Okada Y, Takeyama H, Sato M, Morikawa M, Sobue K, Asai K, Tada T, Kato T, Manabe T
First Department of Surgery, Nagoya City University Medical School, Nagoya, Japan.
Int J Cancer. 1999 Mar 31;81(1):67-73. doi: 10.1002/(sici)1097-0215(19990331)81:1<67::aid-ijc13>3.0.co;2-v.
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 the receptor-tyrosine-kinase superfamily, identified as being a receptor for glial-cell-line-derived neurotrophic factor (GDNF). In an invasion assay, the migration of pancreatic cancer cells was markedly induced by co-cultivation 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. Checkerboard analysis of the migration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-phosphatidylinositol-linked receptor (GFR alpha-1), in pancreatic-cancer cell lines, suggesting that the neural invasion of pancreatic-cancer cells 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.
神经周围浸润是胰腺癌的一个突出临床特征，会导致根治性切除困难。在本研究中，发现人胰腺癌细胞系PaCa-2、AsPC-1、SW1990和Capan-2均大量表达c-ret原癌基因mRNA和RET蛋白，RET蛋白是受体酪氨酸激酶超家族的成员，被确定为胶质细胞源性神经营养因子（GDNF）的受体。在侵袭试验中，与人胶质瘤细胞T98G或A172共培养可显著诱导胰腺癌细胞的迁移，T98G或A172能够产生和分泌GDNF。胶质瘤细胞条件培养基中的抗GDNF抗体抑制了大部分迁移活性。迁移的棋盘分析显示GDNF具有趋化和化学动力学活性。在胰腺癌细胞系中未检测到另一种GDNF受体成分，即糖基磷脂酰肌醇连接受体（GFRα-1）的表达，这表明胰腺癌细胞的神经浸润是通过GDNF与其受体c-ret原癌基因产物的直接相互作用，沿着外周神经节产生的GDNF浓度梯度扩散的。GDNF在人腹腔神经节组织中的免疫化学定位支持了这一观点。
