Cells in focus
Cancer stem cells

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Abstract

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. A number of cell surface markers such as CD44, CD24, and CD133 are often used to identify and enrich CSCs. A regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways controls CSC properties. The clinical relevance of CSCs has been strengthened by emerging evidence, demonstrating that CSCs are resistant to conventional chemotherapy and radiation treatment and that CSCs are very likely to be the origin of cancer metastasis. CSCs are believed to be an important target for novel anti-cancer drug discovery. Herein we summarize the current understanding of CSCs, with a focus on the role of miRNA and epithelial–mesenchymal transition (EMT), and discuss the clinical application of targeting CSCs for cancer treatment.

Introduction

Stem cells are characterized by the capacity for self-renewal and the ability to differentiate into diverse specialized cell types. This concept has been extended from the embryonic stem cells (ESCs) and adult stem cells to cancer stem cells (CSCs) and induced pluripotent stem (IPS) cells. Through self-renewal, more stem cells are generated which maintain an undifferentiated status. Through differentiation, stem cells give rise to a mature cell type. Embryonic stem cells are capable of differentiating into all tissues during embryonic development. Adult stem cells play important roles in replenishing and repairing adult tissues (Lawson et al., 2009). Researchers have successfully reprogrammed somatic cells into stem-like cells – known as induced pluripotent stem cells (iPSCs) – which share many of the characteristics of ESCs (Takahashi and Yamanaka, 2006). Emerging evidence has indicated a subpopulation of stem-like cells within tumors, known as CSCs, which exhibit characteristics of both stem cells and cancer cells. In addition to self-renewal and differentiation capacities, CSCs have the ability to seed tumors when transplanted into an animal host. CSCs can be distinguished from other cells within the tumor by symmetry of their cell division and alterations in their gene expression (Rosen and Jordan, 2009).

microRNAs (miRNAs) are a class of non-coding small RNAs that are single-stranded with ∼20 nt in length. miRNAs regulate the stability or translational efficiency of targeted messenger RNAs through complementary interaction with the 3′ untranslated region of target genes. Over 1000 mammalian miRNAs have been identified or predicted from mammals. It is predicted that one miRNA can target hundreds of genes. The expression of about one-third of human genes is regulated by multiple miRNAs. miRNAs have been demonstrated to regulate a broad range of biological processes including embryonic development, cell cycle, cell proliferation, tumor initiation and progression, cancer metastasis, self-renewal, and differentiation of stem cells (Yu et al., 2010a).

The role for miRNA in regulating stem cells was implicit in the original discovery of miRNA. The first two miRNAs discovered, lin-4 and let-7, are involved in regulating the timing of larval to adult cell fates in Caenorhabditis elegans (Lee et al., 1993, Reinhart et al., 2000). Expression of lin-4 and let-7 was undetectable in the early embryo, increased at late larval stage, and was highly expressed in the adult stage – indicating a potential role in promoting embryonic cell differentiation. Since the identification of miRNAs that were exclusively expressed in ES cells by the Sharp Laboratory (Houbaviy et al., 2003), a role for specific miRNA in stem cell iPSCs and CSCs, has been described. miRNAs are differentially expressed in ES cells (Houbaviy et al., 2003). Key ES cell transcription factors are associated with promotors for miRNAs that are preferentially expressed in ES cells (Marson et al., 2008). Analysis of miRNA in human breast CSCs (hBCSCs) demonstrated concordant regulation of a subset of miRNA in hBCSCs and embryonal carcinoma cells (Shimono et al., 2009). Subsequent studies revealed both similarities, but also distinguishable differences in the miRNA expression profiles of human iPSCs and human ESCs. Interestingly, these studies identify important differences between pluripotent cells and cancer cells. Collectively, these studies suggest both similarities and differences between subsets of stem cell states and cancer with emerging patterns, which are discussed further in Section 3.

Section snippets

Cancer stem cells

The first modern evidence for a role of stem cells in cancer came in 1994 with a study of human acute myeloid leukemia (Lapidot et al., 1994), in which an AML-initiating cell population was identified from AML patients by transplantation into severe combined immune-deficient (SCID) mice. The leukemia-initiating cells were enriched on the basis of cell surface marker expression (CD34+/CD38). In 2003, human CSCs were identified in solid tumors, including breast (Al-Hajj et al., 2003) and brain

Signaling pathways and miRNA regulation of stem cells

CSC self-renewal and differentiation are tightly controlled by multiple regulatory networks, including cytokines from the cancer cell microenvironment. The function of several signaling pathways control cancer progression, including the hedgehog, Notch, and Wnt/β-catenin pathway has been previously reviewed (Reya and Clevers, 2005, DeSano and Xu, 2009). However, herein we review the relationship of these pathways to cellular polarity and cell division symmetry (Fig. 1A–E).

Wnt signaling plays an

Clinical relevance

CSCs are a novel cancer target. Hoey et al. (2009) developed antibodies against delta like 4 ligand (DLL4), a component of Notch signaling pathway. In a mouse model of human colon cancer, anti-DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, anti-DLL4, either alone or in combination with the chemotherapeutic agent irinotecan, reduced CSC function. Jin et al. (2009) applied a monoclonal antibody 7G3, to the IL-3 receptor alpha chain

Acknowledgments

This work was supported in part by grants R01CA070896, R01CA075503, R01CA132115, R01CA107382, R01CA086072 and P30CA056036 from NIH; grants from The Breast Cancer Research Foundation and the Dr. Ralph and Marian C. Faulk Medical Research Trust (R.G.P.); a grant from Pennsylvania Department of Health (R.G.P.) and grants 2012CB966800 from National Basic Research Program of China and 81172515 from Natural Science Foundation of China (to Yu, Z.). There are no conflicts of interest associated with

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