title: Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival.
abstract: Diffuse astrocytic gliomas are the most common human glial tumors with glioblastoma being the most malignant form. Epidermal growth factor receptor (EGFR) gene amplification is one of the most common genetic changes in glioblastoma and can lead to the activation of various downstream signaling molecules, including STAT3, MAPK, and AKT. In this study, we investigated the activation status of these 3 signaling molecules as well as wild-type (EGFRwt) and mutant (EGFRvIII) EGFR in 82 malignant astrocytic gliomas (55 glioblastomas and 27 anaplastic astrocytomas) using immunohistochemistry. The presence of EGFRwt, but not EGFRvIII, immunopositivity correlated significantly with prevalent EGFR gene amplification in glioblastomas. STAT3 and AKT activation correlated significantly with EGFR status, although the correlation for p-STAT3 was attributed exclusively to EGFRvIII. The distribution of these 3 activated molecules varied significantly with tumor grade; although activation of STAT3 was essentially identical between anaplastic astrocytomas and glioblastomas, an increase in the activation of MAPK and AKT appeared to correlate with the progression of anaplastic astrocytoma to glioblastoma. Finally, activated STAT3 and AKT were marginally predictive of improved and worse prognosis, respectively. Taken together, these findings begin to elucidate the interrelationship between these signaling pathways in astrocytic gliomas in vivo.
authors.affiliation: Molecular Pathology Unit and Molecular Neuro-Oncology Laboratory, Department of Pathology, Cancer Center and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mizoguchi
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Derek C
authors.initials: DC
authors.lastname: Bernay
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Nutt
mesh_terms: D001254:Astrocytoma / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D003937:Diagnosis, Differential; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005909:Glioblastoma / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate / Q000639:trends; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases