In vitro pancreatic carcinogenesis

Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures

“…30 However, the specific cell of origin of these tumors remains to be identified. 7,31 In addition, the loss of endocrine phenotype, function and survival following islet isolation 6,9,12,13,32,33 and transplantation [9][10][11] has been implicated in the failure of islet grafts to restore euglycemia in diabetic transplant recipients. In the present study, we extend our previous work on an in vitro model of islet-to-duct transformation 5,8,14 to the char- acterization of the opposing signaling events that underlie this phenotypic switch.…”

“…1 In comparison, it is well known that other pancreatic cells, the acinar and ductal cells, exhibit plasticity. [2][3][4] While recent studies have begun to explore the potential of adult islet plasticity, [5][6][7] the cellular and molecular events that regulate this process remain to be elucidated. 8 An appropriate model for the study of islet plasticity will provide an understanding of mechanisms underlying adult islet cell differentiation.…”

“…Such a model would be useful for the investigation of a variety of pancreatic pathologies, including many pancreatic cancers, where the cell of origin remains to be identified. 7 In addition, this model would allow the investigation of changes in islet cell phenotype following islet isolation. These changes in the differentiated state of isolated islets prior to and following transplantation are suggested to lead to the failure of islets to restore glucohomeostasis in a significant population of transplant recipients.…”

Morphogenetic plasticity of adult human pancreatic islets of Langerhans

“…[3][4][5][6] However, emerging evidence now suggests that adult islets may also be capable of morphogenetic transformation. [7][8][9][10][11] In this regard, it is noteworthy that phenotypic changes in isolated adult islets both after isolation and following transplantation have been associated with their failure to restore normoglycemia. 12,13 Moreover, islet-to-duct transformation has been suggested to play a critical role in the development of pancreatic adenocarcinomas, the most common type of pancreatic cancer, where the cell of origin still remains elusive.…”

“…12,13 Moreover, islet-to-duct transformation has been suggested to play a critical role in the development of pancreatic adenocarcinomas, the most common type of pancreatic cancer, where the cell of origin still remains elusive. 9,14 While the cellular and molecular mechanisms that control islet phenotype in the adult human pancreas remain poorly understood, it is possible that these mechanisms may be those known to direct the development and phenotypic maturation of functional islets during pancreatic morphogenesis. In this regard, the transcription factor pancreatoduodenal homeobox gene-1 (PDX-1), which is critical for pancreatic development, 15 is also a key regulator of a number of factors that define and maintain islet cell phenotype and function including insulin, 16 glucokinase 17 and glucose transporter-2 (GLUT-2).…”