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      Cancer stem cells may contribute to the difficulty in treating cancer

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          Abstract

          Tumour heterogeneity is a phenomenon where each cell that makes up a tumour, contains mutations that differ from that of other cells in the tumour. The clonal evolution and cancer stem cell theories of cancer formation, have been used to explain tumour heterogeneity. The theories both point to the existence of cells within a tumour that are capable of initiating the tumour in a different location. While the clonal evolution theory argues that all cells within a tumour possess this ability, the cancer stem cell theory argues that only a few cells (cancer stem cells or CSCs) within the tumour possess this ability to seed the tumour in a different location. Data supporting the cancer stem cell theory is accumulating. Researchers have targeted these CSCs therapeutically, hypothesizing that since these CSCs are the ‘drivers’ of tumour progression, their death may inhibit tumour progression. This was foiled by tumour cell plasticity, a phenomenon whereby a non-CSC spontaneously de-differentiates into a CSC. Researchers are now working on combinations that kill both CSCs and non-CSCs as well as drugs that prevent non-CSC-to-CSC transition. This review concisely describes CSCs and how they contribute to the difficulty in treating cancer.

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          Principles of tumor suppression.

          Molecular genetic studies of familial cancer syndromes identified and defined the recessive nature of tumor suppressor genes and resolved the paradox of why tumors arising in such families exhibited an autosomally dominant pattern of inheritance. Subsequent characterization of tumor suppressor proteins revealed their widespread involvement in sporadic cancers and pinpointed key mechanisms that protect animals against tumor development. We now recognize that tumor suppressor genes regulate diverse cellular activities, including cell cycle checkpoint responses, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumor angiogenesis. Their study has become a centerpiece of contemporary cancer research.
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            Cell plasticity and heterogeneity in cancer.

            Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies. © 2012 American Association for Clinical Chemistry
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              Cancer stem cell targeted therapy: progress amid controversies

              Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                10 February 2016
                March 2016
                10 February 2016
                : 3
                : 1
                : 7-10
                Affiliations
                [1]Department of Biochemistry, University of Benin, P.M.B. 1154, Edo State, Nigeria
                Article
                S2352-3042(16)00004-0
                10.1016/j.gendis.2016.01.001
                6153461
                a26f506a-77a1-4869-804d-6f207f91fd6c
                Copyright © 2016, Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 10 December 2015
                : 8 January 2016
                Categories
                Article

                cancer stem cells,chemotherapy,de-differentiation,metastasis,tumour heterogeneity,tumour cell plasticity

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