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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

MRI-based morphometric analyses identified a reduction in tumor size in the ephrin-A5−/−Smo mouse model. a Representative images are shown for ephrin-A5−/−Smo mice and their ephrin-A5+/+Smo littermate controls, monitored by sequential MRI. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues (*p ≤ 0.05)
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Fig1: MRI-based morphometric analyses identified a reduction in tumor size in the ephrin-A5−/−Smo mouse model. a Representative images are shown for ephrin-A5−/−Smo mice and their ephrin-A5+/+Smo littermate controls, monitored by sequential MRI. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues (*p ≤ 0.05)

Mentions: To investigate the effect of loss of function of ephrin-A5 on medulloblastoma tumor growth in vivo, an ephrin-A5−/−Smo model was generated which lacks the ephrin-A5 gene and expresses a constitutively activated form of Smoothened (SmoA1) gene in cerebellar granule precursor cells. MR imaging revealed reduced tumor growth in ephrin-A5−/−Smo mice compared to the wild-type ephrin-A5+/+Smo control mice (Fig. 1a, b). Furthermore, Western blot analysis performed on tumor tissue derived from ephrin-A5 knockout mice and their littermate controls established that the tumors from ephrin-A5 knockout mice, which were smaller than in the ephrin-A5 wild-type mice, also had significantly lower levels of phosphorylated Akt (Fig. 2a, b). Decreased PCNA expression was also evident in ephrin-A5 knockout mice compared to ephrin-A5 wild-type mice. However, the difference was not statistically significant (Fig. 2a, c). Total Akt levels seem to be unaltered (Fig. 2a).Fig. 1


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)

MRI-based morphometric analyses identified a reduction in tumor size in the ephrin-A5−/−Smo mouse model. a Representative images are shown for ephrin-A5−/−Smo mice and their ephrin-A5+/+Smo littermate controls, monitored by sequential MRI. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues (*p ≤ 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: MRI-based morphometric analyses identified a reduction in tumor size in the ephrin-A5−/−Smo mouse model. a Representative images are shown for ephrin-A5−/−Smo mice and their ephrin-A5+/+Smo littermate controls, monitored by sequential MRI. b Volumetric tumor growth analysis. Data represent mean ± standard deviation from different tumor tissues (*p ≤ 0.05)
Mentions: To investigate the effect of loss of function of ephrin-A5 on medulloblastoma tumor growth in vivo, an ephrin-A5−/−Smo model was generated which lacks the ephrin-A5 gene and expresses a constitutively activated form of Smoothened (SmoA1) gene in cerebellar granule precursor cells. MR imaging revealed reduced tumor growth in ephrin-A5−/−Smo mice compared to the wild-type ephrin-A5+/+Smo control mice (Fig. 1a, b). Furthermore, Western blot analysis performed on tumor tissue derived from ephrin-A5 knockout mice and their littermate controls established that the tumors from ephrin-A5 knockout mice, which were smaller than in the ephrin-A5 wild-type mice, also had significantly lower levels of phosphorylated Akt (Fig. 2a, b). Decreased PCNA expression was also evident in ephrin-A5 knockout mice compared to ephrin-A5 wild-type mice. However, the difference was not statistically significant (Fig. 2a, c). Total Akt levels seem to be unaltered (Fig. 2a).Fig. 1

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