title: Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors.
abstract: 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 noninvasively using bioluminescent imaging. The human T-cell leukemia virus (HTLV) 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 natural killer (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 long terminal repeat-luciferase (LTR-LUC) mice serves as a reporter for imaging these processes in vivo. Using bioluminescent imaging (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.
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Rauch
authors.forename: Shimon
authors.initials: S
authors.lastname: Gross
authors.forename: John
authors.initials: J
authors.lastname: Harding
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.forename: Michael
authors.initials: M
authors.lastname: Lairmore
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology; D016356:Gene Products, tax / Q000235:genetics; D053804:Granzymes / Q000235:genetics; D015368:Human T-lymphotropic virus 1; D007249:Inflammation / Q000473:pathology*; D007668:Kidney / Q000166:cytology; D007694:Killer Cells, Natural / Q000473:pathology*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011323:Primates; D011401:Promoter Regions, Genetic / Q000502:physiology; D014162:Transfection
chemical_list: D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1; D008156:Luciferases; D053804:Granzymes; C509214:Gzmb protein, mouse