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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.

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Related in: MedlinePlus

PX-866 treatment decreases BASC numbers in KrasLA1 mice.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (×10 magnification) illustrated in lower panels at higher magnification (×40). 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.
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pone-0002220-g004: PX-866 treatment decreases BASC numbers in KrasLA1 mice.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (×10 magnification) illustrated in lower panels at higher magnification (×40). 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)

PX-866 treatment decreases BASC numbers in KrasLA1 mice.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (×10 magnification) illustrated in lower panels at higher magnification (×40). 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-g004: PX-866 treatment decreases BASC numbers in KrasLA1 mice.Immunofluorescent staining to detect cells at terminal bronchi that co-express CCSP and SPC. Encircled BASCs in top panels (×10 magnification) illustrated in lower panels at higher magnification (×40). 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