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Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model.

Bhatia S, Hirsch K, Baig NA, Rodriguez O, Timofeeva O, Kavanagh K, Lee YC, Wang XJ, Albanese C, Karam SD - J Hematol Oncol (2015)

Bottom Line: Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum.Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration.Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

View Article: PubMed Central - PubMed

Affiliation: Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. shilpa.bhatia@ucdenver.edu.

ABSTRACT

Background: Members of the Eph/ephrin gene families act as key regulators of cerebellar development during embryogenesis. Aberrant signaling of Eph family of receptor tyrosine kinases and their ephrin ligands has also been implicated in human cancers. Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum. Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration. In the present study, we investigated the effects of genetic loss of ephrin-A5, EphA4, and EphA7 on the spatiotemporal development of medulloblastoma tumors in the context of the smoothened transgenic mouse model system.

Findings: Radiographic magnetic resonance imaging (MRI) was performed to monitor tumor growth in a genetically engineered mouse model of medulloblastoma. Tumor tissue was harvested to determine changes in the expression of phosphorylated Akt by Western blotting. This helped to establish a correlation between genotype and/or tumor size and survival. Our in vivo data establish that in ND2-SmoA1 transgenic mice, the homozygous deletion of ephrin-A5 resulted in a consistent pattern of tumor growth inhibition compared to their ephrin-A5 wild-type littermate controls, while the loss of EphA4/EphA7 failed to produce consistent effects versus EphA4/EphA7 wild-type mice. A positive correlation was evident between tumor size, p-Akt, and proliferating cell nuclear antigen (PCNA) expression in our transgenic mouse model system, regardless of genotype.

Conclusions: Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis suggests a correlation between p-Akt and PCNA levels and tumor size regardless of genotype in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo mice. a Western blot analysis in tumor tissues indicated expression of p-Akt and PCNA correlative of tumor size. Lysates were collected from mice and Western blot analysis was done to determine the expression of p-Akt, total Akt, and PCNA. b Densitometric analysis of p-Akt expression (*p ≤ 0.05) and c PCNA levels (p = not significant) in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo tumors. Data represent mean ± standard deviation from different tumor tissues
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Fig4: Western blot analysis suggests a correlation between p-Akt and PCNA levels and tumor size regardless of genotype in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo mice. a Western blot analysis in tumor tissues indicated expression of p-Akt and PCNA correlative of tumor size. Lysates were collected from mice and Western blot analysis was done to determine the expression of p-Akt, total Akt, and PCNA. b Densitometric analysis of p-Akt expression (*p ≤ 0.05) and c PCNA levels (p = not significant) in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo tumors. Data represent mean ± standard deviation from different tumor tissues

Mentions: However, when p-Akt levels were examined across the different tumors here, we again found a correlation between tumor size and p-Akt levels irrespective of genotype within this subgroup. Western blot analysis of tumor tissue harvested from EphA4−/−EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/+EphA7−/−Smo mice revealed expression of p-Akt (Fig. 4a, b) and PCNA (Fig. 4a, c) that correlated with actual tumor size. Total Akt levels seem to remain unchanged (Fig. 4a). In conclusion, although the combined loss of EphA4 and EphA7 receptors failed to show consistent effects on tumor growth, the correlation between levels of p-Akt, PCNA, and tumor size persisted.Fig. 4


Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model.

Bhatia S, Hirsch K, Baig NA, Rodriguez O, Timofeeva O, Kavanagh K, Lee YC, Wang XJ, Albanese C, Karam SD - J Hematol Oncol (2015)

Western blot analysis suggests a correlation between p-Akt and PCNA levels and tumor size regardless of genotype in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo mice. a Western blot analysis in tumor tissues indicated expression of p-Akt and PCNA correlative of tumor size. Lysates were collected from mice and Western blot analysis was done to determine the expression of p-Akt, total Akt, and PCNA. b Densitometric analysis of p-Akt expression (*p ≤ 0.05) and c PCNA levels (p = not significant) in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo tumors. Data represent mean ± standard deviation from different tumor tissues
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4561476&req=5

Fig4: Western blot analysis suggests a correlation between p-Akt and PCNA levels and tumor size regardless of genotype in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo mice. a Western blot analysis in tumor tissues indicated expression of p-Akt and PCNA correlative of tumor size. Lysates were collected from mice and Western blot analysis was done to determine the expression of p-Akt, total Akt, and PCNA. b Densitometric analysis of p-Akt expression (*p ≤ 0.05) and c PCNA levels (p = not significant) in EphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4−/−EphA7−/−Smo tumors. Data represent mean ± standard deviation from different tumor tissues
Mentions: However, when p-Akt levels were examined across the different tumors here, we again found a correlation between tumor size and p-Akt levels irrespective of genotype within this subgroup. Western blot analysis of tumor tissue harvested from EphA4−/−EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/+EphA7−/−Smo mice revealed expression of p-Akt (Fig. 4a, b) and PCNA (Fig. 4a, c) that correlated with actual tumor size. Total Akt levels seem to remain unchanged (Fig. 4a). In conclusion, although the combined loss of EphA4 and EphA7 receptors failed to show consistent effects on tumor growth, the correlation between levels of p-Akt, PCNA, and tumor size persisted.Fig. 4

Bottom Line: Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum.Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration.Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

View Article: PubMed Central - PubMed

Affiliation: Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. shilpa.bhatia@ucdenver.edu.

ABSTRACT

Background: Members of the Eph/ephrin gene families act as key regulators of cerebellar development during embryogenesis. Aberrant signaling of Eph family of receptor tyrosine kinases and their ephrin ligands has also been implicated in human cancers. Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum. Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration. In the present study, we investigated the effects of genetic loss of ephrin-A5, EphA4, and EphA7 on the spatiotemporal development of medulloblastoma tumors in the context of the smoothened transgenic mouse model system.

Findings: Radiographic magnetic resonance imaging (MRI) was performed to monitor tumor growth in a genetically engineered mouse model of medulloblastoma. Tumor tissue was harvested to determine changes in the expression of phosphorylated Akt by Western blotting. This helped to establish a correlation between genotype and/or tumor size and survival. Our in vivo data establish that in ND2-SmoA1 transgenic mice, the homozygous deletion of ephrin-A5 resulted in a consistent pattern of tumor growth inhibition compared to their ephrin-A5 wild-type littermate controls, while the loss of EphA4/EphA7 failed to produce consistent effects versus EphA4/EphA7 wild-type mice. A positive correlation was evident between tumor size, p-Akt, and proliferating cell nuclear antigen (PCNA) expression in our transgenic mouse model system, regardless of genotype.

Conclusions: Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

No MeSH data available.


Related in: MedlinePlus