Martinsen Tom C, Kawase Shiro, Håkanson Rolf, Torp Sverre H, Fossmark Reidar, Qvigstad Gunnar, Sandvik Arne K, Waldum Helge L
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7006 Trondheim, Norway.
Carcinogenesis. 2003 Dec;24(12):1887-96. doi: 10.1093/carcin/bgg156. Epub 2003 Aug 29.
In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.
在我们的近交系棉鼠（棉鼠属）中，50%的雌性会因胃酸过少继发高胃泌素血症，在胃的产酸部位发生源自肠嗜铬样（ECL）细胞的自发性肿瘤。尽管胃酸过少背后的机制尚不清楚，但雌性棉鼠是研究ECL细胞相关肿瘤发生的优秀模型。在本研究中，我们想探究这些肿瘤的恶性潜能以及胃泌素受体拮抗剂（YF476）预防其发生的能力。首先，通过剖腹术诊断出9只高胃泌素血症的雌性棉鼠（10月龄）患有胃肿瘤。6个月后将它们处死。其次，18只雌性棉鼠（2月龄）每月皮下注射YF476（500微摩尔/千克体重），持续6个月，而21只年龄匹配的动物接受赋形剂。收集每个胃的样本用于组织学、免疫组织化学和Northern印迹分析。胃肿瘤含有具有ECL细胞免疫组织化学特征的细胞。这些肿瘤有时会侵犯并穿透胃壁，并转移至胃周部位。在腹水中发现了源自ECL的肿瘤细胞。死亡时，接受YF476的18只动物中只有1只出现癌（浸润性生长），而在接受赋形剂的对照组中，21只中有7只出现癌（P = 0.048）。棉鼠的自发性胃肿瘤源自ECL细胞。这些肿瘤能够穿透胃壁并通过腔内播散转移。胃泌素受体阻断降低了此类肿瘤的发生率。我们认为这些肿瘤是ECL细胞癌，并且胃泌素是正常ECL细胞向恶性ECL细胞转化的驱动力。
