AN OVERVIEW OF PANCREATIC CSCS

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The origin of pancreatic CSCs has been controversial. Some studies of genetically engineered mouse models have suggested that pancreatic acinar cells, centroacinar cells (11), or acinar-ductal metaplasia (12) may be the “cell of origin” in pancreatic cancer. The other study suggested that some of the pancreatic epithelial cells characterized by the expression of c-Met+CD133+CD34+CD45-Ter119- and Pdx1 are related to pancreatic carcinogenesis (13,14). However, additional studies are needed to clarify the origin of pancreatic CSCs. CD44+CD24+ESA+ (15) and CD133 (16) are well known as pancreatic CSC markers based on xenograft tumorigenesis. But the detailed function of these markers remains uncertain.

When compared with CD133- cells, CD133+ pancreatic CSCs showed more aggressive behavior, such as increased cell proliferation, migration, and invasion, especially in the presence of pancreatic stromal cells (17). This may be because they underwent epithelial–mesenchymal transition (EMT) more readily (18). CD133+ cells also have higher tumorigenic and metastatic potential than CD44 and CD24 positive cells (19). These foundings uggests that CD133 might be a meaningful cell surface marker of pancreatic cancer stem cells.

CXCR4 has been implicated in mediating pancreatic cancer invasion and metastases (20). Hermann and collegues (21) found that a subpopulation of migrating CD133+CXCR4+ CSCs is essential for PC metastasis. SDF-1, or CXCL12, a specifi c ligand of the CXCR4 receptor, was shown to be the strongest inducer of migration for CD133+ cancer cells in vitro. Thus, they further suggested that strategies aimed at modulating the SDF-1/CXCR4 axis may have important clinical applications to inhibit metastasis of CSCs (21). However, whether CXCR4 expression can be a pancreatic CSC marker is till unconfirmed.

The mechanisms maintaining the "stemness" of CSC is complex. Recently, microRNAs have been found to participate this process. microRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts, usually resulting in translational repression or target degradation and gene silencing (22,23). microRNA (miR)-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination, potentially via the direct modulation of downstream targets Bcl-2 and Notch (24). In addition, 210 miRNAs including miR-99a, miR-100, miR-125b, miR-192 and miR-429, and 258 stem cell-associated mRNAs that were differentially expressed in the pancreatic CSCs. These differentially expressed microRNAs in pancreatic CSCs provide insights into possible linkages between clusters of miRNAs and clusters of stem cell-associated mRNAs in CSCs, which may be benefit for an understanding of CSCs and CSC -targeted cancer therapy (25).

Furthermore, in vitro study imvestigated the molecular mechanisms by which GDC-0449 regulates human pancreatic CSCs characteristics (26). The Sonic Hedgehog (SHH) signaling pathway (27) is aberrantly reactivated and recognized as one of the mediators in the majority of PCs from in vitro and in vivo studies. SHH signaling system plays a key role also in pancreatic CSC biology including in the regulation of CSCs self-renewal, differentiation; and tumorigenic potential (28). SHH signaling pathway at the level of Gli genes has a critical role in normal pancreas development, and dysregulated SHH signaling plays some role in pancreatic cancer (29). Human pancreatic cancers over express Gli (28,30). GDC-0499 inhibited cell viability and induced apoptosis in pancreatic CSCs. This inhibitor also suppressed cell viability, Gli-DNA binding and transcriptional activities, and induced apoptosis through caspase-3 activation and PARP cleavage in pancreatic CSCs (26). Thus, activated Gli genes repress DRs and Fas expressions, up-regulate the expressions of Bcl-2 and PDGFRα and facilitate pancreatic CSCs survival.

In addition to their own elements of CSCs, the niche of CSCs also can impact the stemness of this stem cells (31). Hamada and collegues (31) found that indirect co-culture of pancreatic cancer cells with pancreatic stellate cells (PSCs) enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.