BACKGROUND. Perineural invasion is one of the important prognostic factors for patients with bile duct carcinoma, and extensive surgery has not always improved their prognosis. It is necessary, therefore, to investigate not only clinicopathologic characteristics but also molecular mechanisms in patients with perineural invasion. The authors studied the relation between perineural invasion in patients with bile duct carcinoma and the expression of glial cell line-derived neurotrophic factor (GDNF), GDNF family receptor α1 (GFRα1), and RET receptor tyrosine kinase, which are expressed in both central and peripheral nerve tissues. METHODS. Immunohistochemical staining of GDNF, GFRα1, and RET was performed in 58 paraffin embedded tissue sections, including 38 sections from patients with bile duct carcinoma with perineural invasion and 20 sections from patients with bile duct carcinoma without perineural invasion. The migration of cells that expressed GDNF was analyzed by cocultivation with cells that expressed both RET and GFRα1. RESULTS. Moderate to strong staining of GDNF in tumor cells was observed more frequently in the sections with perineural invasion compared with the sections without invasion (P < 0.05), whereas GFRα1 expression in the same sections was not correlated with perineural invasion. RET expression was undetectable in specimens of bile duct carcinoma. Conversely, RET and GFRα1 expression were detected consistently in peripheral nerve tissues. An in vitro cell migration assay revealed that the migration of cells that expressed GDNF was enhanced by cocultivation with cells that expressed RET and GFRα1. The cell migration was also enhanced by the conditioned media from GDNF-treated cells that expressed RET and GFRα1. CONCLUSIONS. The results suggest that GDNF expression in tumor cells and GFRα1 and RET expression in peripheral nerve tissues may play a role in perineural invasion in patients with bile duct carcinoma through chemoattraction among these molecules.
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