This chapter focuses on five major embryonic signaling networks and discusses the role of their aberrant reactivation in the pathobiology of pancreatic cancer. One of the earliest signaling pathways known to be important in pancreas development is the Notch pathway. Once the transmembrane Notch receptor is activated by binding of its ligands Delta and Serrate, its intracellular domain translocates in the nucleus where it associates with recombination signal binding proteins (RBPs), also known as CSL/CBF1/Su(H)/LAG-1 transcription factors. RBP-j is a part of the trimeric transcription factor Ptf1, which is essential for early pancreas development as well as differentiation and maintenance of exocrine cells. Ptf1 is composed of p48, a pancreas- and cerebellum-specific factor, a class A bHLH protein, and RBP-j. Sonic hedgehog (Shh) and its receptors are highly expressed in the embryonic foregut before any budding of the pancreas. By embryonic day 8, Shh expression is downregulated in the region fated to give rise to the dorsal bud of the pancreas. Shh downregulation would be the key event in restricting the zone of Pdx1 expression that will become the pancreas. The Hedgehog (Hh) signaling pathway is dramatically upregulated during the progression from pancreatic intraepithelial neoplasia (PanIN) lesions to pancreatic ductal adenocarcinoma (PDAC), and PTCH expression is also present in the stromal elements adjacent to the cancer. Transforming growth factor-beta (TGFβ) isoforms are major regulators of pancreatic endocrine and exocrine cell fates, and all three isoforms and their signaling components are expressed in the pancreatic epithelium and surrounding mesenchyme from embryonic to adult stages. The TGFβ superfamily of secreted growth factors consists of several sub-families that include the three mammalian TGFβ isoforms, the activins/inhibins and the bone morphogenetic proteins (BMP).
|Original language||English (US)|
|Title of host publication||Handbook of Cell Signaling, 2/e|
|Number of pages||10|
|State||Published - Dec 1 2010|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)