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      Calcein-effluxing human colon cancer cells are enriched for self-renewal capacity and depend on β-catenin

      1 , 1 , 2

      Oncotarget

      Impact Journals LLC

      cancer stem cell, beta-catenin, Wnt, side population, calcein, CloP, colon cancer

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          Abstract

          Putative cancer stem cells are a subpopulation of cancer cells that give rise to chemotherapy resistance and are therefore of prognostic and therapeutic interest, though their identification remains elusive in colon cancer due to lack of reliable and accurate markers. We previously identified a p53-dependent putative cancer stem cell population, the calcein low population (C loP), based on their exclusive efflux of the fluorescent dye Calcein. This functional identification method enables comparative live cell studies of subpopulations without differential toxicity that occurs with traditional Hoechst methods, which has confounded conclusions and limited the utility of this cancer stem cell marker. In this study, we examined the cancer stem cell-like properties of the C loP population in vivo in comparison with the parental and calcein-high population (C hiP) in human colon cancer xenografts. Serial dilution xenograft experiments in NOD/SCID mice revealed that the C loP is only marginally more tumorigenic compared to the C hiP or parental cells. However, serial passage of these tumors revealed that the C loP is uniquely enriched for self-renewal capacity in vivo compared to the other populations. Immunohistochemical analysis of these tumors revealed that the C loP possesses increased levels of nuclear β-catenin and furthermore, siRNA-mediated knockdown of β-catenin significantly reduced the C loP population. These findings highlight the C loP as an important subpopulation of tumor cells that are exclusively endowed with the ability to self-renew and propagate tumors. The dependency of the C loP on β-catenin provides a molecular explanation for this ability and suggests that this population can and should be therapeutically targeted by inhibition of Wnt signaling.

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          Most cited references 33

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          Cancer stem cells in solid tumours: accumulating evidence and unresolved questions.

          Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.
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            ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays.

            ELDA is a software application for limiting dilution analysis (LDA), with particular attention to the needs of stem cell assays. It is the first limiting dilution analysis software to provide meaningful confidence intervals for all LDA data sets, including those with 0% or 100% responses. Other features include a test of the adequacy of the single-hit hypothesis, tests for frequency differences between multiple data sets, and the ability to take advantage of cases where the number of cells in the sample is counted exactly. A webtool at http://bioinf.wehi.edu.au/software/elda/ provides an easy user interface.
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              Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.

              Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                February 2013
                18 February 2013
                : 4
                : 2
                : 184-191
                Affiliations
                1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute
                2 American Cancer Society, Atlanta, Georgia
                Author notes
                Correspondence to: Wafik S. El-Deiry, wafik.eldeiry@ 123456gmail.com
                3712565
                23468473
                Copyright: © 2013 Allen and El-Deiry

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Categories
                Research Paper

                Oncology & Radiotherapy

                colon cancer, clop, calcein, side population, wnt, beta-catenin, cancer stem cell

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