title: Akt expression may predict favorable prognosis in cholangiocarcinoma.
abstract: BACKGROUND
  Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins has not been reported. Co-expression may reflect cross-talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome.
  
  
  METHODS
  Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 to 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists independently scored the protein expression.
  
  
  RESULTS
  Cyclooxygenase-2, Akt, and p-MAPK were commonly expressed in biliary cancers (100%, 96% and 87% of malignant cells, respectively). EGFR (60%) and p-EGFR (22%) overexpression was also detected. There was a significant association between EGFR and p-EGFR (P = 0.027) and between Akt and p-Akt (P = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK and p-Akt (P = 0.054). Multivariate analysis using the Cox proportional hazard model identified the use of chemotherapy (hazard ratio [HR] = 0.039, P = 0.0002), radiation (HR = 0.176, P = 0.0441) and Akt expression (HR = 0.139, P = 0.006) as the best predictors of overall prognosis.
  
  
  CONCLUSIONS
  Epidermal growth factor receptor signaling intermediates are commonly expressed in cholangiocarcinoma. Expression of Akt and use of systemic chemotherapy or radiation may correlate with improved survival.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. milind.javle@roswellpark.org
authors.forename: Milind M
authors.initials: MM
authors.lastname: Javle
authors.forename: Jihnhee
authors.initials: J
authors.lastname: Yu
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.forename: Krishdeep S
authors.initials: KS
authors.lastname: Chadha
authors.forename: Krishdeep C
authors.initials: KC
authors.lastname: Chadha
authors.forename: Renuka V
authors.initials: RV
authors.lastname: Iyer
authors.forename: Jason
authors.initials: J
authors.lastname: Foster
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kuvshinoff
authors.forename: John F
authors.initials: JF
authors.lastname: Gibbs
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Black
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
mesh_terms: D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018426:SEER Program; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases