Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha.
OBJECTIVE
The progenitor cells responsible for transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia remain uncharacterized. During pancreatic development, differentiated cell types arise from ductal progenitor cells expressing the Pdx1 homeodomain transcription factor. The aims of this study were, first, to evaluate the role of Pdx1-expressing stem cells in MT-TGFalpha transgenic mice, and second, to further characterize cell proliferation and differentiation in this model.


METHODS
To assess Pdx1 gene expression in normal and metaplastic epithelium, we performed in vivo reporter gene analysis using heterozygous Pdx1(lacZ/+) and bigenic Pdx1(lacZ/+)/MT-TGFalpha mice.


RESULTS
Pdx1(lacZ/+)/MT-TGFalpha bigenics showed up-regulated Pdx1 expression in premalignant metaplastic ductal epithelium. In addition to Pdx1 gene activation, TGF-alpha-induced metaplastic epithelium demonstrated a pluripotent differentiation capacity, as evidenced by focal expression of Pax6 and initiation of islet cell neogenesis. The majority of Pdx1-positive epithelial cells showed no expression of insulin, similar to the pattern observed during embryonic development.


CONCLUSIONS
Overexpression of TGF-alpha induces expansion of a Pdx1-expressing epithelium characterized by focal expression of Pax6 and initiation of islet neogenesis. These findings suggest that premalignant events induced by TGF-alpha in mouse pancreas may recapitulate a developmental program active during embryogenesis.
Song
S Y
SY
Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center and Nashville VAMC, Nashville, TN 37232-2736, USA.
Gannon
M
M
Washington
M K
MK
Scoggins
C R
CR
Meszoely
I M
IM
Goldenring
J R
JR
Marino
C R
CR
Sandgren
E P
EP
Coffey
R J
RJ
Wright
C V
CV
Leach
S D
SD
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D004848:Epithelium / Q000502:physiology; D018398:Homeodomain Proteins; D007515:Islets of Langerhans / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D010183:Pancreatic Ducts / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D018398:Homeodomain Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C084010:pancreatic and duodenal homeobox 1 protein