TY - JOUR
T1 - Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia
AU - Zhu, Liqin
AU - Shi, Guanglu
AU - Schmidt, C. Max
AU - Hruban, Ralph H.
AU - Konieczny, Stephen F.
N1 - Funding Information:
Supported by the National Institutes of Health ( DK55489 to S.F.K. and National Cancer Institute Specialized Program of Research Excellence grant P50CA62924 to R.H.H. ), the Department of Defense Breast Cancer Research Program ( BC043093 to S.F.K. ), the Phi Beta Psi Sorority Cancer Fund (to S.F.K.), Indiana University/Purdue University Collaborative Biomedical Research Pilot Grant Program (to S.F.K. and C.M.S.), the Lustgarten Foundation for Pancreatic Cancer (to S.F.K.), and the American Association for Cancer Research-Pancreatic Cancer Action Network Career Development Award in Pancreatic Cancer Research (to C.M.S.).
PY - 2007/7
Y1 - 2007/7
N2 - A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on KrasG12D expression, we took advantage of LSL-KrasG12D/+/p48Cre/+ mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinarductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that KrasG12D-induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.
AB - A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on KrasG12D expression, we took advantage of LSL-KrasG12D/+/p48Cre/+ mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinarductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that KrasG12D-induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.
UR - http://www.scopus.com/inward/record.url?scp=34547667454&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547667454&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2007.061176
DO - 10.2353/ajpath.2007.061176
M3 - Article
C2 - 17591971
AN - SCOPUS:34547667454
SN - 0002-9440
VL - 171
SP - 263
EP - 273
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -