Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors
Journal - Blood
Early events in tumor development are spontaneous, microscopic,and affected by the microenvironment. We developed a mouse modelof spontaneous lymphoma in which malignant transformation iscoupled with light emission that can be detected noninvasivelyusing bioluminescent imaging. The human T-cell leukemia virus(HTLV) type 1 transcriptional transactivator Tax is an oncogenesufficient to produce lymphoma in transgenic animal models.Using the granzyme B promoter to restrict Tax expression tothe mature natural killer (NK)/T-cell compartment, we have reproducedmany elements of HTLV-associated adult T-cell leukemia/lymphoma.Tax activates signaling cascades associated with transformation,inflammation, and tumorigenesis. Here, we report that Tax-mediatedactivation of luciferase in long terminal repeat-luciferase(LTR-LUC) mice serves as a reporter for imaging these processesin vivo. Using bioluminescent imaging (BLI), we discovered thatmicroscopic intraepithelial lesions precede the onset of peripheralsubcutaneous tumors, tumorigenesis progresses through earlyreversible stages, and Tax is sufficient for inducing tumors.Based on these findings, we propose that Tax expression in activatedlymphocytes initiates a cascade of events that leads to NK/Tcell recruitment, activation, and transformation. The use ofBLI expands our ability to interrogate the role of Tax in tumorigenesisin vivo and has made the association of inflammation with tumorinitiation amenable for study.