In another study, Hong et al. (41) reported that an ATP-binding cassette (ABC) transporter, ABCB1 (MDR1), was significantly augmented during the acquisition of drug resistance to gemcitabine. Pancreatic CSCs have been shown to be resistant to gemcitabine, the most commonly used chemotherapeutic agent for PC, in multiple studies (12),(14),(38),(41),(42). Treatment with gemcitabine can therefore enrich the CSC population

likely through selection process that eventually leads to treatment failure (12),(38),(42). Emerging evidence suggests that Hedgehog pathway is important to CSC #Wee1 inhibitor keyword# signaling (43). To support the critical role of pancreatic CSCs in the development of drug resistance, combined treatment with gemcitabine and cyclopamine, a small molecule smoothened antagonist, not only Inhibitors,research,lifescience,medical induced tumor regression but also decreased in CSC markers and Hedgehog signaling (42). In addition, ABC transporter inhibitor verapamil resensitized drug-resistant CSCs to gemcitabine in a dose-dependent manner (41). Accumulating evidence suggests that EMT is important in cancer progression conceivably

through commencing Inhibitors,research,lifescience,medical stem cell properties to cancer cells (4),(6),(11). Several studies have reported that pancreatic CSCs also possess mesenchymal features (12)-(14),(39),(44)-(46). During the EMT, mesenchymal cells are characterized by decreased expression of epithelial marker E-cadherin and increased expression of genes that encode members of the Snail family of transcriptional repressors (8),(39). Rasheed et al. (39) reported that the expression of CDH1 that encodes for E-cadherin and of SNAI2 that encodes for Slug was decreased up to 5-fold and increased up to 51-fold, Inhibitors,research,lifescience,medical respectively, in ALDH+ CSCs compared with unsorted tumor cells (39). Both Shah et al. (12) and Du et al. (14) reported that drug-resistant CSCs

have decreased expression of E-cadherin and increased expression of vimentin, which are features of EMT. Transforming growth factor-β (TGF-β) is Inhibitors,research,lifescience,medical a regulator of many types of physiological and pathological EMT (11). When incubated in the presence of TGF-β, the side population (SP) cells, a CSC enriched fraction Phosphatidylinositol diacylglycerol-lyase from PC cell line, changed their shape into mesenchymal-like appearance including spindle shaped assembly. This alteration was associated with significant reduction of E-cadherin expression level and induction of the expression of Snail and matrix metalloproteinase-2. When incubated in the absence of TGF-β, these cells restored epithelial-like appearance and the expression of E-cadherin. These results suggest that SP cells from PC possess superior potentials of phenotypic switch, i.e., EMT and mesenchymal-epithelial transition (MET) (44). Reversal of EMT phenotype has been shown to restore drug sensitivity (5),(46). Arumugam et al.