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, Wah Mak Tak, Toru Nakano, Masamitsu Nakazato, Akira Suzuki

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)

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 (SOPten flox/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 SOPten flox/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 SOPten flox/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.

Original languageEnglish
Pages (from-to)2929-2940
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number10
DOIs
Publication statusPublished - 2007 Oct 1

ASJC Scopus subject areas

  • Medicine(all)

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