BioScientifica, Endocrine-Related Cancer, 1(24), p. 31-40, 2017
DOI: 10.1530/erc-16-0443
Full text: Unavailable
Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of thePRKAR1Agene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles ofprkar1ain mouse cells expressingpdx1(Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4–5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deletingprkar1a. The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Δ-Prkar1amice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most commonly produced peptides (insulin, c-peptide, glucagon, gastrin and somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotentpdx1+/insulin−cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with completeprkar1adeficiency. In conclusion, this mouse model supports the role ofprkar1aas a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions.