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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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PI3K promotes tumorigenesis in KrasLA1 mice.(A) PI3K expression increases with malignant progression. Representative immunohistochemical staining of lesions in the tissue microarray and their quantification in adjacent bar graphs. Calibration bar in lower right panel represents 100 μm. Scores of mixed (solid/papillary) adenomas are included in bar graphs but not in PI3K staining images. (B) PI3K is required for tumor growth. Mean changes in tumor multiplicity and volume determined by micro-computed tomography performed before and after treatment. (* P<0.05 compared to vehicle). (C) PX-866 inhibits PI3K in lung tissues. Western blotting of Ser473-phosphorylated AKT (P-AKT) and Ser21/9-phosphorylated GSK3 (P-GSK3α/β) in whole lung lysates from mice (n = 7 in each treatment cohort). Positions of molecular weight markers are indicated on the left. (D) PX-866 decreases tumor cell proliferation. Representative immunohistochemical staining of Ser28-phosphorylated histone H3 (P-H3) in adenomas in the tissue microarray (x 20 magnification, areas with positive cells encircled) and quantification of staining in 16 lesions from vehicle-treated mice and 4 lesions from PX-866-treated mice (bar graph, * P<0.05 compared to vehicle). Inset illustrates encircled cells at ×40 magnification. Calibration bars represent 200 μm.
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pone-0002220-g001: PI3K promotes tumorigenesis in KrasLA1 mice.(A) PI3K expression increases with malignant progression. Representative immunohistochemical staining of lesions in the tissue microarray and their quantification in adjacent bar graphs. Calibration bar in lower right panel represents 100 μm. Scores of mixed (solid/papillary) adenomas are included in bar graphs but not in PI3K staining images. (B) PI3K is required for tumor growth. Mean changes in tumor multiplicity and volume determined by micro-computed tomography performed before and after treatment. (* P<0.05 compared to vehicle). (C) PX-866 inhibits PI3K in lung tissues. Western blotting of Ser473-phosphorylated AKT (P-AKT) and Ser21/9-phosphorylated GSK3 (P-GSK3α/β) in whole lung lysates from mice (n = 7 in each treatment cohort). Positions of molecular weight markers are indicated on the left. (D) PX-866 decreases tumor cell proliferation. Representative immunohistochemical staining of Ser28-phosphorylated histone H3 (P-H3) in adenomas in the tissue microarray (x 20 magnification, areas with positive cells encircled) and quantification of staining in 16 lesions from vehicle-treated mice and 4 lesions from PX-866-treated mice (bar graph, * P<0.05 compared to vehicle). Inset illustrates encircled cells at ×40 magnification. Calibration bars represent 200 μm.

Mentions: We postulated that PI3K is required for malignant progression in lung cancer and tested this hypothesis by using KrasLA1 mice as a model of lung tumorigenesis. Several weeks after birth, KrasLA1 mice exhibit multifocal AAH lesions that, by 2–3 months of age, coalesce into solid or papillary adenomas, which enlarge and undergo histologic transformation into adenocarcinomas by 6–8 months [7]. We first evaluated the expression of PI3K (p110α and β isoforms) in lung tissues at different stages of tumorigenesis (AAH, adenoma, or adenocarcinoma). These PI3K isoforms were detected and their abundance increased with malignant progression (AAH lesions versus adenocarcinomas: P = 0.006 for p110α; P<0.001 for p110β) (Figure 1A).


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)

PI3K promotes tumorigenesis in KrasLA1 mice.(A) PI3K expression increases with malignant progression. Representative immunohistochemical staining of lesions in the tissue microarray and their quantification in adjacent bar graphs. Calibration bar in lower right panel represents 100 μm. Scores of mixed (solid/papillary) adenomas are included in bar graphs but not in PI3K staining images. (B) PI3K is required for tumor growth. Mean changes in tumor multiplicity and volume determined by micro-computed tomography performed before and after treatment. (* P<0.05 compared to vehicle). (C) PX-866 inhibits PI3K in lung tissues. Western blotting of Ser473-phosphorylated AKT (P-AKT) and Ser21/9-phosphorylated GSK3 (P-GSK3α/β) in whole lung lysates from mice (n = 7 in each treatment cohort). Positions of molecular weight markers are indicated on the left. (D) PX-866 decreases tumor cell proliferation. Representative immunohistochemical staining of Ser28-phosphorylated histone H3 (P-H3) in adenomas in the tissue microarray (x 20 magnification, areas with positive cells encircled) and quantification of staining in 16 lesions from vehicle-treated mice and 4 lesions from PX-866-treated mice (bar graph, * P<0.05 compared to vehicle). Inset illustrates encircled cells at ×40 magnification. Calibration bars represent 200 μm.
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Related In: Results  -  Collection

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pone-0002220-g001: PI3K promotes tumorigenesis in KrasLA1 mice.(A) PI3K expression increases with malignant progression. Representative immunohistochemical staining of lesions in the tissue microarray and their quantification in adjacent bar graphs. Calibration bar in lower right panel represents 100 μm. Scores of mixed (solid/papillary) adenomas are included in bar graphs but not in PI3K staining images. (B) PI3K is required for tumor growth. Mean changes in tumor multiplicity and volume determined by micro-computed tomography performed before and after treatment. (* P<0.05 compared to vehicle). (C) PX-866 inhibits PI3K in lung tissues. Western blotting of Ser473-phosphorylated AKT (P-AKT) and Ser21/9-phosphorylated GSK3 (P-GSK3α/β) in whole lung lysates from mice (n = 7 in each treatment cohort). Positions of molecular weight markers are indicated on the left. (D) PX-866 decreases tumor cell proliferation. Representative immunohistochemical staining of Ser28-phosphorylated histone H3 (P-H3) in adenomas in the tissue microarray (x 20 magnification, areas with positive cells encircled) and quantification of staining in 16 lesions from vehicle-treated mice and 4 lesions from PX-866-treated mice (bar graph, * P<0.05 compared to vehicle). Inset illustrates encircled cells at ×40 magnification. Calibration bars represent 200 μm.
Mentions: We postulated that PI3K is required for malignant progression in lung cancer and tested this hypothesis by using KrasLA1 mice as a model of lung tumorigenesis. Several weeks after birth, KrasLA1 mice exhibit multifocal AAH lesions that, by 2–3 months of age, coalesce into solid or papillary adenomas, which enlarge and undergo histologic transformation into adenocarcinomas by 6–8 months [7]. We first evaluated the expression of PI3K (p110α and β isoforms) in lung tissues at different stages of tumorigenesis (AAH, adenoma, or adenocarcinoma). These PI3K isoforms were detected and their abundance increased with malignant progression (AAH lesions versus adenocarcinomas: P = 0.006 for p110α; P<0.001 for p110β) (Figure 1A).

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