Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma

The paucity of premalignant material available for study makes it difficult to assign pathogenic roles to the myriad phenotypic abnormalities found in lung cancer. Chemically and transgenically induced primary lung tumors in mice, however, share many of the morphological, histogenic, and biochemical features of human adenocarcinoma. Genetic factors guide the susceptibility to these tumors in both mice and humans. The reproducible natural history of these investigator-initiated lesions allows molecular characterization at each stage of progression, as well as delineation of pharmacological agents which encourage or retard their appearance. Experimental tools which can be used with this mouse model include inbred and recombinant inbred strains that vary in susceptibility to lung tumorigenesis, sensitivity to tumor-promoting agents, and tumor growth characteristics; the ability to isolate the cells of tumor origin with a high degree of purity; immortalized but nontumorigenic cell lines for comparison with neoplastic cell lines; and transgenic mice with an accelerated rate of tumorigenesis for the study of benign to malignant progression over a conveniently short time course. Among the relevant information thus far garnered about mouse lung tumors is the fact that K-ras protooncogene polymorphisms predict susceptibility to tumor development; K-ras mutation is an early event, and the nature of this mutation may determine the benign or malignant fate of the tumors; and the autonomous growth of neoplastic lung epithelial cells is maintained by a resistance to growth-inhibitory signals, and this is mediated by depletion of intracellular receptors and altered signal transduction pathways.