The study of the mechanisms of perineural invasion for pancreatic cancer cell

神经周围浸润是胰腺癌的一个显著临床特征，给手术治疗带来困难。在本研究中，发现人胰腺癌细胞系PaCa-2、AsPC-1、SW 1990和Capan-2均表达丰富的c-ret原癌基因mRNA和RET蛋白，RET蛋白是被鉴定为胶质细胞源性神经营养因子（GDNF）的受体的受体酪氨酸激酶超家族成员。在侵袭试验中，胰腺癌细胞的迁移显着诱导与人类胶质瘤细胞，T98 G或A172，能够产生和分泌GDNF的共培养。胶质瘤细胞条件培养基中的抗GDNF抗体抑制了大部分的迁移活性。迁移的双板分析显示GDNF的趋化活性和趋化动力学活性。在胰腺癌细胞系中没有检测到GDNF受体的另一种成分--糖基磷脂酰肌醇连接受体（GFR-1）的表达，这表明胰腺癌细胞的神经侵袭沿着由外周神经节产生的GDNF的浓度梯度扩散，GDNF通过与其受体（c-ret原癌基因产物）的直接相互作用而产生。GDNF在人腹腔神经节组织中的免疫化学定位支持这一论点。

Perineural invasion is a prominent clinical feature of pancreatic cancer which causes difficulty in curative resection. In the present study, the human pancreatic cancer cell lines, PaCa-2, AsPC-1, SW1990 and Capan-2, were all found to express abundant c-ret proto-oncogene mRNA and RET protein, a member of receptor tyrosine kinase superfamily identified to be a receptor for glial cell line-derived neurotrophic factor (GDNF). In an invasion assay, the migration of pancreatic cancer cells was markedly induced by cocultivation with human glioma cells, T98G or A172, capable of producing and secreting GDNF. Anti GDNF antibody in conditioned media of glioma cells suppressed much of the migratory activity. Checker board analysis of the migration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-phoshatidylinositol-linked receptor (GFR_-1), in pancreatic cancer cell lines, suggesting that the neural invasion of pancreatic cancer cell spreads along a concentration gradient of GDNF produced from peripheral ganglions through direct interaction of GDNF with its receptor, the c-ret proto-oncogene product. Immunochemical localization of GDNF in human celiac ganglionic tissue supported this contention.