GASTROENTEROLOGY 1995;109:1415-1420 ALIMENTARY TRACT Effect of Endogenous Hypergastrinemia on Gastrin Receptor Expressing Human Colon Carcinoma Transplanted to Athymic Rats MING CHU,* FINN CILIUS NIELSEN,* LENNART FRANZI~N, ~ JENS F. REHFELD, ~ JENS J. HOLST, II and KURT BORCH* Departments of *Surgery and ~Pathology, UniversityHospital of Link6ping, Link6ping, Sweden; and Departments of tClinical Biochemistry and IIMedical Physiology, Universityof Copenhagen, Copenhagen, Denmark Background & Aims: The effect of endogenous hyper- gastrinemia on growth of human colon carcinoma is not known. Our aim was to study the growth of human colon carcinoma in an animal model with endogenous hypergastrinemia. Methods: Human colon carcinoma was transplanted to the colon of 40 athymic rats. Of these, 25 underwent gastric fundectomy to accomplish endogenous hypergastrinemia, and 15 were sham oper- ated to serve as controls. The duration of the study was 8 weeks. During the last week, 12 fundectomized animals received a gastrin (cholecystokinin B) receptor antagonist. Metaphase arrest index, local invasion, and distant spread of the tumor were investigated. Ex- pression of gastrin and cholecystokinin B receptor mes- senger RNA was examined by reverse-transcription polymerase chain reaction. Results: Tumor spread by direct extension outside the colon was observed in all animals, and liver metastases were observed in 10 of the 25 fundectomized animals. Sham-operated animals showed none of these features. The metaphase arrest index of the tumor did not differ between fundectom- ized animals given the cholecystokinin B receptor an- tagonist and sham-operated animals, whereas it was significantly increased in fundectomized animals not given the antagonist. The tumor expressed both gastrin and cholecystokinin B receptor messenger RNA. Con- clusions: The results indicate that endogenous hyper- gastrinemia may promote proliferation and spread of human colon carcinoma expressing cholecystokinin B receptor. l 'n rats and hamsters, pentagastrin, gastrin 17, and .endogenous hypergastrinemia have been reported to stimulate growth of the colon mucosa.*-6 Gastrin recep- tors have been shown in normal colon mucosa in rats and in normal colon mucosa and colon carcinoma in humans] -1° Gastric antrum exclusion, leading to hyper- gastrinemia, has been shown to enhance carcinogenesis in the colon of the rat. 11 Furthermore, it has been shown that pentagastrin stimulates the growth of colon carci- noma xenografts in athymic mice, resulting in reduced survival. 12 Although there are contradicting studies, I3 iv these findings indicate that gastrin, at least under certain circumstances, may stimulate growth of the colon mucosa and colon carcinoma. In rats and hamsters, resection of the oxyntic gland area of the stomach induces hypergastrinemia. <.3'18 The effect of this model on growth and spread of human colon carcinoma is not known. Subcutaneous and intramuscular human tumor xeno- grafts in immunodeficient mice have low or nonexistent metastatic capability, even when they are derived from tumors that are highly metastatic in the patient. 19'2° However, when histologically intact human colon carci- noma is transplanted to the colon in the immunodeficient animal, local and distant spread occurs] 1 We studied the effect of gastric fundectomy with hypergastrinemia on the cellular proliferation and spread of a human colon carcinoma orthotopically transplanted to immunodefi- cient rats. Materials and Methods The study was approved by the local animal wetfare committee, and the patient from whom tumor tissue was col- lected gave informed consent regarding the examinations per- formed. A fresh tumor specimen was obtained from a 74-year-old woman undergoing right-sided hemicolectomy for carcinoma in the ascending colon, There were no liver metastases, and histological examination showed a poorly differentiated adeno- carcinoma with moderate to pronounced cellular pleomor- phism and numerous mitoses. There was local serosal involve- ment but no lymph node metastases (Dukes' stage B). Gastroscopy showed normal gastric mucosa, as did histological © 1995 by the American Gastroenterological Association 0016-5085/95/83.00