Activation of the serine/threonine protein kinase Akt during the progression of Barrett neoplasia.
Esophageal adenocarcinoma has demonstrated a rapid increase in incidence over the last 10 years. This increase mirrors a dramatic rise in that of Barrett esophagus, which is associated with esophageal adenocarcinoma in at least 95% of cases. In an attempt to understand the pathogenesis of esophageal adenocarcinoma, attention has turned to the antiapoptotic and oncogenic pathways. Here we demonstrated that Akt was frequently activated in Barrett esophagus-related adenocarcinoma. Remarkably, the levels of Akt activation were associated with tumor progression. After institutional review board ethics approval, 60 archival tissue specimens of esophageal adenocarcinoma arising on a background of Barrett esophagus were selected for immunohistochemical staining with phosphorylated Akt (p-Akt) antibody. The slides were scored by 2 independent observers. Approximately 80% of high-grade dysplasia and esophageal adenocarcinoma cases demonstrated strong to moderate Akt activity. Sixty-two percent of Barrett mucosa revealed low Akt activity, the remaining cases being p-Akt negative. None of the low-grade dysplasia cases exhibited strong p-Akt staining, whereas only weak p-Akt activity is seen in a portion of metaplastic Barrett mucosa, Akt is highly activated in high-grade dysplasia and esophageal adenocarcinoma arising from Barrett esophagus. These findings suggest a role of p-Akt in the progression of Barrett esophagus to esophageal adenocarcinoma and provide the rationale for using p-Akt inhibitor API-2/triciribine, which is currently in clinical trial, in the treatment of esophageal adenocarcinoma.
Sagatys
Elizabeth
E
Division of Anatomic Pathology, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
Garrett
Christopher R
CR
Boulware
David
D
Kelley
Scott
S
Malafa
Mokenge
M
Cheng
Jin Q
JQ
Sebti
Said
S
Coppola
Domenico
D
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D001471:Barrett Esophagus / Q000201:enzymology* / Q000473:pathology*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*
D051057:Proto-Oncogene Proteins c-akt