The Notch Pathway Is Important in Maintaining the Cancer Stem Cell Population in Pancreatic Cancer

Abstract

BackgroundPancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized.MethodsExpression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.ResultsNotch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.ConclusionThe Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.

Hes1: a key role in stemness, metastasis and multidrug resistance

“…25 The same phenomenon can be observed in colon cancer, as well as pancreatic cancer. 26,27 The Notch-Hes1 pathway also functions significantly in maintaining breast cancer stem cells. 28 During a leukemia blast crisis, patient samples that were tested exhibited elevated levels of Hes1.…”

“…Aberrant Notch-Hes1 axis is presented in cancer stem cells, such as glioblastoma, breast cancer, pancreatic cancer, and osteosarcoma. 27,36,72,73 The inhibition of the Notch signaling pathway can reverse cancer cell survival and induce apoptosis. In glioma, the up-regulation of Notch enhances Nestin and CD133 expression.…”

Pancreatic Ductal Adenocarcinoma Stem Cells

“…A very important question for the development of possible therapies is which signaling pathways in CSC might mediate the pathophysiological characteristics and therefore mediate properties like "metastasis" and "drug resistance" [53,54]. Recently, several signaling pathways such as Notch [55], Hedgehog [56], Wnt [57]…”

Pancreatic Cancer Stem Cells

“…Signaling pathways, including Notch, Wnt, PTEN, SHH (Sonic hedgehog), BMP-4, and BMI-1, have already been verified in cancers from solid organs [7,[28][29][30][31]. Phosphoinositide-3 kinase (PI3K)/Akt signaling has been implicated in the regulation of diverse cellular functions, including cell proliferation, growth, survival, migration, metabolism, angiogenesis, and tumorigenesis [32,33].…”

“…For example, Wnt/-catenin signaling has been reported to result in increased tolerance of DNA damage, rendering CSCs resistant to radiation [90,91]. And Notch pathway has been implicated in the failure of cancers in breast, pancreas to response with high efficacy to chemo-and radiation therapy [30,92,93]. In addition, TGF-beta pathway was found to play a role in the metastasis of breast cancer by David and colleagues [50].…”