Roles of Tumor Suppressor Signaling on Reprogramming and Stemness Transition in Somatic Cells (original) (raw)
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Rapid progress made in various areas of regenerative medicine in recent years occurred both at the cellular level, with the Nobel prize-winning discovery of reprogramming (generation of induced pluripotent stem (iPS) cells) and also at the biomaterial level. The use of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 (called commonly "Yamanaka factors") for the conversion of differentiated cells, back to the pluripotent/embryonic stage, has opened virtually endless and ethically acceptable source of stem cells for medical use. Various types of stem cells are becoming increasingly popular as starting components for the development of replacement tissues, or artificial organs. Interestingly, many of the transcription factors, key to the maintenance of stemness phenotype in various cells, are also overexpressed in cancer (stem) cells, and some of them may find the use as prognostic factors. In this review, we describe various methods of iPS creation, followed by over...
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The cancer stem cell (CSC) hypothesis is an evolving concept of oncogenesis that has recently gained wide acceptance. By definition, CSCs exhibit continuous proliferation and self-renewal, and they have been proposed to play significant roles in oncogenesis, tumor growth, metastasis, chemoresistance, and cancer recurrence. The reprogramming of cancer cells using induced pluripotent stem cell (iPSC) technology is a potential strategy for the identification of CSC-related oncogenes and tumorsuppressor genes. This technology has some advantages for studying the interactions between CSC-related genes and the cancer microenvironment. This approach may also provide a useful platform for studying the mechanisms of CSCs underlying cancer initiation and progression. The present review summarizes the recent advances in cancer cell reprogramming using iPSC technology and discusses its potential clinical use and related drug screening. Cancer stem cells (CSCs) have been recognized as a small subset of cells within a tumor that are endowed with stem cell-like properties, including the abilities of self-renewal, pluripotency, cancer generation and drug resistance (1-7). The primary strategy used for inducing CSCs is to enrich the cells using classical stem cell markers such as CD13, CD24, CD44, CD47, CD90 and CD133, followed by other techniques including side-population analysis, sphere formation, and so on (8-11). This cell population is then transplanted into immunodeficient SCID mice to examine its in vivo tumorigenic potential (7-9). Such cells are examined further according to their cancer markers such as WNT, Notch, Hedgehog, transforming growth factor β, epithelial-mesenchymal transition (EMT)/mesenchymalepithelial transition (MET) signaling proteins, and epigenetic factors (12-15). Putative CSC subpopulations that are capable of initiating tumor development at a lower cell number are tested for self-renewal capacity using serial dilutions of cells to identify the CSCs. In addition to these classical techniques, some techniques, such as reprogramming, are now a research focus, although the driver and the passenger mutation are present in the genome (12-15). Current cancer cell-reprogramming techniques such as somatic cell nuclear transfer (16) and the generation of induced pluripotent stem cells (iPSCs) (17-19), are used to identify oncogenes, anti-oncogenes and epigenomes. The breakthrough came in 2006, when Takahashi and Yamanaka introduced the concept of iPSCs by generating stem cells 3367 This article is freely accessible online.
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Recent studies in the field of cancer stem cells have revealed that the alterations in key gene products involved in the epithelial-mesenchymal transition (EMT) program, altered metabolic pathways such as enhanced glycolysis, lipogenesis and/or autophagy and treatment resistance may occur in cancer stem/progenitor cells and their progenies during cancer progression. Particularly, the sustained activation of diverse developmental cascades such as hedgehog, epidermal growth factor receptor (EGFR), Wnt/β-catenin, Notch, transforming growth factor-β (TGF-β)/TGF-βR receptors and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) can play critical functions for high self-renewal potential, survival, invasion and metastases of cancer stem/progenitor cells and their progenies. It has also been observed that cancer cells may be reprogrammed to re-express different pluripotency-associated stem cell-like markers such as Myc, Oct-3/4, Nanog and Sox-2 along the EMT process and under stressful and hypoxic conditions. Moreover, the enhanced expression and/or activities of some drug resistance-associated molecules such as Bcl-2, Akt/molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), hypoxia-inducible factors (HIFs), macrophage inhibitory cytokine-1 (MIC-1) and ATP-binding cassette (ABC) multidrug transporters frequently occur in cancer cells during cancer progression and metastases. These molecular events may cooperate for the survival and acquisition of a more aggressive and migratory behavior by cancer stem/progenitor cells and their progenies during cancer transition to metastatic and recurrent disease states. Of therapeutic interest, these altered gene products may also be exploited as molecular biomarkers and therapeutic targets to develop novel multitargeted strategies for improving current cancer therapies and preventing disease relapse.
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While standard therapies can lead to an initial remission of aggressive cancers, they are often only a transient solution. The resistance and relapse that follows is driven by tumor heterogeneity and therapy-resistant populations that can reinitiate growth and promote disease progression. There is thus a significant need to understand the cell types and signaling pathways that not only contribute to cancer initiation, but also those that confer resistance and drive recurrence. Here, we discuss work showing that stem cells and progenitors may preferentially serve as a cell of origin for cancers, and that cancer stem cells can be key in driving the continued growth and functional heterogeneity of established cancers. We also describe emerging evidence for the role of developmental signals in cancer initiation, propagation, and therapy resistance and discuss how targeting these pathways may be of therapeutic value.
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Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.