The roles of FOXM1 in pancreatic stem cells and carcinogenesis

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.

Figure 1

Model of the genetic progression of pancreatic carcinogenesis. The genetic alterations that occur during pancreatic carcinogenesis can be classified as early (activating mutation of KRAS), intermediate (inactivation of CDKN2A), and late (inactivation of TP53 and SMAD4 and activation of some pathways in PCSCs) events. Markers of PCSCs, including CD24, CD44, CXCR4, ESA, and Nestin, are detected in different sites during pancreatic carcinogenesis (in order of increasing percentage): normal ducts, low-grade PanIN lesions, high-grade PanIN lesions, and PDACs. FOXM1 may play a critical role in the early stages of PDAC development via cross-talk with major signaling pathways. Other gene mutations may occur during PanIN formation but are not illustrated in this model.

Figure 2

Signaling pathways in PCSCs. The HH and Notch developmental pathways are highly active in PCSCs and may be activated by a series of respective ligands. The SHH/Gli signaling pathway plays a pivotal role in maintenance of stemness (self-renewal) via regulation of the expression of the pluripotency-maintaining factors Nanog, Oct4, c-Myc, and Sox2. Upon activation by interaction with ligands, Notch is cleaved and translocated to the nucleus for transcriptional activation of Notch target genes, including hairy and enhancer of split-1, nuclear factor κB (NF-κB), cyclin D1, and c-Myc. The Wnt/β-catenin pathway is vitally involved in cell fate determination via binding to the transcription factor T-cell factor/lymphocyte enhancer factor (TCF/LEF). PI3K/AKT signaling is involved in PCSCs by directly interacting with CD133. FOXM1 plays a pivotal role in PCSCs by directly stimulating stem-like characteristics and cross-talk with other pathways. Abnormal signaling pathways also may involve PCSCs but are not illustrated in this figure. IGF, insulin-like growth factor; EGF, epidermal growth factor; Jag, Jagged; IGF-1R, insulin-like growth factor-1 receptor; EGFR, epidermal growth factor receptor; ICN, intracellular domain of Notch.