ABSTRACT
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as 'cadherin switch'. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC). METHODS: CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF-ß1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients (n=38), and the associations with clinicopathological factors and survival rates. RESULTS: TGF-ß1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017). CONCLUSION: Cadherin switch promotes cancer progression via TGF-ß-induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.
Subject(s)
Cadherins/metabolism , Cholangiocarcinoma/pathology , Epithelial-Mesenchymal Transition , Transforming Growth Factor beta/physiology , Aged , Blotting, Western , Cell Proliferation , Cholangiocarcinoma/metabolism , Disease Progression , Electrophoresis, Polyacrylamide Gel , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Male , Microscopy, Confocal , Middle Aged , Signal TransductionABSTRACT
A 58-year-old man was diagnosed as having advanced gallbladder cancer (T4, P0, H0, N0, stage IVa) with direct invasion to the liver, transverse colon and duodenum. Therefore, extended cholecystectomy and bile duct resection with a partial resection of the transverse colon and the duodenum were performed in March 1992. Histopathological examination revealed moderately differentiated tubular adenocarcinoma of si, ly1, v1, hinf3, binf3, n0. Three years and eight months after the operation, multiple liver metastases were diagnosed by abdominal CT. Repeated hepatic arterial infusion chemotherapy with 5-FU 500 mg/body/w, MMC 4 mg/body/2w and EPI 40 mg/body/4w was performed starting in January 1996. Four months later, the lesions in the liver were reduced in size, and abdominal CT 10 months after the chemotherapy showed a partial response. However, the liver metastasis of the right lobe was enlarged on an abdominal CT in August 1997. Repeated hepatic arterial infusion chemotherapy with the same regimen was performed again starting in March 1998. Ten months later, the liver metastasis was slightly enlarged, but the greater part of the metastasis showed necrosis on an abdominal CT in January 1999. However, peritonitis carcinomatosa was observed later and the patient died 8 years after the operation.