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Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.

Becker M, Korn C, Sienerth AR, Voswinckel R, Luetkenhaus K, Ceteci F, Rapp UR - PLoS ONE (2009)

Bottom Line: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared.Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth.Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

View Article: PubMed Central - PubMed

Affiliation: Bayerisches Krebsforschungszentrum, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1.

Principal findings: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

Significance: The data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

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Related in: MedlinePlus

Lack of Bmi1 expression correlates with reduced tumor growth but not incidence in BXB11 mice.A) Paraffin embedded lung sections from BXB11 and Bmi1−/−BXB11 lungs were stained for Bmi1 (green) and DAPI (blue). Dotted white lines delineate tumors. Scale bar = 30 µm. B) H&E staining of lung sections from BXB11 and Bmi1−/−BXB11 mice at the age of two weeks and three months demonstrates reduced tumor burdon in Bmi1−/−BXB11 lungs. Scale bar = 200 µm. C and D) Analysis of tumor incidence and growth within the lungs of BXB11 and Bmi1−/−BXB11 mice. Data presented as Box-and-Whiskers plots, for details of data presentation see figure legend of Figure 1 (n≥4 animals per genotype and age, for details see experimental materials). Note that tumor incidence is increased by a factor of two when compared to Figure 1A) because of the FVB/N genetic background introduced through mating with the Bmi1−/− mice. n.d. = not determined because tumors were confluent. p-values were calculated using Student's t-test only p-values indicating significance are shown.
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pone-0004230-g002: Lack of Bmi1 expression correlates with reduced tumor growth but not incidence in BXB11 mice.A) Paraffin embedded lung sections from BXB11 and Bmi1−/−BXB11 lungs were stained for Bmi1 (green) and DAPI (blue). Dotted white lines delineate tumors. Scale bar = 30 µm. B) H&E staining of lung sections from BXB11 and Bmi1−/−BXB11 mice at the age of two weeks and three months demonstrates reduced tumor burdon in Bmi1−/−BXB11 lungs. Scale bar = 200 µm. C and D) Analysis of tumor incidence and growth within the lungs of BXB11 and Bmi1−/−BXB11 mice. Data presented as Box-and-Whiskers plots, for details of data presentation see figure legend of Figure 1 (n≥4 animals per genotype and age, for details see experimental materials). Note that tumor incidence is increased by a factor of two when compared to Figure 1A) because of the FVB/N genetic background introduced through mating with the Bmi1−/− mice. n.d. = not determined because tumors were confluent. p-values were calculated using Student's t-test only p-values indicating significance are shown.

Mentions: Based on the observation that Bmi1 is expressed in BXB11 induced tumors and the previously described role of Bmi1 in tumor stem cell self-renewal [14], [22], [23] we decided to further study the role of Bmi1 for the development of C-RAF BXB adenomas (Figure 2A). We generated compound mice expressing the SP-C C-RAF BXB transgene on the Bmi1 knock out background. As the genomic deletion of Bmi1 had no effect on lung development and structure of the adult lung (Figure S2) any alterations in tumor growth can be attributed to Bmi1. The analysis of the Bmi1−/− SP-C C-RAF BXB mice is hampered by the short life span of these mice that is caused by the deletion of Bmi1 [24] and rarely allowed monitoring of tumor development for more than three months.


Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.

Becker M, Korn C, Sienerth AR, Voswinckel R, Luetkenhaus K, Ceteci F, Rapp UR - PLoS ONE (2009)

Lack of Bmi1 expression correlates with reduced tumor growth but not incidence in BXB11 mice.A) Paraffin embedded lung sections from BXB11 and Bmi1−/−BXB11 lungs were stained for Bmi1 (green) and DAPI (blue). Dotted white lines delineate tumors. Scale bar = 30 µm. B) H&E staining of lung sections from BXB11 and Bmi1−/−BXB11 mice at the age of two weeks and three months demonstrates reduced tumor burdon in Bmi1−/−BXB11 lungs. Scale bar = 200 µm. C and D) Analysis of tumor incidence and growth within the lungs of BXB11 and Bmi1−/−BXB11 mice. Data presented as Box-and-Whiskers plots, for details of data presentation see figure legend of Figure 1 (n≥4 animals per genotype and age, for details see experimental materials). Note that tumor incidence is increased by a factor of two when compared to Figure 1A) because of the FVB/N genetic background introduced through mating with the Bmi1−/− mice. n.d. = not determined because tumors were confluent. p-values were calculated using Student's t-test only p-values indicating significance are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2626631&req=5

pone-0004230-g002: Lack of Bmi1 expression correlates with reduced tumor growth but not incidence in BXB11 mice.A) Paraffin embedded lung sections from BXB11 and Bmi1−/−BXB11 lungs were stained for Bmi1 (green) and DAPI (blue). Dotted white lines delineate tumors. Scale bar = 30 µm. B) H&E staining of lung sections from BXB11 and Bmi1−/−BXB11 mice at the age of two weeks and three months demonstrates reduced tumor burdon in Bmi1−/−BXB11 lungs. Scale bar = 200 µm. C and D) Analysis of tumor incidence and growth within the lungs of BXB11 and Bmi1−/−BXB11 mice. Data presented as Box-and-Whiskers plots, for details of data presentation see figure legend of Figure 1 (n≥4 animals per genotype and age, for details see experimental materials). Note that tumor incidence is increased by a factor of two when compared to Figure 1A) because of the FVB/N genetic background introduced through mating with the Bmi1−/− mice. n.d. = not determined because tumors were confluent. p-values were calculated using Student's t-test only p-values indicating significance are shown.
Mentions: Based on the observation that Bmi1 is expressed in BXB11 induced tumors and the previously described role of Bmi1 in tumor stem cell self-renewal [14], [22], [23] we decided to further study the role of Bmi1 for the development of C-RAF BXB adenomas (Figure 2A). We generated compound mice expressing the SP-C C-RAF BXB transgene on the Bmi1 knock out background. As the genomic deletion of Bmi1 had no effect on lung development and structure of the adult lung (Figure S2) any alterations in tumor growth can be attributed to Bmi1. The analysis of the Bmi1−/− SP-C C-RAF BXB mice is hampered by the short life span of these mice that is caused by the deletion of Bmi1 [24] and rarely allowed monitoring of tumor development for more than three months.

Bottom Line: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared.Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth.Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

View Article: PubMed Central - PubMed

Affiliation: Bayerisches Krebsforschungszentrum, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1.

Principal findings: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

Significance: The data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

Show MeSH
Related in: MedlinePlus