Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma.
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 alpha1 (GFRalpha1), and RET receptor tyrosine kinase, which are expressed in both central and peripheral nerve tissues.


METHODS
Immunohistochemical staining of GDNF, GFRalpha1, 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 GFRalpha1.


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 GFRalpha1 expression in the same sections was not correlated with perineural invasion. RET expression was undetectable in specimens of bile duct carcinoma. Conversely, RET and GFRalpha1 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 GFRalpha1. The cell migration was also enhanced by the conditioned media from GDNF-treated cells that expressed RET and GFRalpha1.


CONCLUSIONS
The results suggest that GDNF expression in tumor cells and GFRalpha1 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.
Iwahashi
Naoko
N
Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.
Nagasaka
Tetsuro
T
Tezel
Gaye
G
Iwashita
Toshihide
T
Asai
Naoya
N
Murakumo
Yoshiki
Y
Kiuchi
Kazutoshi
K
Sakata
Keita
K
Nimura
Yuji
Y
Takahashi
Masahide
M
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology*; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement; D018920:Coculture Techniques; D029721:Drosophila Proteins; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009423:Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila