Jiang S, Kopras E, McMichael M, Bell R H, Ulrich C D
University of Cincinnati Medical Center, Ohio 45267-0595, USA.
Cancer Res. 1997 Apr 15;57(8):1475-80.
Vasoactive intestinal peptide (VIP) appears to be responsible for atropine-resistant, neurally mediated pancreatic ductal bicarbonate secretion and plays a role in both stimulation and inhibition of neoplastic growth in other organs. cDNAs encoding high affinity VIP-1 and VIP-2 receptors have been cloned, and these receptors may be differentiated based on the ability of VIP-1, but not VIP-2, receptors to couple to adenylyl cyclase in response to stimulation with micromolar concentrations of secretin. Recent data from our laboratory suggest expression of a low affinity secretin receptor in seven cell lines derived from human ductal pancreatic adenocarcinomas. In combination with the recent use of (123)I-labeled VIP to successfully image pancreatic adenocarcinomas in humans and the high affinity binding of both VIP and pituitary adenylate cyclase-activating peptides to sections from human pancreatic tumors, these findings suggest that VIP-1 receptors may be expressed on the majority of neoplastic pancreatic duct epithelial cells in vivo. To initially test the hypothesis that expression of VIP-1 receptors plays an important role in the pathophysiology of human ductal pancreatic adenocarcinomas, we used reverse transcription-PCR with Southern blot hybridization to confirm expression of VIP-1 and VIP-2 receptor mRNA in the vast majority of 28 human ductal pancreatic adenocarcinomas. Based on the cellular heterogeneity of these tumors, we also assessed VIP receptor subtype expression in seven well-characterized, secretin-responsive cell lines derived from human ductal pancreatic adenocarcinomas. Only VIP-1 receptor mRNA was detected in all seven secretin-responsive cell lines. A half-maximal increase in intracellular cyclic AMP was obtained with 0.5-5 nM VIP in each of these cell lines, consistent with expression of high affinity VIP receptors. The ability of 1 microM, but not 1 nM, secretin to stimulate intracellular cyclic AMP generation in these cells was consistent with VIP-1 receptor expression. Interestingly, 100 pM, but not 1 microM, VIP stimulated significant growth of VIP-1 receptor-bearing Capan-2 cells both in the absence and presence of serum. Because VIP-1 receptors appear to be expressed in the majority of neoplastic pancreatic duct cell lines and VIP stimulates growth of VIP-1 receptor-bearing Capan-2 cells in vitro, this peptide may well play an important role in the pathophysiology of tumors expressing these receptors in vivo.
血管活性肠肽（VIP）似乎是抗阿托品、神经介导的胰腺导管碳酸氢盐分泌的原因，并且在刺激和抑制其他器官的肿瘤生长中发挥作用。编码高亲和力VIP-1和VIP-2受体的cDNA已被克隆，并且这些受体可以根据VIP-1（而非VIP-2）受体在微摩尔浓度的促胰液素刺激下与腺苷酸环化酶偶联的能力来区分。我们实验室最近的数据表明，在源自人导管胰腺腺癌的7种细胞系中表达了低亲和力促胰液素受体。结合最近使用（123）I标记的VIP成功对人胰腺腺癌进行成像以及VIP和垂体腺苷酸环化酶激活肽与人胰腺肿瘤切片的高亲和力结合，这些发现表明VIP-1受体可能在体内大多数肿瘤性胰腺导管上皮细胞上表达。为了初步检验VIP-1受体的表达在人导管胰腺腺癌的病理生理学中起重要作用这一假设，我们使用逆转录聚合酶链反应（RT-PCR）和Southern印迹杂交来确认28例人导管胰腺腺癌中的绝大多数中VIP-1和VIP-2受体mRNA的表达。基于这些肿瘤的细胞异质性，我们还评估了源自人导管胰腺腺癌的7种特征明确的、对促胰液素反应性的细胞系中VIP受体亚型的表达。在所有7种对促胰液素反应性的细胞系中仅检测到VIP-1受体mRNA。在这些细胞系中的每一种中，0.5 - 5 nM的VIP可使细胞内环状AMP增加至最大值的一半，这与高亲和力VIP受体的表达一致。1 μM而非1 nM的促胰液素刺激这些细胞中细胞内环状AMP生成的能力与VIP-1受体表达一致。有趣的是，100 pM而非1 μM的VIP在无血清和有血清的情况下均刺激了表达VIP-1受体的Capan-2细胞的显著生长。由于VIP-1受体似乎在大多数肿瘤性胰腺导管细胞系中表达，并且VIP在体外刺激表达VIP-1受体的Capan-2细胞生长，这种肽很可能在体内表达这些受体的肿瘤的病理生理学中起重要作用。
