On the origin of induced pancreatic islet tumors: a radioautographic study.

Endocrine tumors of the pancreas are induced in a high percentage of young rats by injections of streptozotocin and nicotinamide (SZ/NA). Benign tumors first appear 20 to 36 weeks after drug injections. To determine the possible site of their origin, the incorporation of [3H]thymidine into islets, ducts, acini, microtumors, and gross tumors was examined by radioautography of histologic sections at 1 to 36 weeks after drug injection. Drug treatment led to early (1- to 6-week) increases in nuclear 3H labeling of exocrine pancreatic structures (ductal and acinar cells), which may involve DNA repair processes. A secondary increase in labeling of duct cells during the period of tumor emergence supports the assumption that SZ/NA-induced tumors are of ductal origin. Microtumors and gross tumors also exhibited markedly elevated rates of [3H]thymidine incorporation compared to control islets. Nontumorous islet tissue, which exhibited a gradual decrease in volume due to B-cell destruction by the drug injection, showed about 10-fold higher 3H labeling than islets of controls at all time points. The results suggest that in addition to ductal precursors, islets that survive SZ/NA-induced injury may also provide sites of focal endocrine cell differentiation to tumor tissue. Once established, both microtumors and gross tumors continue to grow by accelerated cell division.

Morphometric analysis of the endocrine cell composition of rat pancreas following treatment with streptozotocin and nicotinamide.

Using immunohistochemistry and linear scanning, a morphometric analysis was made of the composition of the rat endocrine pancreas at sequential intervals after combined injections of streptozotocin (SZ) and nicotinamide (NA). One week after treatment, the volume of islet tissue was significantly higher than that of the corresponding, saline-injected controls, probably as the result of acute hyperplasia of insulin- and somatostatin-positive cells. However, at all time periods thereafter (6, 20, and 36 weeks), the drug-treated rats showed decreased islet volumes compared to controls. Analysis of aggregate (total) volumes of hormone producing cells at various time periods after drug treatment indicated that decreases in insulin (B-cell) volumes only partially accounted for the observed changes in total islet volume. There were, in addition, early decreases in glucagon (A-cell) and increases in somatostatin (D-cell) volumes. The results suggest that SZ/NA treatment caused limited islet B-cell destruction and transient changes in the proportions of islet A and D cells. Microscopic endocrine tumors were observed at 20 weeks, and both gross and microscopic tumors were observed 36 weeks after SZ/NA treatment. When islet and tumor tissues were included in computation, aggregate volumes of insulin and somatostatin-positive cells were markedly increased, with no significant changes in glucagon-positive cell volumes compared to controls, indicating that the tumors were rich in B and D cells, but poor in A cells. These results are discussed in relation to changes in glucose tolerance and serum insulin levels, and to islet cell volumes following treatment with a diabetogenic dose of streptozotocin alone.