Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice
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
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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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 1

Abnormal lung morphogenesis and lung epithelial cell hyperplasia in SOPtenflox/flox(E10–E16) mice.

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Abnormal lung morphogenesis and lung epithelial cell hyperplasia in SOPt...
(A) Gross appearance of representative neonates. Skin color is normal in WT(E10–E16) neonates but cyanotic in SOPtenflox/flox(E10–E16) (KO) littermates. (B) Histologic analysis of neonatal lungs. Left: normal alveolar (Al) and bronchiolar (Br) epithelial cells from a WT(E10–E16) neonate. Right: epithelial cell hyperplasia in alveoli and a bronchiole from a SOPtenflox/flox(E10–E16) neonate. Scale bars: 50 μm. (C) Increased total cell numbers in lungs. Total cells from WT(E10–E16) and SOPtenflox/flox(E10–E16) lungs at P0 were counted. Data are expressed as the mean total lung cells ± SD for 4 mice/group. *P < 0.05, Student’s t test. (D) Histological analysis of lungs at various embryonic stages. Lung sections were prepared from SOPtenflox/flox(E10–E16) mice at the indicated gestational stages and stained with H&E. Representative sections from WT(E10–E16) and SOPtenflox/flox(E10–E16) embryos are shown. No differences were detected between the WT and mutant embryos at E14.5 or E16.6, but dramatic differences were visible from E17.5 onward. WT(E10–E16) lungs showed dilatation of distal tubules and mesenchyme thinning at E17.5, with progression of septation from E17.5 to P0. SOPtenflox/flox(E10–E16) lungs showed fewer saccular structures during this period. Scale bars: 200 μm.