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

Yang Y, Iwanaga K, Raso MG, Wislez M, Hanna AE, Wieder ED, Molldrem JJ, Wistuba II, Powis G, Demayo FJ, Kim CF, Kurie JM - PLoS ONE (2008)

Bottom Line: The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.

Show MeSH

Related in: MedlinePlus

KrasLA1 mice have an accumulation of BASCs at terminal bronchi.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (x10 magnification) illustrated in lower panels at higher magnification (x40). Bar graph indicates percentages of terminal bronchi with the indicated numbers of BASCs. Calibration bars in images of H&E stained tissues represent 50 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2376060&req=5

pone-0002220-g002: KrasLA1 mice have an accumulation of BASCs at terminal bronchi.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (x10 magnification) illustrated in lower panels at higher magnification (x40). Bar graph indicates percentages of terminal bronchi with the indicated numbers of BASCs. Calibration bars in images of H&E stained tissues represent 50 μm.

Mentions: We next determined whether the anti-tumor effect of PX-866 in KrasLA1 mice was partly due to inhibition of BASC expansion. At the terminal bronchi, a subset of epithelial cells expressed both clara cell specific protein (CCSP) and surfactant protein-C (SPC) (Figure 2), which is a hallmark of BASCs [8]. Quantification of dual-positive cells in wild-type mice (with 83 bronchi) and K-rasLA1 mice (with 66 bronchi) revealed that no wild-type mice had more than 3 BASCs per terminal bronchus, whereas a subset of terminal bronchi in K-rasLA1 mice had 4 to 7 (P = 0.042, wild-type versus KrasLA1) (Figure 2). Thus, a subset of terminal bronchi in KrasLA1 mice had BASC expansion. Furthermore, triple immunofluorescence studies revealed that BASCs expressed p110α and had detectable phosphorylation of AKT (Figure 3), a downstream mediator of PI3K, providing evidence of PI3K activation in these cells. Using tissue sections from the KrasLA1 mice treated with PX-866 (with 88 terminal bronchi) or vehicle (with 81 terminal bronchi), we determined the number of BASCs per terminal bronchus in the treatment groups. The vehicle-treated mice had a subset of terminal bronchi with 4 to 7 BASCs per terminal bronchus, whereas none of the PX-866-treated mice had more than three BASCs per terminal bronchus (P = 0.025, vehicle versus PX-866-treated) (Figure 4).


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

Yang Y, Iwanaga K, Raso MG, Wislez M, Hanna AE, Wieder ED, Molldrem JJ, Wistuba II, Powis G, Demayo FJ, Kim CF, Kurie JM - PLoS ONE (2008)

KrasLA1 mice have an accumulation of BASCs at terminal bronchi.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (x10 magnification) illustrated in lower panels at higher magnification (x40). Bar graph indicates percentages of terminal bronchi with the indicated numbers of BASCs. Calibration bars in images of H&E stained tissues represent 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376060&req=5

pone-0002220-g002: KrasLA1 mice have an accumulation of BASCs at terminal bronchi.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (x10 magnification) illustrated in lower panels at higher magnification (x40). Bar graph indicates percentages of terminal bronchi with the indicated numbers of BASCs. Calibration bars in images of H&E stained tissues represent 50 μm.
Mentions: We next determined whether the anti-tumor effect of PX-866 in KrasLA1 mice was partly due to inhibition of BASC expansion. At the terminal bronchi, a subset of epithelial cells expressed both clara cell specific protein (CCSP) and surfactant protein-C (SPC) (Figure 2), which is a hallmark of BASCs [8]. Quantification of dual-positive cells in wild-type mice (with 83 bronchi) and K-rasLA1 mice (with 66 bronchi) revealed that no wild-type mice had more than 3 BASCs per terminal bronchus, whereas a subset of terminal bronchi in K-rasLA1 mice had 4 to 7 (P = 0.042, wild-type versus KrasLA1) (Figure 2). Thus, a subset of terminal bronchi in KrasLA1 mice had BASC expansion. Furthermore, triple immunofluorescence studies revealed that BASCs expressed p110α and had detectable phosphorylation of AKT (Figure 3), a downstream mediator of PI3K, providing evidence of PI3K activation in these cells. Using tissue sections from the KrasLA1 mice treated with PX-866 (with 88 terminal bronchi) or vehicle (with 81 terminal bronchi), we determined the number of BASCs per terminal bronchus in the treatment groups. The vehicle-treated mice had a subset of terminal bronchi with 4 to 7 BASCs per terminal bronchus, whereas none of the PX-866-treated mice had more than three BASCs per terminal bronchus (P = 0.025, vehicle versus PX-866-treated) (Figure 4).

Bottom Line: The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.

Show MeSH
Related in: MedlinePlus