Expression status of folate receptor alpha is a predictor of survival in pancreatic ductal adenocarcinoma
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Lei Cai1,2,*, Theodoros Michelakos1,*, Cristina R. Ferrone1, Liyuan Zhang1, Vikram Deshpande3, Qi Shen3, Albert DeLeo4, Teppei Yamada1, Gong Zhang1, Soldano Ferrone1,5 and Xinhui Wang1
1Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
2Department of Hepatobiliary, Southwest Hospital, Third Military Medical University, Chongqing, China
3Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
4University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA
5Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
*Lei Cai and Theodoros Michelakos contributed equally to this paper
Xinhui Wang, email: [email protected]
Keywords: folate receptor alpha, pancreatic ductal adenocarcinoma, predictor of survival, smoking, alcohol consumption
Received: January 28, 2017 Accepted: March 01, 2017 Published: April 05, 2017
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognosis among malignancies. Thus, the identification of markers useful in developing innovative diagnostic and therapeutic methods is an imperative need. Folate receptor alpha (FRα) has been associated with prognosis in several cancers and has served as a target of novel anti-tumor therapies. However, FRα expression in PDAC and its correlation with the clinical course of the disease has not been thoroughly investigated. In this study, we analyzed FRα expression in 140 PDAC specimens and 7 PDAC cell lines in order to define the significance of FRα expression in PDAC and its potential role as a target for immunotherapy. Immunohistochemical analysis demonstrated that FRα expression intensity was low, intermediate and high in 22(16%), 73(52%) and 45(32%) PDACs, respectively. The staining was located in both membrane and cytoplasm in most cases (123, 88%). Lower FRα expression was associated with cigarette smoking (p<0.001), alcohol consumption (p<0.001), and lymphovascular invasion (p=0.002). Additionally, lower FRα expression was associated with poor overall survival (5-year overall survival: low 13%, intermediate 31%, high 33%; p=0.006). FRα expression (HR=0.61; p=0.03) and Charlson Comorbidity Index (HR=1.16; p=0.01) emerged as independent predictors of survival. The analysis by flow cytometry of 7 PDAC cell lines (AsPC-1, Capan-2, MIA PaCa-2, PANC-1, PDAC2, PDAC3, and PDAC5) demonstrated the highest expression of FRα on the PDAC3 cell line (45%). Therefore, a higher FRα expression is predictive of a favorable prognosis in PDAC and FRα may represent a promising target for novel treatments, including immunotherapy.
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