Insulin Growth Factor-Binding Protein 2 Overexpression Correlates with Disease Specific Survival in Biliary Tract Adenocarcinoma
F Bao, A Yopp, WR Jarnagin, LH Blumgart, RP DeMatteo, M D'Angelica, DS Klimstra. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: The insulin-like growth factor (IGF) signaling pathway is involved in the tumorigenesis of some human malignancies. The mitogenic and anti-apoptotic activities of IGFs are regulated by six IGF binding proteins (IGFBP-1 to IGFBP-6), among which IGFBP-2 is the most commonly overexpressed in malignancies such as breast, prostate, ovarian carcinomas and glioblastomas. But their roles in biliary tract adenocarcinoma have not been investigated.
Design: A tissue microarray (TMA) was constructed from paraffin-embedded specimens of 128 patients with resected biliary adenocarcinomas, including 55 hilar cholangiocarcinomas, 23 peripheral cholangiocarcinomas, 32 gallbladder adenocarcinomas and 18 distal common bile duct adenocarcinomas. Immunohistochemical analysis using antibodies against IGF-2, IGFBP-2 and a downstream effector molecule, pancreatic endoplasmic reticulum kinase (PERK) was performed.
Results: Cytoplasmic staining for IGF-2, IGFBP-2 and PERK was detected in 19%, 36% and 8% of biliary tract adenocarcinomas, respectively. The percentages of expression of each marker in the four tumor types are listed in table 1.
Table1. Expression of IGF-2, IGFBP-2 and PERK in the four tumor types
Kaplan-Meier survival analysis showed the expression of IGFBP-2 was associated with disease-specific survival time (DSS) (p<0.001). The expression of IGF-2 was not correlated with prognosis (p=0.476). The expression of PERK showed a trend towards prolonged DSS, (p=0.144). After stratifying the data based on the tumor site, the strong correlation with prognosis remained for the hilar and peripheral cholangiocarcinomas (p = 0.006 and 0.014, respectively).
Conclusions: IGFBP-2 overexpression correlates with disease specific survival in biliary tract adenocarcinoma, specifically in hilar and peripheral cholangiocarcinomas. It has been shown that IGFBP-2 expression is negatively regulated by PTEN and positively regulated by PI3K and Akt activation. Evaluation of the upstream and downstream target molecules of PI3K-Akt-mTOR pathway, namely PTEN, pAkt, p16 and p27, in a larger patient cohort of patients would be of interest and, along with our current data, may form the basis for treatment of patients with mTOR-targeted therapy.
Category: Liver & Pancreas
Tuesday, March 10, 2009 2:30 PM
Platform Session: Section E, Tuesday Afternoon