A TRANSGENIC MOUSE MODEL FOR LUNG ADENOCARCINOMA

Lung cancer is a leading cause of tumor-related deaths in humans but i ts origin and development are poorly understood. To study the biology of these tumors, appropriate animal and cell culture models will be of eminent importance. Uteroglobin isa marker protein for the nonciliate d epithelial Clara cells lining the respiratory and terminal bronchiol i of the lung. We have used the promoter and 5'-flanking sequences of the rabbit uteroglobin gene to target expression of the SV40 T antigen to the lung of transgenic mice. All transgenic founders as well as th e descendants from an established line, UT7.1, developed multifocal br onchioloalveolar adenocarcinomas originating from Clara cells. At leas t three different stages in tumor development with progressive loss of the differentiated phenotype can be distinguished by immunohistochemi cal data and in situ hybridization. Only in the initial stage did bron chiolar cells express both uteroglobin and SV40 T antigen, whereas at later stages, only SV40 T antigen was detected, and the most advanced tumors were negative for both proteins. Starting from the lungs of UT7 .1 mice, a bronchiolar cell line was established that maintains the fe atures of differentiated Clara cells. This system provides a useful mo del for further studying the development and progression of lung adeno carcinomas in vivo and in vitro.