Chen, M. S. et al. Wnt/-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J. Cell Sci. 120, 468-477
ABSTRACT The COMMA-Dbeta-geo cell line has been shown to contain a permanent subpopulation of progenitor cells that are enriched in outgrowth potential. Using the COMMA-Dbeta-geo cell line as a model, we sought to study the radioresistance of mammary progenitor cells. Using the putative progenitor cell marker stem cell antigen 1 (Sca1), we were able to isolate a discrete subpopulation of Sca1(+) multipotent cells from the immortalized COMMA-Dbeta-geo murine mammary cell line. At a clinically relevant dose, the Sca1(+) cells were resistant to radiation (2 Gy). Sca1(+) cells contained fewer gamma-H2AX(+) DNA damage foci following irradiation, displayed higher levels of endogenous beta-catenin, and selectively upregulated survivin after radiation. Expression of active beta-catenin enhanced self-renewal preferentially in the Sca1(+) cells, whereas suppressing beta-catenin with a dominant negative, beta-engrailed, decreased self-renewal of the Sca1(+) cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-Dbeta-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.
- SourceAvailable from: Ling Tian
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- "However, a previous study has suggested that β-catenin-positive hepatocytes exhibit growth and survival advantages that allow them to repopulate β-catenin-null livers (Thompson et al., 2011). Furthermore, expression of active β-catenin enhances self-renewal of Sca1+ cells, which have been identified as the primary mammary gland progenitor cells, whereas suppressing β-catenin decreases selfrenewal of the Sca1+ cells (Chen et al., 2007). Therefore, the Wnt pathway has been recognized as an attractive target for directed antistem-cell and anti-self-renewal therapeutics (Behbod and Rosen, 2005). "
ABSTRACT: Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, while luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 cells significantly stimulated the repopulation of their living cells. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the activated nuclear β-catenin was significantly decreased. Wnt agonist 68166 significantly decreased, whereas Wnt antagonist significantly increased repopulation in HT29 and Panc1 tumor cells in a dose dependent manner. β-catenin shRNA significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1, hedgehog, and Gli1 were increased in irradiated cells. Our results highlighted the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggested that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation.Disease Models and Mechanisms 04/2015; 8(4):385-391. DOI:10.1242/dmm.018887 · 4.97 Impact Factor
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- "The Wnt/β-catenin pathway can be aberrantly activated by irradiation exposure, resulting in the accumulation of β-catenin in the cytoplasm, its subsequent translocation into the nucleus, and the transcription of β-catenin target genes . This aberrant activation of the Wnt/β-catenin pathway has been implicated in radioresistance of solid tumors such as glioblastoma , breast cancer , and head and neck cancer . But the mechanism by which the Wnt pathway contributes to radioresistance is unclear. "
ABSTRACT: Cancer cells that survive fractionated irradiation can be radioresistant and cause tumor recurrence. However, the molecular mechanisms underlying the development of radioresistance in cancer cells remain elusive. The aim of this study was to investigate the role of WISP-1 in the development of radioresistance in esophageal carcinoma during fractionated irradiation. Radioresistant esophageal cancer cells were generated from normal esophageal cancer cells via fractionated irradiation, and expression levels of related proteins were determined by Western blot. Radiosensitivity of cells was established by clonogenic cell survival assays, and cell cycle distribution was evaluated by flow cytometry. Protein distributions were determined by immunofluorescence, and cell toxicity was evaluated by cell counting kit-8 assays. In vivo validations were performed in a xenograft transplantation mouse model. Our data indicate that WISP-1 plays an important role in the development of radioresistance in esophageal cancer cells during fractionated irradiation. The overexression of WISP-1 in esophageal cancer cells was associated with radioresistance. Depletion of extracellular WISP-1 by antibody neutralizing reversed radioresistance and directly induced mitotic catastrophe resulting in cell death. WISP-1 may be a candidate therapeutic target in the treatment of recurrent esophageal carcinoma after radiotherapy.PLoS ONE 04/2014; 9(4):e94751. DOI:10.1371/journal.pone.0094751 · 3.23 Impact Factor
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- "This event promoted the translocation of β-catenin from the cytosol to the nucleus, which increased transcriptional activity of the Wnt/β-catenin pathway, leading to radiation resistance . Other preclinical investigations have shown that radiation may enrich progenitor cells with an activated Wnt/β-catenin signalling pathway, which leads to the development of radiation resistance in breast cancer cells . Finally, in head and neck cancer cell lines, radiation has been shown to induce the translocation of β-catenin to the nucleus, conferring radiation resistance through upregulation of Ku expression . "
ABSTRACT: Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/beta-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of beta-catenin/E-cadherin, and to determine whether these changes are associated with survival. The Immunohistochemical expression of nuclear beta-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis. CRT induced significant changes in the expression of nuclear beta-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear beta-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear beta-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear beta-catenin expression after CRT almost reached the cut-off for significance (p = 0.06). In our study, preoperative CRT for LARC induced significant changes in nuclear beta-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.BMC Cancer 03/2014; 14(1):192. DOI:10.1186/1471-2407-14-192 · 3.36 Impact Factor