Related Experiment Video
Updated: May 4, 2026
Studying Wnt Signaling During Patterning of Conducting Airways
Published on: October 16, 2016
Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice
Shigehisa Yanagi1, Hiroyuki Kishimoto, Kohichi Kawahara
1Department of Molecular Biology, Akita University School of Medicine, Akita, Japan.
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/Pten(flox/flox) (SOPten(flox/flox)) mice] that was under the control of doxycycline. Ninety percent of SOPten(flox/flox) mice that received doxycycline in utero [SOPten(flox/flox)(E10-16) mice] died of hypoxia soon after birth. Surviving SOPten(flox/flox)(E10-16) mice and mice that received doxycycline postnatally [SOPten(flox/flox)(P21-27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPten(flox/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 SOPten(flox/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 SOPten(flox/flox)(E10-16) and SOPten(flox/flox)(P21-27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPten(flox/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.
Insights
Loss of the PTEN tumor suppressor gene in mice causes lung cancer. PTEN is crucial for normal lung development and preventing lung adenocarcinoma by maintaining bronchioalveolar stem cell homeostasis.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The PTEN gene is a critical tumor suppressor frequently mutated in human cancers.
- Understanding PTEN's role in lung carcinogenesis is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the function of PTEN in lung development and tumorigenesis using a mouse model.
- To elucidate the molecular mechanisms by which PTEN loss contributes to lung adenocarcinoma.
Main Methods:
- Generation of a doxycycline-inducible, bronchioalveolar epithelium-specific Pten null mutation in mice (SOPten(flox/flox)).
- Administration of doxycycline in utero or postnatally to induce Pten deletion.
- Histological, biochemical, and genetic analyses of lung tissues, including assessment of bronchioalveolar stem cells (BASCs) and oncogenic signaling pathways.
Main Results:
- Conditional Pten deletion in mouse lungs led to hyperplasia, impaired surfactant production, and spontaneous lung adenocarcinomas.
- Increased numbers of bronchioalveolar stem cells (BASCs) and elevated expression of Spry2, Akt, c-Myc, Bcl-2, and Shh were observed.
- Urethane treatment accelerated tumor development, and K-ras mutations were frequent in induced lung adenocarcinomas.
Conclusions:
- PTEN is essential for normal lung morphogenesis and acts as a crucial suppressor of lung carcinogenesis.
- PTEN's tumor-suppressive function in the lung is likely mediated through the regulation of BASC homeostasis and key signaling pathways.
More Related Videos
09:02Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment
Published on: June 28, 2018
09:45Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
Published on: April 12, 2021