Transforming Growth Factor-β Receptor Type II Deletion Increases the Multiplicity and Growth of K-ras–induced Lung Cancers

Abstract

Transforming growth factor-β (TGF-β) is a pluripotent regulator of epithelial growth and homeostasis and functions as a tumor suppressor in numerous malignancies. TGF-β signaling defects are common in many malignancies, including non–small cell lung cancer (NSCLC); however, the mechanisms by which defective TGF-β signaling promotes lung cancer growth and development are relatively unknown. We generated a novel NSCLC mouse model by simultaneously activating oncogenic KrasG12D expression and deleting TGF-β receptor type II (TGF-βRII) in airway epithelial cells. Genetic manipulation was targeted to the airway by K5Cre*PR, which uses a keratin 5 (K5) promoter to direct expression of an RU486-inducible, Cre recombinase-progesterone receptor fusion protein to epithelial cells. K5Cre*PR.lox-stop-lox-KrasG12D.TGF-βRII flox/flox mice treated with tracheal RU486 develop multifocal NSCLC beginning at approximately 32 weeks of age. Interestingly, these animals develop both thyroid transcription factor (TTF)-positive adenocarcinomas and K5-positive squamous cell carcinomas. TGF-βRII deletion increases tumor multiplicity from 3.2 ± 1.7 to 49 ± 10 tumors per animal and increases average tumor size from 0.71 to 1.04 mm, compared with tumors generated in K5Cre*PR.LSL-KrasG12D mice (P < 0.05 for both comparisons). In addition, K5Cre*PR.LSL-KrasG12D.TGFβRII flox/flox mice have both increased serum and bronchoalveolar lavage (BAL) TGF-β1 levels as well as increased BAL macrophages. Mechanistically, TGF-βRII deletion increases the multiplicity and growth of K-ras–induced lung cancers through mechanisms involving increased proliferation and increased inflammation.