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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

Representative MRI scans show that genetic alteration of EphA4/EphA7 genotype yields no consistent effect on tumor size in the Smo medulloblastoma animal model. EphA4−/−EphA7−/−Smo mice and their EphA4+/−EphA7−/−Smo and EphA4+/+EphA7−/−Smo littermate controls were followed by serial MRI. Representative images are shown for aEphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/−EphA7−/−Smo pairs. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues. (p = not significant)
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Fig3: Representative MRI scans show that genetic alteration of EphA4/EphA7 genotype yields no consistent effect on tumor size in the Smo medulloblastoma animal model. EphA4−/−EphA7−/−Smo mice and their EphA4+/−EphA7−/−Smo and EphA4+/+EphA7−/−Smo littermate controls were followed by serial MRI. Representative images are shown for aEphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/−EphA7−/−Smo pairs. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues. (p = not significant)

Mentions: To determine the role of EphA4/EphA7 receptors on medulloblastoma tumor growth, sequential MRI was performed. Mice from different cohorts (EphA4−/−EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/+EphA7−/−Smo) were examined. Imaging analyses were performed, and while some EphA4−/−EphA7−/−Smo mice had smaller tumors when compared to EphA4+/+EphA7−/−Smo and EphA4+/−EphA7−/−Smo mice, no consistent trend was observed (Fig. 3a, b).Fig. 3


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)

Representative MRI scans show that genetic alteration of EphA4/EphA7 genotype yields no consistent effect on tumor size in the Smo medulloblastoma animal model. EphA4−/−EphA7−/−Smo mice and their EphA4+/−EphA7−/−Smo and EphA4+/+EphA7−/−Smo littermate controls were followed by serial MRI. Representative images are shown for aEphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/−EphA7−/−Smo pairs. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues. (p = not significant)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4561476&req=5

Fig3: Representative MRI scans show that genetic alteration of EphA4/EphA7 genotype yields no consistent effect on tumor size in the Smo medulloblastoma animal model. EphA4−/−EphA7−/−Smo mice and their EphA4+/−EphA7−/−Smo and EphA4+/+EphA7−/−Smo littermate controls were followed by serial MRI. Representative images are shown for aEphA4+/+EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/−EphA7−/−Smo pairs. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues. (p = not significant)
Mentions: To determine the role of EphA4/EphA7 receptors on medulloblastoma tumor growth, sequential MRI was performed. Mice from different cohorts (EphA4−/−EphA7−/−Smo, EphA4+/−EphA7−/−Smo, and EphA4+/+EphA7−/−Smo) were examined. Imaging analyses were performed, and while some EphA4−/−EphA7−/−Smo mice had smaller tumors when compared to EphA4+/+EphA7−/−Smo and EphA4+/−EphA7−/−Smo mice, no consistent trend was observed (Fig. 3a, b).Fig. 3

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