The roles of FOXM1 in pancreatic stem cells and carcinogenesis

Quan et al. Molecular Cancer 2013, 12:159 http://www.molecular-cancer.com/content/12/1/159 REVIEW Open Access The roles of FOXM1 in pancreatic stem cells and carcinogenesis Ming Quan1,3, Peipei Wang2, Jiujie Cui1,3, Yong Gao2 and Keping Xie3* 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. Keywords: Transcription factors, Oncogenic switch, Progression, Stem cells, Therapeutic targets, Molecular biomarkers Introduction The incidence of pancreatic cancer is increasing annually, especially in industrialized countries [1]. Despite ever-increasing research efforts over the past few decades, prognoses for pancreatic cancer remain among the poorest for all cancers. It is also one of the leading causes of cancer-related mortality in developed countries, with a median survival duration of 6 months and 5-year overall survival rate of less than 5% [2,3]. Conventional therapies, such as surgery, radiation therapy, chemotherapy, and combinations of them, have had a limited impact on the course of this aggressive neoplasm, which is characterized by rapid metastasis and resistance to these therapies [4]. Researchers recently demonstrated that the presence of cancer stem cells (CSCs) in pancreatic tumors contributes to the early metastasis and chemotherapeutic drug resistance of pancreatic cancer [5]. Therefore, elucidating the molecular mechanisms underlying the critical * Correspondence: 3 Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA Full list of author information is available at the end of the article roles of pancreatic CSCs (PCSCs) in pancreatic cancer development and progression is imperative. CSC research has resulted in many advances in the fundamental understanding and clinical management of several solid tumors, including brain, breast, head and neck, lung, prostate, colon, ovarian, and pancreatic cancer [5-11]. CSCs are now widely accepted to be a subpopulation of tumor cells with the capacity for extensive proliferation, self-renewal, multipotency, high tumorigenicity, and treatment resistance. Moreover, CSCs have a high propensity for invasiveness and metastasis [12]. CSCs in pancreatic cancer cases are characterized by expression of the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA; epithelial cell adhesion molecule [EpCAM]) [13]. Authors reported that CD133+ cells in primary pancreatic tumors and pancreatic cancer cell lines represent those with enhanced, potent proliferative capacity [14]. Increasingly, studies have demonstrated that the presence of PCSCs combined with drug resistance and high levels of metastasis contribute to therapy failure, resulting in the high mortality rates for pancreatic cancer [5]. Furthermore, researchers have © 2013 Quan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Quan et al. Molecular Cancer 2013, 12:159 http://www.molecular-cancer.com/content/12/1/159 proposed that Forkhead box protein M1 (FOXM1) is involved in the self-renewal of PCSCs, and tumorigenesis and metastasis of pancreatic cancer cells [15]. FOXM1 is a member of the Forkhead box transcription factor superfamily, which consists of more than 50 members sharing a conserved winged-helix DNAbinding domain. FOXM1 is a proliferation-specific transcription factor whose expression is correlated with the proliferative ability of cells [16]. FOXM1 is well known to be a key cell-cycle regulator for both transition from G1 to S phase and progression from G2 phase to mitosis [17]. Increasing evidence suggests that FOXM1 expression is substantially elevated in most human malignancies, such as glioblastoma, lung cancer, hepatocellular carcinoma (HCC), breast cancer, and pancreatic cancer, and plays a crucial role in tumorigenesis, angiogenesis, invasion, and metastasis [17-23]. Also, several recent studies suggested that FOXM1 is involved in self-renewal and proliferation of CSCs [15,24,25]. However, the molecular mechanisms by which FOXM1 signaling regulates PCSCs in pancreatic cancer development and progression remain poorly understood. A deeper comprehension of PSCSs would likely provide a new perspective on and increased understanding of the mechanisms that govern the development of pancreatic cancer. In this review, we briefly describe the crucial role of FOXM1 in 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. The roles of FOXM1 and signaling pathways in the early stages of pancreatic ductal adenocarcinoma development 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 lesion (...truncated)