The Notch signaling pathway is well known to be responsible for maintaining the balance between cell proliferation and death and plays instrumental roles in the formation of multiple human tumors, including pancreatic cancer [
60,
97]. Notch genes encode for proteins that can be activated via interaction with a family of their ligands. Humans have four Notch receptors—Notch1, Notch2, Notch3, and Notch4—with five related ligands—Delta-like1, Delta-like3, Delta-like 4, Jagged1, and Jagged2. Upon activation, Notch is cleaved, releasing the intracellular domain of Notch, which then can be translocated to the nucleus for transcriptional activation of Notch target genes, including hairy and enhancer of split-1, nuclear factor κB, cyclin D1, and c-myc [
98]. Emerging evidence clearly suggests that activation of the Notch signaling pathway is mechanistically associated with molecular characteristics of CSCs in PDAC cases [
79,
99]. For example, Forced overexpression of Notch1 may increase the formation of pancreatospheres, which is consistent with expression of the CSC surface markers CD44 and EpCAM. This suggests that activation of Notch1 signaling is related to the self-renewal capacity of PCSCs [
78]. Authors recently reported that expression of Oct4, Nanog, and PDX1 as markers of self-renewal of PCSCs occurred in Notch2
+ BxPC-3 and Panc-1 human pancreatic cancer cells [
100]. Also, these investigators found that expression of ALDH, a PCSC surface marker, was associated with poor overall survival durations in PDAC patients. Treatment with PF-03084014, a selective γ-secretase inhibitor, alone or in combination with gemcitabine is effective in reducing the number of ALDH
+ tumor cells [
101]. In a glioblastoma study, Notch blockade by GBI appeared to deplete stem-like cancer cells via reduced proliferation and increased apoptosis associated with decreased AKT and signal transducer and activator of transcription 3 phosphorylation, which was consistent with reduced expression of the CSC markers CD133, Nestin, Bmi1, and olig2 [
102]. A growing body of published reports strongly suggest that Notch signaling is biologically relevant to CSCs in pancreatic cancer.