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      SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer

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          Abstract

          Background

          The transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). Furthermore, SOX2 is a repressor of the transcriptional activity of β-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/β-catenin signalling pathway, indicated by nuclear expression of β-catenin, we wanted to investigate the expression patterns of SOX2 and β-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression.

          Methods

          The expression of SOX2 and β-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry.

          Results

          Elevated protein expression of SOX2 significantly correlated with the presence of lymph node- ( p = 0.006) and distant metastases ( p = 0.022). Nuclear β-catenin expression correlated significantly only with distant metastases ( p = 0.001). Less than 10% of cases showed a coexpression of high levels of β-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases ( p = 0.007) and distant spread ( p = 0.028).

          Conclusion

          We demonstrated that increased expression of either SOX2 or nuclear β-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.

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          Most cited references30

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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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            Module map of stem cell genes guides creation of epithelial cancer stem cells.

            Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.
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              A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

              Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2011
                14 December 2011
                : 11
                : 518
                Affiliations
                [1 ]Pathologisches Institut, Ludwig-Maximilians-Universität München, Munich, Germany
                [2 ]Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
                [3 ]Tumorregister München des Tumorzentrums München am Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie der Ludwig-Maximilians-Universität München, Munich, Germany
                [4 ]Institut für Medizinische Mikrobiologie und Immunologie, Technische Universität München, Munich, Germany
                Article
                1471-2407-11-518
                10.1186/1471-2407-11-518
                3267776
                22168803
                9cc82eb9-1adf-4aa8-a1a3-c501c70e4e59
                Copyright ©2011 Neumann et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 July 2011
                : 14 December 2011
                Categories
                Research Article

                Oncology & Radiotherapy
                metastasis,sox2,colon cancer,β-catenin
                Oncology & Radiotherapy
                metastasis, sox2, colon cancer, β-catenin

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