Increased PDX-1 expression is associated with outcome in patients with pancreatic cancer.
BACKGROUND
During pancreatic development, pancreatic duodenal homeobox gene-1 (PDX-1) is expressed in pancreatic duct cells that have the potential to differentiate into islets. Therefore, PDX-1 is thought to be a marker of de-differentiated cells with the capacity to redifferentiate into several pancreatic cell types. We analyzed PDX-1 expression in human pancreatic cancer specimens, pancreatic cancer cell lines, and the effects of forced expression of PDX-1 in pancreatic cancer cells.


METHODS
Thirty-five pancreatic adenocarcinomas were immunohistochemically stained with a polyclonal rabbit antibody against mouse PDX-1. Correlations with tumor characteristics were made with chi-squared analysis. The influence of clinicopathologic factors on survival was assessed. The expression of PDX-1 in pancreatic cancer cells was examined. Replication-deficient recombinant adenoviruses were constructed by the cosmid-adenoviral DNA terminal protein complex method. PANC-1 cells were infected with Ad-pdx-1 or Ad-LacZ. PANC-1 cells that were infected with adenovirus were used in a cell growth assay and a migration assay and for morphologic analysis.


RESULTS
Interestingly, 43% of pancreatic cancers were positive for PDX-1 expression, and 57% of pancreatic cancers were negative (normal pancreatic exocrine tissue shows little or no staining for PDX-1). Lymph node metastasis (P =.02) and histologic grade (P =.04) were correlated significantly with PDX-1 expression. Patients with positive PDX-1 had a significantly worse prognosis than those patients with negative PDX-1 (P =.02). Importantly, PDX-1 was an independent variable that effected overall survival (P =.03). Pancreatic cancer cell lines showed no PDX-1 expression. There were no significant differences in cell proliferation or morphologic condition between Ad-pdx-1- and Ad-lacZ-infected PANC-1 cells. However, Ad-pdx-1-infected PANC-1 cells did show a significantly higher migration rate than Ad-lacZ-infected PANC-1 cells.


CONCLUSIONS
Re-expression of PDX-1 may represent a return to a more de-differentiated state by more aggressive pancreatic cancers and may also represent an important new tumor marker for these aggressive cancers.
Koizumi
Masayuki
M
Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan.
Doi
Ryuichiro
R
Toyoda
Eiji
E
Masui
Toshihiko
T
Tulachan
Sidhartha S
SS
Kawaguchi
Yoshiya
Y
Fujimoto
Koji
K
Gittes
George K
GK
Imamura
Masayuki
M
D000368:Aged; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002455:Cell Division; D002465:Cell Movement; D005260:Female; D018014:Gene Transfer Techniques; D018398:Homeodomain Proteins; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011379:Prognosis; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein