69
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of selective inhibitors of cancer stem cells by high-throughput screening.

          Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

            Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer.

              The cellular mechanisms underlying the increasing aggressiveness associated with ovarian cancer progression are poorly understood. Coupled with a lack of identification of specific markers that could aid early diagnoses, the disease becomes a major cause of cancer-related mortality in women. Here we present direct evidence that the aggressiveness of human ovarian cancer may be a result of transformation and dysfunction of stem cells in the ovary. A single tumorigenic clone was isolated among a mixed population of cells derived from the ascites of a patient with advanced ovarian cancer. During the course of the study, yet another clone underwent spontaneous transformation in culture, providing a model of disease progression. Both the transformed clones possess stem cell-like characteristics and differentiate to grow in an anchorage-independent manner in vitro as spheroids, although further maturation and tissue-specific differentiation was arrested. Significantly, tumors established from these clones in animal models are similar to those in the human disease in their histopathology and cell architecture. Furthermore, the tumorigenic clones, even on serial transplantation continue to establish tumors, thereby confirming their identity as tumor stem cells. These findings suggest that: (a) stem cell transformation can be the underlying cause of ovarian cancer and (b) continuing stochastic events of stem and progenitor cell transformation define the increasing aggression that is characteristically associated with the disease.
                Bookmark

                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                January 2014
                30 January 2014
                1 January 2014
                : 5
                : 1
                : e1039
                Affiliations
                [1 ]Departmemt of Pathology, Dalian Medical University , Dalian 116044, P.R. China
                [2 ]The Key Laboratory of Tumor Stem Cell Research of Liaoning province, Dalian Medical University , Dalian 116044, P.R. China
                [3 ]Academic Affair Department of Dalian Medical University , Dalian 116044, P.R. China
                [4 ]Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University , Guilin 541001, P.R. China
                Author notes
                [* ]Department of Pathology, Dalian Medical University , No. 9 West Section, Lvshun South Road, Dalian 116044, P.R. China. Tel/Fax: +86 411 8611 0299; E-mail: yr0806@ 123456hotmail.com (BS) or Tel/Fax: +86 411 8611 0050; E-mail: lilianhong0051@ 123456163.com (LL)
                Article
                cddis2013515
                10.1038/cddis.2013.515
                4040703
                24481453
                f0147b44-4be4-4953-be15-5e8938efb68e
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 05 September 2013
                : 01 November 2013
                : 04 November 2013
                Categories
                Original Article

                Cell biology
                wnt signaling,gastric cancer stem cells,salinomycin
                Cell biology
                wnt signaling, gastric cancer stem cells, salinomycin

                Comments

                Comment on this article