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


RESULTS
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.
Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. shilpa.bhatia@ucdenver.edu.
Shilpa
S
Bhatia
Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. kellen.hirsch@ucdenver.edu.
Kellen
K
Hirsch
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. nab48@georgetown.edu.
Nimrah A
NA
Baig
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. rodriguo@georgetown.edu.
Olga
O
Rodriguez
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. Olga.Timofeeva@georgetown.edu.
Olga
O
Timofeeva
Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. kevin.kavanagh@ucdenver.edu.
Kevin
K
Kavanagh
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. yl285@georgetown.edu.
Yi Chien
YC
Lee
Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. XJ.Wang@ucdenver.edu.
Xiao-Jing
XJ
Wang
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. albanese@georgetown.edu.|Department of Pathology, Georgetown University School of Medicine, Washington, DC, 20057, USA. albanese@georgetown.edu.
Christopher
C
Albanese
Present address: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA. sana.karam@ucdenver.edu.|Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA. sana.karam@ucdenver.edu.
Sana D
SD
Karam
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D036386:Ephrin-A5 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011859:Radiography; D036122:Receptor, EphA4 / Q000235:genetics* / Q000378:metabolism; D036141:Receptor, EphA7 / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D047368:Tumor Burden / Q000235:genetics
D036386:Ephrin-A5; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D036122:Receptor, EphA4; D036141:Receptor, EphA7; D051057:Proto-Oncogene Proteins c-akt