Abstract
Intestinal metaplasia in pyloric mucosa and presence of intestinal-type tumor cells in gastric tumors in Wistar rats during gastrocarcinogenesis were examined by paradoxical concanavalin A staining and biochemical pepsinogen (Pg) assay. Gastric cancer was induced by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) given in drinking water at a level of 50 µg/ml for either 16 weeks (Group 1) or 8 weeks (Group 2). Rats were subsequently maintained on water without MNNG for an additional 64 or 72 weeks. An untreated control group (Group 3) was kept for 80 weeks. Rats from each group were examined after 8, 16, 24, 32, 40, 48, 56, 64, 72, and 80 weeks.
Changes associated with MNNG treatment included intestinal metaplasia of pyloric mucosa, adenomatous hyperplasia of pyloric mucosa, and well-differentiated adenocarcinoma of pyloric mucosa. By using paradoxical concanavalin A staining and hematoxylin and eosin staining, cells in pyloric mucosa of all rats and in both adenomatous hyperplasia and well-differentiated adenocarcinoma of MNNG-treated rats could be classified into two categories. These are termed gastric types (pyloric gland cell type and surface mucous cell type) and intestinal types (intestinal-absorptive cell type and goblet-cell type). Quantitative analyses of proportions of gastric and intestinal types were performed by a general purpose color image processor.
Intestinal metaplasia appeared in the pylorus, first in MNNG-treated rats 16 weeks after the beginning of MNNG administration, and later in untreated control rats after 40 weeks. The percentage areas of intestinal metaplasia per area of pyloric mucosa were less than 1% in all groups. Adenomatous hyperplasia without intestinal-type cells appeared earlier in Group 1 (32 weeks) and Group 2 (40 weeks) than did adenomatous hyperplasia with intestinal-type cells, the latter being observed after 40 weeks in Group 1 and after 56 weeks in Group 2. Only cells of the gastric type were observed in 21 of 30 adenomatous hyperplasias and in 19 of 36 well-differentiated adenocarcinomas. The others consisted chiefly of cells of the gastric type but partly contained cells of the intestinal type. However, the percentage area of the intestinal type was extremely small, being less than 3.5%. Adenomatous hyperplasias or well-differentiated adenocarcinomas composed only of cells of the intestinal type were not observed. Occasionally, tumor cells of the gastric type and the intestinal type were present in the same tubule.
Pg 1 (one of three pepsinogen isozymes) in the pyloric mucosa disappeared or decreased early and did not return. Pg 1 was also consistently and greatly reduced in adenomatous hyperplasias and adenocarcinomas, whereas Pg 3 and Pg 4 remained.
The present results showed that gastric adenocarcinomas induced by MNNG in rats were composed mainly of tumor cells of the gastric type. These findings also suggest that neoplastic germ cells produce mainly gastric-type cells and sometimes produce intestinal-type cells. Most tumor cells apparently originate from areas of mucosa composed of gastric-type cells.
This research was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture of Japan and the Ministry of Health and Welfare of Japan.
