Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis.
Notch signaling regulates cell fate decisions in a wide variety of adult and embryonic tissues. Here we show that Notch pathway components and Notch target genes are upregulated in invasive pancreatic cancer, as well as in pancreatic cancer precursors from both mouse and human. In mouse pancreas, ectopic Notch activation results in accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, previously identified as a precursor lesion for pancreatic cancer. Notch is also activated as a direct consequence of EGF receptor activation in exocrine pancreas and is required for TGF alpha-induced changes in epithelial differentiation. These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.
Miyamoto
Yoshiharu
Y
Departments of Surgery, Oncology, and Pathology, The Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Maitra
Anirban
A
Ghosh
Bidyut
B
Zechner
Ulrich
U
Argani
Pedram
P
Iacobuzio-Donahue
Christine A
CA
Sriuranpong
Virote
V
Iso
Tatsuya
T
Meszoely
Ingrid M
IM
Wolfe
Michael S
MS
Hruban
Ralph H
RH
Ball
Douglas W
DW
Schmid
Roland M
RM
Leach
Steven D
SD
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D044584:Carcinoma, Ductal / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins; D064231:Nestin; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D015854:Up-Regulation
D015415:Biomarkers; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D051880:Receptors, Notch; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors