LUNG TUMOR LOCATION AND LYMPHOCYTE INFILTRATION IN MICE ARE GENETICALLY DETERMINED

Abstract

Lung cancer is a heterogeneous disease with individual differences in histological type, rate of progression, and response to therapy. Definition of the molecular and genetic basis of specific tumor characteristics would provide a better assessment of prognosis and a basis for a more individualized therapy. Here the authors compare the quantitative and qualitative phenotypes of lung tumors in mice of O20/A and OcB-9/Dem strains subjected to 2 regimens of N-ethyl-N-nitrosourea (ENU) treatment: (1) prenatal tumor induction by a single intraperitoneal (IP) injection of 40 mg/kg body weight into pregnant females and (2) after the same prenatal induction, the progeny received on weeks 9 and 11 additional IP ENU injections. The numbers, size, and histological characteristics of tumors were determined microscopically in semiserial lung sections. Unexpectedly, the authors observed very highly significant strain differences in a novel polymorphic phenotype-peribronchial versus nonperibronchial location of lung tumors, as well as in frequency of lymphocyte infiltration. To assess the reproducibility of these genetic differences, the authors classified both tumor location and lymphocyte infiltration also in an independent set of lung tumors that were induced in these strains in experiments performed more than 10 years ago in a different mouse facility and found the same strain differences. These results indicate that these qualitative phenotypes are very robust (P(c) 5.52 x 10(-6) and 2.27 x 10(-8), respectively) and relatively independent of environmental influences. They likely reflect different stages of lung differentiation at the time of tumor induction and differences in molecules involved in intercellular signaling, respectively. The definition of genes controlling these traits will provide novel insights into the determination of tumor phenotype.