Abstract
This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0.0363). In vitro experiment, we used five TrkB-expressing GBC cell lines with or without K-ras mutation. TrkB-mediated signaling increased proliferation and the invasiveness by inducing epithelial mesenchymal transition, and activating matrix metalloproteinases-2 (MMP-2) and MMP-9. Inhibition of TrkB-mediated signaling also decreased hypoxia-inducible factor-1α, vascular endothelial growth factor A (VEGF-A), VEGF-C, and VEGF-D expression. In vivo experiment, inhibition of TrkB-mediated signaling suppressed tumorigenicity and tumor growth in GBC. These findings demonstrate that TrkB-mediated signaling contributes to the induction of malignant phenotypes (proliferation, invasiveness, angiogenesis, lymphangiogenesis, and tumorigenesis) in GBC, and could be a promising therapeutic target regardless of K-ras mutation status.
Highlights
Bile tract cancer (BTC) is the sixth leading cause of cancer death in Japan, and has been reported more frequently in Japan compared with other countries [1]
We revealed that Tropomyosin-related kinase B (TrkB) overexpression in the invasive front correlated significantly with invasion depth, UICC stage (Table 1), and poor patient prognosis (Figure 1D)
Xiong L et al reported that Brain derived neurotrophic factor (BDNF) is overexpressed in gallbladder cancer (GBC) [12]; another previous report described overexpression of neurotrophins in the invasive front, and demonstrated that higher neurotrophin expression is associated with unfavorable clinicopathological findings and poor patient prognosis [13]
Summary
Bile tract cancer (BTC) is the sixth leading cause of cancer death in Japan, and has been reported more frequently in Japan compared with other countries [1]. The BTC encompasses diverse diseases, including cancers of the extrahepatic bile ducts, intrahepatic bile ducts, and gallbladder Of these cancers, gallbladder cancer (GBC) occurs most frequently and has the poorest prognosis [2]. Complete surgical resection is the only potentially curative treatment; most GBC cases have developed into locally advanced disease or have metastasized by the time of diagnosis. This is due to the anatomy of gallbladder; the gallbladder has thin wall and is surrounded by rich vascular and lymphatic systems. Effective targeted molecular therapies have been developed www.impactjournals.com/oncotarget for several solid tumor types, but no such treatment is currently available for GBC. Development of novel molecular therapeutic targets is strongly required for improving outcomes for patients with GBC
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