Origin and Development of the Precursor Lesions in Experimental Pancreatic Cancer in Rats

Abstract

SUMMARY:Notwithstanding the importance of understanding how pancreatic ductal adenocarcinoma develops, the process remains controversial. A key question is whether the cells of origin of the tubular complexes that constitute precursor lesions are derived from a single cell type or from multiple types. Suggestions that they arise solely from centroacinar cells or ductal cells have been based on inference due to their morphologic appearance in tissue from patients or investigation of limited numbers of tubular complexes in animal models later in the carcinogenic process. The present study establishes clearly that two steps are involved; rapid transdifferentiation to produce tubular complexes followed later by transformation of the component cells. Animals were killed at intervals beginning 1 day after implantation of the carcinogen dimethylbenzanthracene. Transdifferentiation of acinar cells to ductal cells does not require cell division. Transition of lobules to tubular complexes begins by 2 days after implantation of carcinogen. Within 4 days after implantation well-developed tubular complexes are present. Islets participate in the process. Ductal adenocarcinoma is observed by 1 month after implantation of carcinogen. Chymotrypsin and cytokeratin localized by immunocytochemistry indicate acinar and ductal cell characteristics. Acino-ductal transdifferentiation persists in carcinogen-implanted animals, but not in controls implanted with sodium chloride crystals or subjected to sham implantation. The precursor lesions (tubular complexes) are formed by the transdifferentiation of acinar cells and to a lesser extent islet cells, with the incorporation of the duct cells pre-existing in the lobules. Therefore, cells that at one time were acinar cells, islet cells, and duct cells, provide the precursor cells for the ductal adenocarcinoma that develops from tubular complexes. The results raise the question whether the transdifferentiated cells in the tubular complexes of patients with chronic pancreatitis are more susceptible to carcinogenic influences, resulting in the increased rate of pancreatic cancer. (Lab Invest 2003, 83:853-859).

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

“…29,30 In our study, the transient feature of this response in both control and ElasCCK2 pancreas appears to represent a reaction to acinar cell trauma resulting from 1 single carcinogen exposure. 31 Second, our results provide evidence for a relationship between expression of the CCK2 receptor and the susceptibility to azaserine. Indeed, areas of tubular complexes and adenomas were larger together with a higher acinar proliferation in treated ElasCCK2 pancreas compared to controls.…”

“…19,36 This process has also been reported to occur in experimental pancreatic cancer in rats. 31 The fact that altering epithelial differentiation can promote formation of precursor lesions was further demonstrated in the TGF alpha transgenic model with accelerated tumor formation upon losing p53. 43 Although its direct relevance to the cancer remains to be validated, similar alteration in acinar differentiation was observed in human pancreas and associated with carcinoma.…”

Tubular complexes as a source for islet neogenesis in the pancreas of diabetes-prone BB rats

“…[19][20][21][22] Thus, TC have been considered to be a general reaction of acinar cells to damage 23 that results in acinar to duct dedifferentiation. 5,11 TC have been observed in the Long-Evans rat model of type II diabetes, 24 but they have not been reported in rodent models of spontaneous type I diabetes.…”

“…Normal pancreas has a tubular arrangement early in life. 7 TC have been observed in several conditions involving pancreatic damage or stress such as pancreatitis, 8 duct ligation, 9 partial pancreatic duct obstruction by wrapping, 10 chemically induced carcinogenesis, [11][12][13] 90% pancreatectomy, 14 and chronic hyperglycemia induced by glucose infusion. 15 It is commonly accepted that TC formation in the pancreas is the result of acinar to duct dedifferentiation.…”

“…15 It is commonly accepted that TC formation in the pancreas is the result of acinar to duct dedifferentiation. 4,11,[16][17][18] In vitro studies also demonstrated that acinar cells from humans and animals can transform into ductlike cells by dedifferentiation. [19][20][21][22] Thus, TC have been considered to be a general reaction of acinar cells to damage 23 that results in acinar to duct dedifferentiation.…”