Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among all cancers. Over the past several decades, investigators have made great advances in the research of PDAC pathogenesis. Importantly, identification of pancreatic cancer stem cells (PCSCs) in pancreatic cancer cases has increased our understanding of PDAC biology and therapy. PCSCs are responsible for pancreatic tumorigenesis and tumor progression via a number of mechanisms, including extensive proliferation, self-renewal, high tumorigenic ability, high propensity for invasiveness and metastasis, and resistance to conventional treatment. Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia. The molecular mechanisms that control PCSCs are related to alterations of various signaling pathways, for instance, Hedgehog, Notch, Wnt, B-cell-specific Moloney murine leukemia virus insertion site 1, phosphoinositide 3-kinase/AKT, and Nodal/Activin. Also, authors have reported that the proliferation-specific transcriptional factor Forkhead box protein M1 is involved in PCSC self-renewal and proliferation. In this review, we describe the current knowledge about the signaling pathways related to PCSCs and the early stages of PDAC development, highlighting the pivotal roles of Forkhead box protein M1 in PCSCs and their impacts on the development and progression of pancreatic intraepithelial neoplasia.
Highlights
The incidence of pancreatic cancer is increasing annually, especially in industrialized countries [1]
We briefly describe the crucial role of Forkhead box protein M1 (FOXM1) in pancreatic cancer stem cells (PCSCs) in pancreatic cancer development and progression with a focus on recent insight into the cross-talk between FOXM1 and signaling pathways in PCSCs here and below
These findings provide convincing evidence that FOXM1 plays a central role in the early stages of Pancreatic ductal adenocarcinoma (PDAC) development via cross-talk with signaling pathways related to pancreatic intraepithelial neoplasia (PanIN) and PSCSs
Summary
The incidence of pancreatic cancer is increasing annually, especially in industrialized countries [1]. Additional studies demonstrated that FOXM1 plays a key role in maintenance of stem cell pluripotency in vivo by inducing the expression of pluripotency genes, including Oct, Nanog, and Sox2 [75] Taken together, these findings provide convincing evidence that FOXM1 plays a central role in the early stages of PDAC development via cross-talk with signaling pathways related to PanIN and PSCSs. Major signaling pathways in PCSCS Increasing evidence supports the existence of CSCs in pancreatic tumors. Multiple lines of evidences supported that the SHH/Gli signaling pathway is highly activated in PCSCs and plays a pivotal role in maintenance of stemness (self-renewal) by regulating the expression of pluripotencymaintaining factors, including Nanog, Oct, c-Myc, and Sox2 [77,88,89,90,91,92]. Direct evidence of a role for FOXM1 in the PCSC niche is lacking, FOXM1 conceivably has a crucial role in PCSCs partially through regulation of PCSC niche-associated signaling pathways
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