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.