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

胰腺癌细胞神经周围侵袭机制的研究

• 批准号: 10470262
• 负责人: MANABE Tadao
• 金额: $ 9.66万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470262/
• 关键词: pancreatic cancer; perineural invasion; GDNF; ret; Ret; rat

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.

神经侵袭是胰腺癌的一个突出临床特征，根治性切除困难。本研究发现人胰腺癌细胞株PACA-2、ASPC-1、SW1990和CAPAN-2均表达丰富的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，被鉴定为胶质细胞源性神经营养因子(GDNF)的受体。在侵袭实验中，胰腺癌细胞与能够产生和分泌GDNF的人胶质瘤细胞T98G或A172共培养可显著诱导胰腺癌细胞的迁移。胶质瘤细胞条件培养液中的抗GDNF抗体抑制了大部分的迁移活性。迁移的棋盘分析显示GDNF具有趋化和趋化活性。在胰腺癌细胞系中未检测到GDNF受体的另一组分--糖基磷脂酰肌醇连接受体(GFR-1)的表达，提示胰腺癌细胞的神经侵袭是通过GDNF与其受体(原癌基因c-ret产物)的直接相互作用而沿着外周神经节产生的GDNF浓度梯度扩散的。GDNF在人的腹膜神经节组织中的免疫化学定位支持这一观点。

项目成果

Manabe, T.: "Liver regeneration after portal vein embolization"Journal of Gastroenterology. 34. 152-153 (1999)

Manabe, T.：“门静脉栓塞术后的肝脏再生”胃肠病学杂志。

Okada, Y.: "Noncardiogenic pulmonary edema as the chief manifestation of a pheochromocytoma : A case report of MEN 2A with pedigree analysis of the RET proto-oncogene"Tohoku J. Exp. Med.. 188. 177-187 (1999)

Okada, Y.：“非心源性肺水肿是嗜铬细胞瘤的主要表现：MEN 2A 病例报告及 RET 原癌基因的系谱分析”Tohoku J. Exp.

Okada Y., Takeyama H., Sato M., Morikawa M., Sobue K., Asai K., Tada T., Kato T., Manabe T.: "Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neu

Okada Y.、Takeyama H.、Sato M.、Morikawa M.、Sobue K.、Asai K.、Tada T.、Kato T.、Manabe T.：“腹腔神经节细胞侵袭胰腺癌细胞的实验意义

Manabe T.: "Liver regeneration after portal vein embolization"Journal of Gastroenterology. 34(1). 152-153 (1999)

Manabe T.：“门静脉栓塞术后的肝脏再生”胃肠病学杂志。

Yuji Okada, Hiromitu Takeyama, Mikinori Sato and Tadao Manabe: "Neurotrophic Factor derived Invasion of Pancreatic Cancer"Japanese Journal of Gastroenterol Surgery. 31(4). 995-998 (1998)

Yuji Okada、Hiromitu Takeyama、Mikinori Sato 和 Tadao Manabe：“神经营养因子衍生的胰腺癌侵袭”日本胃肠外科杂志。