{at}dom.wustl.edu.
Early events in tumor development are spontaneous, microscopic, and affected by the microenvironment. We developed a mouse model of spontaneous lymphoma in which malignant transformation is coupled with light emission that can be detected non-invasively using bioluminescent imaging. The human T-cell leukemia virus type 1 transcriptional transactivator Tax, is an oncogene sufficient to produce lymphoma in transgenic animal models. Using the granzyme B promoter to restrict Tax expression to the mature NK/T cell compartment, we have reproduced many elements of HTLV-associated adult T-cell leukemia/lymphoma. Tax activates signaling cascades associated with transformation, inflammation, and tumorigenesis. Here we report that Tax mediated activation of luciferase in LTR-LUC mice serves as a reporter for imaging these processes in vivo. Using BLI, we discovered that microscopic intraepithelial lesions precede the onset of peripheral subcutaneous tumors, tumorigenesis progresses through early reversible stages, and Tax is sufficient for inducing tumors. Based on these findings, we propose that Tax expression in activated lymphocytes initiates a cascade of events that leads to NK/T cell recruitment, activation, and transformation. The use of BLI expands our ability to interrogate the role of Tax in tumorigenesis in vivo, and has made the association of inflammation with tumor initiation amenable for study.
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