enng and Adenocarcinoma--Mucinous

Pathohistological studies of resected human stomachs and of experimental gastric cancers induced by ENNG have revealed that undifferentiated carcinomas arise at the neck region of glandular tubules both in the fundic and the pyloric mucosa, and tumor cells disclose the earliest invasion in the lamina propria by dripping from the glandular tubule. At earlier stages, the carcinoma cells tend to be confined to the middle level of the mucosa, and they extend to the horizontal direction of the mucosa. Most carcinomas at earlier stages comprise the diploid cell line. When tumors grow beyond a size of 2 cm in diameter in the mucosal layer, they begin to invade into the submucosal layer. As tumors grow, aneuploid and polyploid cancer cells arise in the diploid cell population. This is a kind of tumor progression. Aneuploid cancer cells disclose a more invasiveness, and they are ready to invade into the deep layer of the gastric wall. Scirrhous cancers are mostly composed of aneuploid cells, and it is suggested that small mucosal cancers which exclusively consist of aneuploid cells may become scirrhous cancers in a relatively short period.

Topics: Adenocarcinoma, Mucinous; Animals; Cell Division; DNA, Neoplasm; Dogs; Humans; Methylnitronitrosoguanidine; Ploidies; Stomach Neoplasms

Signet-ring-cell carcinomas were induced in the stomach of 12 beagle dogs by p.o. administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), and the morphology and modes of cell proliferation in an incipient stage of cancer growth were studied with bromodeoxyuridine (BrdUrd) incorporation. From 5 to 27 months after the completion of 8 months' carcinogen treatment, minute carcinomas were found in the stomachs of 9 dogs. Before sacrifice, the dogs were given a single or repeated i.v. injections of BrdUrd for 1-3 days. Minute signet-ring-cell carcinomas were found to form a layered structure, in which the cancer cells proliferated in the lamina propria at the gland-neck level and differentiated to postmitotic signet-ring cells at the upper and lower levels of the mucosa. From repeated injections of BrdUrd, the time required for all the proliferative cells to be labelled with BrdUrd (reflecting the maximum cell-cycle time) was estimated to be 1.7 days for the normal glands, and 2.7 days for minute signet-ring-cell carcinomas. From the labelling index with BrdUrd as well as from the morphology, earliest carcinomas were identified in the single gland. There remained atrophic normal epithelium commonly in the single-gland lesions. Proliferative atypical cells appeared to be shed into the stroma passively through the atrophy and subsequent collapse of the gland rather than through active invasion. This may be a reason why cancer cells in minute signet-ring cell carcinomas preserved the normal pattern of cell renewal movement to form the layered structure.

Topics: Adenocarcinoma, Mucinous; Alcian Blue; Animals; Bromodeoxyuridine; Cell Division; Dogs; Gastric Mucosa; Immunoenzyme Techniques; Methylnitronitrosoguanidine; Precancerous Conditions; Stomach Neoplasms

A signet ring cell carcinoma in the gastric antrum of a Cynomolgus monkey induced by N-ethyl-N'-nitro-N-nitrosoguanidine was sequentially studied by endoscopy, biopsy, and autopsy. The carcinoma was first detected on the angulus of the stomach at the 38th month as a slightly elevated lesion. Sixty-one months later this tumor was found to be still in the "early" (intramucosal) stage. Another, independent, initial gastric cancer was also discovered. This is the first example of an induced gastric carcinoma remaining in the "early" stage during a six-year follow-up period after the initial histologic diagnosis.

Topics: Adenocarcinoma, Mucinous; Animals; Biopsy; Carcinogens; Gastroscopy; Macaca; Methylnitronitrosoguanidine; Stomach Neoplasms; Time Factors

The cell kinetic alteration in the background mucosa of canine gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was evaluated by cytofluorometry in which the rate of S and G2 + M phase cell in gastric mucosal cells could be calculated, and a triphasic alteration was demonstrated; an initial reduction phase, an increase phase and a plateau phase with a high value. The initial reduction phase was caused by non-specific toxicity of ENNG as observed in drug induced gastric mucosal lesions, and subsequent increase and plateau phases originated from the action of ENNG itself to activate the mucosal turn-over and from histological changes in the background mucosa such as regenerative hyperplastic change after mucosal erosion and atrophic changes, sometimes including intestinal metaplastic change. Further, in comparison to carcinogenesis in chemically induced gastric cancer with and without a surfactant (Tween 60), it was suggested that one of the promotion effects of Tween 60 was closely related with activation of the mucosal turn-over.

Topics: Adenocarcinoma, Mucinous; Animals; Cell Cycle; Cell Transformation, Neoplastic; DNA, Neoplasm; Dogs; Flow Cytometry; Gastric Mucosa; Gastroscopy; Male; Methylnitronitrosoguanidine; Polysorbates; RNA, Neoplasm; Stomach Neoplasms

N-Ethyl-N'-nitro-N-nitrosoguanidine [(ENNG) CAS: 63885-23-4] was administered to 5 Macaca monkeys (Macaca mulatta and M. irus) at a concentration of 200 or 300 micrograms/ml for 11-26 months in their drinking water. Gastric carcinomas in the pyloric region were observed in all 5 monkeys between experimental months 11 and 38. Histologically, these carcinomas were mainly poorly differentiated adenocarcinomas and signet-ring cell carcinomas, and a few moderately and well-differentiated adenocarcinomas were also found. The macroscopic and histologic appearances of these carcinomas were similar to those in humans.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Female; Femoral Neoplasms; Macaca fascicularis; Macaca mulatta; Male; Methylnitronitrosoguanidine; Osteosarcoma; Stomach Neoplasms; Tracheal Neoplasms

Topics: Adenocarcinoma, Mucinous; Animals; Disease Models, Animal; Dogs; Female; Gastric Mucosa; Male; Metaplasia; Methylnitronitrosoguanidine; Stomach Neoplasms

Signet ring cell carcinoma was induced in canine stomachs by N-ethyl-N'-nitro-N-nitrosoguanidine, and modes of cell proliferation and turnover in the carcinoma were studied by 3H-thymidine autoradiography in conjunction with morphometric analysis. From 2 to 15 months after the cessation of 8 months carcinogen treatment, carcinomas in an early stage were obtained. Most of the cancer tissues confined to the lamina propria showed a layered structure. This comprised three layers; the superficial and the deep layer were composed of signet ring cells, and the middle layer was composed of small round cells. The dogs were labeled with 3H-thymidine by s.c. injection and by local infusion of the celiac artery. Flash-labeled autoradiographs revealed that most 3H-thymidine incorporating cancer cells were located around the middle layer, with a small amount of mucin. Using a pulse labeling experiment, those labeled carcinoma cells were shown to migrate from the middle layer towards the surface. Morphometric analysis of the autoradiographs showed that the small cells in the middle layer migrated upwards and produced mucin to become full-blown signet ring cells by 5.5 days. In 15 days, most labeled cancer cells in the superficial layer had disappeared. This mode of cellular turnover appeared to mimic a cell renewal system of the normal gastric mucosa. If the cancer cells turn over in this way, the tumor must grow slowly, remaining as an intramucosal cancer for a relatively long period.

Topics: Adenocarcinoma, Mucinous; Animals; Autoradiography; Carcinogens; Cell Division; Cell Survival; Dogs; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

An experimental trial in the induction of canine gastric cancers was conducted to study the relationship between the histological differentiation of adenocarcinoma and the duration of administration of the carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Twenty-three adult Beagle dogs were divided into three groups according to the duration of administration. Over 3 months administration, the total dose of ENNG per animal was 5.85 g, and only signet ring cell carcinomas and poorly differentiated adenocarcinomas were induced in the antral mucosa of the stomach in 5 of 10 recipients. During 6 and 9 months administration, the total doses per animal were 11.70 g and 17.55 g, well differentiated adenocarcinomas were observed in 12 of 13 animals and they coexisted with poorly differentiated adenocarcinomas and/or signet ring cell carcinomas. Atrophic hyperplastic gastritis and hyperplastic polyps were seen in the same stomach. The results of this study suggest that a greater amount of carcinogen, i.e., a higher total dose, is required for the development of well differentiated adenocarcinoma than for inducing poorly differentiated adenocarcinoma and signet ring cell carcinoma.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Dogs; Drug Administration Schedule; Female; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

150 micrograms/day of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was administered to a total of 8 dogs, (4 mongrels at age of 4 months and 4 beagles at age of 6 months) over a period of 8 months by Kurihara 's method. As a result of the administration, we found development of minute cancer as follows: In 3 animals, male beagle killed at 575th day, male mongrel at 1, 105th days and male mongrel at 1, 245th days, a total of 20 neoplasms of the stomach was found (18 early cancers and 2 advanced cancers). 13 of which being the minute cancer measuring less than 0.5 cm. There were 11 mucosal cancers and 2 submucosal cancers. When classified by the macroscopic pathological type, none was classified as the elevated type (I, IIa types), 5 lesions as the flat type (IIb type), and 8 lesions as the depression type (IIc type). Two lesions of submucosal cancer belonged to IIc type. When classified by the histological type, 2 were classified as papillary adenocarcinoma, 2 as well differentiated tubular adenocarcinoma, 1 as moderately differentiated tubular adenocarcinoma, 5 as poorly differentiated adenocarcinoma and 3 as signet-ring cell carcinoma.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Animals; Dogs; Male; Methylnitronitrosoguanidine; Neoplasm Staging; Stomach Neoplasms

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adenoma; Animals; Dogs; Male; Methylnitronitrosoguanidine; Stomach Neoplasms