Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer

• Published in: PloS one Vol. 3; no. 5; p. e2220
• Main Authors: Yang, Yanan, Iwanaga, Kentaro, Raso, Maria Gabriela, Wislez, Marie, Hanna, Amy E, Wieder, Eric D, Molldrem, Jeffrey J, Wistuba, Ignacio I, Powis, Garth, Demayo, Francesco J, Kim, Carla F, Kurie, Jonathan M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2008; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Analysis; Animal models; Animals; Apoptosis; Bronchi - pathology; Cancer; Cell culture; Chromosome 10; Deactivation; Disease Models, Animal; Expansion; Gene amplification; Genes, ras; Gonanes - pharmacology; Health aspects; Health risk assessment; Homology; Inactivation; K-Ras protein; Kinases; Leukemia; Lung cancer; Lung diseases; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Morphogenesis; Mutation; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Oncology/Lung Cancer; Pharmacology; Phosphatase; Phosphatases; Phosphatidylinositol 3-Kinases - metabolism; Phospholipids; Population; Proteins; Pulmonary Alveoli - pathology; Senescence; Stem cell transplantation; Stem cells; Stem Cells - cytology; Tensin; Therapeutics; Tumorigenesis; Tumors; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002220

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Developing more effective NSCLC therapeutics will require the elucidation of the genetic and biochemical bases for this disease. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-ras-induced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined. We used genetic and pharmacologic approaches to modulate the activity of phosphatidylinositol 3-kinase (PI3K), a key mediator of oncogenic K-ras, in two genetic mouse models of lung adenocarcinoma. Oncogenic K-ras-induced BASC accumulation and tumor growth were blocked by treatment with a small molecule PI3K inhibitor and enhanced by inactivation of phosphatase and tensin homologue deleted from chromosome 10, a negative regulator of PI3K. We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.