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      Modular Cre/lox System and Genetic Therapeutics for Colorectal Cancer

      review-article
      *
      Journal of Biomedicine and Biotechnology
      Hindawi Publishing Corporation

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          Abstract

          The Cre/lox system is a powerful tool for targeting therapeutic effectors in a wide variety of human disorders. I review a Cre/lox Wnt-targeted system that has shown promise against Wnt-positive colorectal cancer cell lines. In addition to Wnt-specific targeting of cell death inducers, the modular nature of this gene therapy model system can be exploited by designing positive and negative feedback loops to either amplify or inhibit Wnt activity for experimental or therapeutic benefit. I discuss the structural components and performance parameters of the system, the implication of these findings with respect to cancer stem cells, as well as the general applicability of this system to any disorder characterized by differential gene expression. I also consider the issue of gene delivery as well as in vivo testing requirements necessary for the further characterization and development of this system.

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          Most cited references55

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          Lessons from hereditary colorectal cancer.

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            Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression.

            The dissemination of tumour cells is the prerequisite of metastases and is correlated with a loss of epithelial differentiation and the acquisition of a migratory phenotype, a hallmark of malignant tumour progression. A stepwise, irreversible accumulation of genetic alterations is considered to be the responsible driving force. But strikingly, metastases of most carcinomas recapitulate the organization of their primary tumours. Although current models explain distinct and important aspects of carcinogenesis, each alone can not explain the sum of the cellular changes apparent in human cancer progression. We suggest an extended, integrated model that is consistent with all aspects of human tumour progression - the 'migrating cancer stem (MCS)-cell' concept.
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              FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.

              Using the cytoplasmic domain of Fas in the yeast two-hybrid system, we have identified a novel interacting protein, FADD, which binds Fas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8. FADD contains a death domain homologous to the death domains of Fas and TNFR-1. A point mutation in FADD, analogous to the lpr mutation of Fas, abolishes its ability to bind Fas, suggesting a death domain to death domain interaction. Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme. These findings suggest that FADD may play an important role in the proximal signal transduction of Fas.
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                Author and article information

                Journal
                J Biomed Biotechnol
                JBB
                Journal of Biomedicine and Biotechnology
                Hindawi Publishing Corporation
                1110-7243
                1110-7251
                2009
                30 September 2009
                : 2009
                : 358230
                Affiliations
                Department of Basic Sciences, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA
                Author notes
                *Michael Bordonaro: mbordonaro@ 123456tcmedc.org

                Recommended by Phillip Bird

                Article
                10.1155/2009/358230
                2754659
                19809520
                3c2236b6-77b1-456b-a57f-82e089b1801f
                Copyright © 2009 Michael Bordonaro.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 March 2009
                : 9 June 2009
                : 15 July 2009
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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