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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

BASCs identified in small bronchi/bronchioles of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice but not KrasLox/+; CCSPCre/+ mice.Immunofluorescent staining to detect cells that co-express CCSP and SPC. BASCs (encircled) illustrated at ×10 magnification. Bar graph illustrates percentages of bronchi with the indicated numbers of BASCS. Calibration bar in lower right panel represents 100 μm.
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pone-0002220-g008: BASCs identified in small bronchi/bronchioles of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice but not KrasLox/+; CCSPCre/+ mice.Immunofluorescent staining to detect cells that co-express CCSP and SPC. BASCs (encircled) illustrated at ×10 magnification. Bar graph illustrates percentages of bronchi with the indicated numbers of BASCS. Calibration bar in lower right panel represents 100 μm.

Mentions: As expected, triple immunofluorescence staining (CCSP/SPC/PTEN) revealed loss of PTEN expression in BASCs from mice that were both Pten-deficient and K-ras-transformed (PtenΔ5/Δ5; KrasLox/+; CCSPCre/+) but not in mice that were only K-ras-transformed (KrasLox/+; CCSPCre/+) (Figure 6). Quantification of BASCs per terminal bronchus at 4 weeks revealed that Pten-deficiency alone (PtenΔ5/Δ5; CCSPCre/+) was not sufficient to change BASC numbers relative to that of control mice (Ptenflox/flox; CCSP+/+) (Figure 7). However, comparison of BASC numbers in PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice to that of KrasLox/+; CCSPCre/+ mice demonstrated that Pten deficiency strikingly enhanced BASC expansion by oncogenic K-ras (P = 0.006, PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ versus KrasLox/+; CCSPCre/+) (Figure 7). In addition to these findings at the terminal bronchi, clusters of CCSPpos SPCpos cells were observed in the bronchioles and small bronchi of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice; these cell clusters were evident as early as 4 weeks of age and were not present in the bronchi or bronchioles of KrasLox/+; CCSPCre/+ mice (Figure 8). We conclude that Pten inactivation cooperated with oncogenic K-ras to enhance BASC accumulation.


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)

BASCs identified in small bronchi/bronchioles of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice but not KrasLox/+; CCSPCre/+ mice.Immunofluorescent staining to detect cells that co-express CCSP and SPC. BASCs (encircled) illustrated at ×10 magnification. Bar graph illustrates percentages of bronchi with the indicated numbers of BASCS. Calibration bar in lower right panel represents 100 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2376060&req=5

pone-0002220-g008: BASCs identified in small bronchi/bronchioles of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice but not KrasLox/+; CCSPCre/+ mice.Immunofluorescent staining to detect cells that co-express CCSP and SPC. BASCs (encircled) illustrated at ×10 magnification. Bar graph illustrates percentages of bronchi with the indicated numbers of BASCS. Calibration bar in lower right panel represents 100 μm.
Mentions: As expected, triple immunofluorescence staining (CCSP/SPC/PTEN) revealed loss of PTEN expression in BASCs from mice that were both Pten-deficient and K-ras-transformed (PtenΔ5/Δ5; KrasLox/+; CCSPCre/+) but not in mice that were only K-ras-transformed (KrasLox/+; CCSPCre/+) (Figure 6). Quantification of BASCs per terminal bronchus at 4 weeks revealed that Pten-deficiency alone (PtenΔ5/Δ5; CCSPCre/+) was not sufficient to change BASC numbers relative to that of control mice (Ptenflox/flox; CCSP+/+) (Figure 7). However, comparison of BASC numbers in PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice to that of KrasLox/+; CCSPCre/+ mice demonstrated that Pten deficiency strikingly enhanced BASC expansion by oncogenic K-ras (P = 0.006, PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ versus KrasLox/+; CCSPCre/+) (Figure 7). In addition to these findings at the terminal bronchi, clusters of CCSPpos SPCpos cells were observed in the bronchioles and small bronchi of PtenΔ5/Δ5; KrasLox/+; CCSPCre/+ mice; these cell clusters were evident as early as 4 weeks of age and were not present in the bronchi or bronchioles of KrasLox/+; CCSPCre/+ mice (Figure 8). We conclude that Pten inactivation cooperated with oncogenic K-ras to enhance BASC accumulation.

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