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The roles of FOXM1 in pancreatic stem cells and carcinogenesis.

Quan M, Wang P, Cui J, Gao Y, Xie K - Mol. Cancer (2013)

Bottom Line: Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. kepxie@mdanderson.org.

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.

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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.
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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.

Mentions: Over the past few decades, increasing evidence has demonstrated that almost all pancreatic cancers progress from diverse premalignant lesions to invasive carcinomas. Precursors of pancreatic cancer include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and intraductal tubular papillary neoplasms (ITPNs) [26-28]. Pancreatic carcinoma in general may arise from any of these precursor lesions, yet pancreatic ductal adenocarcinoma (PDAC) in particular is much more closely associated with PanIN than with the other precursor lesions. PanIN lesions are classified as PanIN-1, -2, or -3 based on the degree of morphologic atypia and the genetic events during pancreatic carcinogenesis [26,28]. In this section, we describe the roles of signaling pathways related to PanIN in the early stages of PDAC development and the cross-talk between FOXM1 and these pathways (FigureĀ 1).


The roles of FOXM1 in pancreatic stem cells and carcinogenesis.

Quan M, Wang P, Cui J, Gao Y, Xie K - Mol. Cancer (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3924162&req=5

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.
Mentions: Over the past few decades, increasing evidence has demonstrated that almost all pancreatic cancers progress from diverse premalignant lesions to invasive carcinomas. Precursors of pancreatic cancer include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and intraductal tubular papillary neoplasms (ITPNs) [26-28]. Pancreatic carcinoma in general may arise from any of these precursor lesions, yet pancreatic ductal adenocarcinoma (PDAC) in particular is much more closely associated with PanIN than with the other precursor lesions. PanIN lesions are classified as PanIN-1, -2, or -3 based on the degree of morphologic atypia and the genetic events during pancreatic carcinogenesis [26,28]. In this section, we describe the roles of signaling pathways related to PanIN in the early stages of PDAC development and the cross-talk between FOXM1 and these pathways (FigureĀ 1).

Bottom Line: Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. kepxie@mdanderson.org.

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.

Show MeSH
Related in: MedlinePlus