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Promotion by Neurotensin of Gastric Carcinogenesis Induced by TV

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Promotion by Neurotensin of Gastric Carcinogenesis Induced by TV [CANCER RESEARCH 49, 843-846, February 15, 1989] Promotion by Neurotensin of Gastric Carcinogenesis Induced by TV-Methyl-W-nitro-W-nitrosoguanidine in Wistar Rats Masaharu Tat sut a, ' Hiroyasu lishi, Miyako Baba, and Haruo Taniguchi Departments of Gastrointestinal Oncology [M. T., H. l., M. B,] and Pathology [H. T.], The Center for Adult Diseases, Osaka, 3-3, Nakamichi ÃŒ-chôme, Higashinari-ku, Osaka 537, Japan ABSTRACT water containing MNNG (25 ^g/ml) for 25 wk. The MNNG (Aldrich Chemical Co., Milwaukee, WI) was dissolved in drinking water at a The effects of neurotensin on the incidence and histology of gastric cancers induced by Ar-methyl-Ar'-nitro-Ar-nitrosoguanidine were investi concentration of 1 mg/ml and kept in a cool dark place. The stock solution was replaced within 1 wk. Just before use, the stock solution gated in Wistar rats. Rats were given 100 or 200 MUper kg of body was diluted to 25 Mg/ml and given to the rats every other day from weight of neurotensin s.c. every other day in depot form after 25 wk of bottles covered with aluminum foil to prevent denaturation of MNNG P.O.treatment with the carcinogen. Prolonged alternate-day administra by light. The MNNG in the stock solution and in the diluted solution tion of neurotensin at 200 ¿tgperkg of body weight resulted in a significant was stable for at least 1 wk and 2 days, respectively (12). From Wk 26, increase in the incidence of gastric cancers of the glandular stomach by the MNNG-treated rats were given normal tap water and divided into Wk 52. However, it did not influence the histológica!appearance of the three groups. The three groups were treated as follows until the end of gastric cancers. Furthermore, it caused a significant increase in the the experiment. Group 1 (25 rats) received the vehicle, olive oil, only. labeling indices of the epithelial cells of the antrum and of gastric cancers. Groups 2 and 3 (25 rats each) received neurotensin in depot form at In contrast, the administration of neurotensin at 100 UKper kg of body dosages of 100 and 200 Mgper kg of body weight per day, respectively. weight had a slight, but not significant, influence on the development of From Wk 26, Group 4 (20 rats) received olive oil only, but was not gastric cancers. These findings indicate that neurotensin promotes gastric treated with MNNG nor neurotensin. Groups 5 and 6 (20 rats each) carcinogenesis, and that this effect may be related to its effect in increas received neurotensin only in depot form at dosages of 100 and 200 /ig ing proliferation of epithelial cells in the antral mucosa and in gastric per kg of weight per day, respectively, but were not treated with MNNG. cancers. Neurotensin (Peptide Institute, Inc., Osaka, Japan) was given as suspension in olive oil. Injections were given s.c. in various sites every INTRODUCTION other day in a volume of 1 ml per kg of body weight, between 2 and 3 Neurotensin is one of the gastrointestinal peptides present in p.m. each day. The rats in Groups 1 and 4 received 1 ml per kg of body brain and gut (1-3). The pharmacological and biochemical weight of plain olive oil, administered as for Groups 2 and 3. The experimental groups were kept in different cages in the same properties of neurotensin strongly suggest that the peptide acts room throughout the experiment and had free access to regular chow as a neurotransmitter or neuromodulator in the central nervous pellets (Oriental Yeast Co., Tokyo, Japan). system and as a hormone in the periphery (4, 5). Specific Animals that survived for more than 45 experimental wk were neurotensin receptors have been characterized not only in brain included in the effective numbers, because the first tumor of the glan and in intact cells of neural or nonneural origin, but also in dular stomach was found in a rat in Group 1 that died in Wk 46. gastrointestinal membrane preparations (6). Thus, neurotensin Animals were killed when they became moribund during the experi has important roles in the physiology and pathophysiology of ment, or at the end of Wk 52. All rats were autopsied, and the stomach the gastrointestinal system. and other organs were carefully examined. The stomach was opened along the greater curvature, pinned flat on a cork mat, and fixed with Recently, a number of reports have appeared regarding the Zamboni's solution (13) for histológica!examination. The fixed stom effect of gastrointestinal peptides on the growth of experimen ach was cut into longitudinal strips 3 mm wide. The specimens were tally induced tumors (7). We previously reported that prolonged administration of tetragastrin in depot form after MNNG2 embedded in paraffin, and serial sections 5 ¿imthickwere stained with hematoxylin and eosin. Sections were examined without knowledge of treatment resulted in a significant reduction in the incidence of which group they were from. gastric cancers in the glandular stomach of Wistar rats (8). Histologically, adenocarcinomas were defined as lesions in which Recently we found that this effect may be closely related to the neoplastic glands had penetrated the muscularis mucosae to involve the effect of gastrin in decreasing cell proliferation of the antral submucosa or deeper layers. As previously reported, the adenocarci mucosa (9). Feurle et al. (IO, 11) found that neurotensin can nomas were classified as highly well differentiated, well differentiated, act as a trophic factor on gastric antrum, leading to an increase or poorly differentiated (9). On the basis of their mucin-producing activity, well-differentiated adenocarcinomas were subdivided into a in the thickness of the gastric antrum. Moreover, Amar et al. (6) identified neurotensin receptors in the human colonie ade- common type and a mucinous type, and poorly differentiated cancers were subdivided into anaplastic and signet-ring cell carcinomas. nocarcinoma cell line. These findings suggest that neurotensin The labeling indices of the gastric mucosa and gastric cancers were affects the growth of gastric cancers. Therefore, in the present examined in Wk 30 and/or Wk 52. The labeling indices were measured work, we examined the effect on the development of gastric with an immunohistochemical analysis kit for assaying BrdUrd incor cancers of treating rats with neurotensin after MNNG treat poration (14,15) (Becton Dickinson Immunocytometry System, Moun ment. tain View, CA), by the modified method described by Tada et al. (16). Briefly, the rats were starved for 12 h and then received one of the MATERIALS AND METHODS following s.c. injections: 1 ml per kg of body weight olive oil (Groups 1 and 4); or 100 or 200 ^g per kg of body weight neurotensin (Groups A total of 135 young male Wistar rats about 5 wk old, initially weighing 90 to 100 g, was used. Seventy-five rats were given drinking 2 and 5 and Groups 3 and 6, respectively). Three h later, the rats received an i.p. injection of 20 mg per kg of body weight of BrdUrd, Received 4/29/88; revised 9/16/88; accepted 11/7/88. and they were killed l h later with ether. Before killing, blood was The costs of publication of this article were defrayed in part by the payment obtained by cardiac puncture for determination of gastrin. The stomach of page charges. This article must therefore be hereby marked advertisement in was fixed in 70% ethanol for 4 h. Sections 3 ^m thick were immersed accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' To whom requests for reprints should be addressed. in 2 N HC1 solution for 30 min at room temperature and then in 0. l M 2The abbreviations used are: MNNG, /V-methyN/V'-nitro-A'-nUrosoguanidine; Na2B4O7 to neutralize the acid. The sections were then stained with Brill rd, bromodeoxyuridine. anti-BrdUrd monoclonal antibody (diluted 1:100) for 2 h at room 843 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1989 American Association for Cancer Research. PROMOTION BY NEUROTENSIN OF GASTRIC CANCERS temperature, washed, stained with biotin-conjugated horse anti-mouse Table 1 Incidence of gastric cancers in each group antibody (at a dilution of 1:200) for 30 min, and stained with avidin- (g)Group123456Treatment"MNNG Body wt of rats biotin-peroxidase complex for 30 min. The reaction product was located no. of with gastric with 3,3'-diaminobenzidine tetrahydrochloride. Cells containing rats181920101010No.cancer5 ±6'337 (28)'10(53)14 BrdUrd were identified by the presence of dark pigment over their oilMNNG+ olive ±6394 nuclei. For analysis of the labeling index of the gastric mucosa, the +neurotensin,lOOxg/kgMNNG±5334 ±9393 numbers of BrdUrd-labeled and unlabeled cells in the zone of prolifer +neurotensin,200 ±3352 ±7425 (70)''0(0)0(0)0(0) ating cells were counted without knowing which treatment group the Mg/kgOlive samples were from (17). The zone of proliferating cells in the fundic oilNeurotensin, ±7359 ±6400 mucosa was defined as a rectangle 250 pm wide between the highest 100Neurotensin, ±9355 ±7408 and lowest labeled cells in a well-oriented section. Ten such rectangular 200Mg/kgWk26335 ±2Wk52402±6Effective areas were selected in each rat. In the antral mucosa, all cells below the highest labeled cell in each pit-gland column were regarded as being " Treatment regimens: MNNG + olive oil, 1 ml/kg of olive oil given every within the zone of the proliferating cells. We selected 100 well-oriented other day after MNNG treatment for 25 wk; MNNG + neurotensin, 100 »ig/kg, column pits and glands in each rat.
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