Abstract
BackgroundCholangiocarcinoma remains to be a tumor with very few treatment choices and limited prognosis. In this study, we sought to determine the prognostic role of fms-related tyrosine kinase 1/vascular endothelial growth factor receptor 1 (FLT1/VEGFR1), heparanase (HPSE) and epidermal growth factor receptor (EGFR) gene expression in patients with resected CCC.Methods47 formalin-fixed paraffin embedded FFPE tumor samples from patients with resected CCC were analyzed. FFPE tissues were dissected using laser-captured microdissection and analyzed for FLT1, FLT4, HPSE, Hif1a, VEGFA/C, HB-EGF, PDGFA, PDGF-RA and EGFR mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference genes (beta-actin, b2mg, rplp2, sdha).Results EGFR, FLT1 and HPSE expression levels were significantly associated with overall survival (OS). FLT1 showed the strongest significant independent association with overall survival in a multivariate cox regression analysis when compared to the other genes and clinicopathological factors with a nearly 5 times higher relative risk (4.74) of dying earlier when expressed in low levels (p = 0.04). ROC Curve Analysis revealed that measuring EGFR potentially identifies patients at risk of a worsened outcome with a sensitivity of 80% and a specificity of 75% (p = 0.01).Conclusions EGFR and FLT1 seem to be potential markers to identify those patients at high risk of dying from cholangiocarcinoma. Therefore these markers may help to identify patient subgroups in need for a more aggressive approach in a disease that is in desperate need for new approaches.
Highlights
The treatment of solid tumors has seen a lot of progress over the last few years with significant survival benefits in diseases like breast and colorectal cancer especially through the development of several new molecular entities
We investigated the prognostic values of fmsrelated tyrosine kinase 1/vascular endothelial growth factor receptor 1 (FLT1/VEGFR1), heparanase (HPSE), hypoxia inducible factor 1, alpha subunit (Hif1a), fms-related tyrosine kinase 4/ vascular endothelial growth factor receptor 3 (FLT4/VEGFR3), vascular endothelial growth factor A & C (VEGFA/C), plateletderived growth factor alpha polypeptide A (PDGFA), PDGF receptor, alpha polypeptide (PDGF-RA) heparin-binding EGF-like growth factor (HB-EGF), and epidermal growth factor receptor (EGFR) gene expressions as well as their interrelationships in cholangiocarcinoma
FLT1 expression was correlated to HPSE expression (p,0.0001; Correlation Coefficient, CC = 0.74)
Summary
The treatment of solid tumors has seen a lot of progress over the last few years with significant survival benefits in diseases like breast and colorectal cancer especially through the development of several new molecular entities. In cholangiocarcinoma respectively cancers of the biliary tract the treatment choices remain very limited [1,2]. By previous work we already identified several candidate biomarkers that are associated with the overall survival of patients in various cancer types. These genes have a strong correlation with angiogenesis (Hif1a, FLT1) [4,5] and lead to alterations of the extracellular matrix and remodeling of subepithelial and subendothelial basal membranes (heparanase, HPSE) [6,7] and seem to be directly involved in the aggressiveness of cancers. Cholangiocarcinoma remains to be a tumor with very few treatment choices and limited prognosis. We sought to determine the prognostic role of fms-related tyrosine kinase 1/vascular endothelial growth factor receptor 1 (FLT1/VEGFR1), heparanase (HPSE) and epidermal growth factor receptor (EGFR) gene expression in patients with resected CCC
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