Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice
Shigehisa Yanagi, … , Masamitsu Nakazato, Akira Suzuki
Shigehisa Yanagi, … , Masamitsu Nakazato, Akira Suzuki
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2929-2940. https://doi.org/10.1172/JCI31854.
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Research Article Oncology

Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice

Abstract

PTEN is a tumor suppressor gene mutated in many human cancers. We generated a bronchioalveolar epithelium–specific null mutation of Pten in mice [SP-C-rtTA/(tetO)7-Cre/Ptenflox/flox (SOPtenflox/flox) mice] that was under the control of doxycycline. Ninety percent of SOPtenflox/flox mice that received doxycycline in utero [SOPtenflox/flox(E10–16) mice] died of hypoxia soon after birth. Surviving SOPtenflox/flox(E10–16) mice and mice that received doxycycline postnatally [SOPtenflox/flox(P21–27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPtenflox/flox mice of both ages. Histological and biochemical examinations of the lungs of SOPtenflox/flox(E10–16) mice revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, enlarged alveolar epithelial cells, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells (BASCs), putative initiators of lung adenocarcinomas, were increased. Lungs of SOPtenflox/flox(E10–16) mice showed increased expression of Spry2, which inhibits the maturation of alveolar epithelial cells. Levels of Akt, c-Myc, Bcl-2, and Shh were also elevated in SOPtenflox/flox(E10–16) and SOPtenflox/flox(P21–27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPtenflox/flox(P21–27) lungs. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis.

Authors

Shigehisa Yanagi, Hiroyuki Kishimoto, Kohichi Kawahara, Takehiko Sasaki, Masato Sasaki, Miki Nishio, Nobuyuki Yajima, Koichi Hamada, Yasuo Horie, Hiroshi Kubo, Jeffrey A. Whitsett, Tak Wah Mak, Toru Nakano, Masamitsu Nakazato, Akira Suzuki

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Figure 4

Bronchiolar and alveolar epithelial cell hyperplasia and increased cell size in SOPtenflox/flox mice that received doxycycline postnatally.

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Bronchiolar and alveolar epithelial cell hyperplasia and increased cell ...
(A) Histologic analyses of lungs from WT(P21–P27) and SOPtenflox/flox(P21–P27) and WT(P84–P90) and SOPtenflox/flox(P84–P90) mice. Mild epithelial cell hyperplasia in alveoli and a bronchiole could be observed at both time points. Scale bars: 50 μm. (B) Transmission electron micrographs of the lung septa from WT(P21–P27) and SOPtenflox/flox(P21–P27) and WT(P84–P90) and SOPtenflox/flox(P84–P90) mice. The increased sizes of AE-I and AE-II cells can be seen in SOPtenflox/flox lungs at both time points. Lamellar bodies and apical microvilli, which are signature structures of AE-II cells, are visible within the AE-II cells of both WT and SOPtenflox/flox lungs. Scale bars: 5 μm. (C) IHC analysis of SP-C, AQP5, and CCSP expression in lungs of WT(P21–P27) and SOPtenflox/flox(P21–P27) mice (left panels) and WT(P84–P90) and SOPtenflox/flox(P84–P90) mice (right panels). Although the numbers of AE-I and AE-II cells were increased in lungs of SOPtenflox/flox(P21–P27) and SOPtenflox/flox(P84–P90) mice, no significant differences between WT and SOPtenflox/flox mice were observed in the staining intensity of SP-C, AQP5, or CCSP at either time point. Scale bars: 50 μm.