Prkar1a gene knockout in the pancreas leads to neuroendocrine tumorigenesis.
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 the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (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 deleting prkar1a 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-Prkar1a mice 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 multipotent pdx1+/insulin- cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with complete prkar1a deficiency. In conclusion, this mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions.
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Emmanouil
E
Saloustros
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Paraskevi
P
Salpea
Diagnostic and Research Services BranchDivision of Veterinary Resources (DVR), Office of Research Services (ORS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Matthew
M
Starost
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Sissi
S
Liu
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Fabio R
FR
Faucz
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Edra
E
London
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Eva
E
Szarek
Department of PediatricsMetabolism Division, John Hopkins University, Baltimore, Maryland, USA.
Woo-Jin
WJ
Song
Department of PediatricsMetabolism Division, John Hopkins University, Baltimore, Maryland, USA.
Mehboob
M
Hussain
Section on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA stratakc@mail.nih.gov.
Constantine A
CA
Stratakis
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D063646:Carcinogenesis; D056733:Carney Complex / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D007328:Insulin / Q000097:blood; D008297:Male; D018345:Mice, Knockout; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010179:Pancreas / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology
D001786:Blood Glucose; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D007328:Insulin; C517835:Prkar1a protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases
PRKAR1A; metastasis; mouse model; neuroendocrine tumors; pancreas