Circadian clock regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions in glioma and breast cancer cells
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Abstract In malignant cells, some reports demonstrated that Side population (SP) cells expressed tumor-initiating activity, chemotherapy resistance and metastatic potential. We previously reported that SP cells play a pivotal role of local invasion and in vivo liver metastasis in pancreatic cancer (Int-J-Cancer 124:2771, 2009). The augmentation of metastatic activity in SP cells appeared to relate to epithelial-to-mesenchymal transition (EMT), as SP cells were highly responsive to TGF-beta-mediated EMT and local invasion. However, the mechanisms by which SP cells undergo EMT in vivo remains unknown. Cancer associate fibroblasts (CAFs) have recently been implicated in important aspects of epithelial solid tumor biology, considered migrate to tumor sites and contribute to neoplastic progression, tumor growth, angiogenesis, and invasion/metastasis. In addition, recent reports have demonstrated that CAFs are derived from hematopoietic precursor/stem cells from bone marrow. Thus, bone marrow derived mesenchymal stem cells (MSCs) would be an attractive candidate for CAFs which enhance cancer metastasis by mediating EMT. The AIM of present study is to examine whether bone marrow-derived MSCs have ability to mediate EMT of pancreatic cancer SP cells. METHODS: Human bone marrow-derived MSCs were isolated by flowcytometry. Panc-1 cells were co-cultured with or without MSCs, and tumorigenesity was compared by implantation into NOD/SCID mice. Either unsorted panc-1 cells or Panc-1-derived SP cells were co-cultured in the presence or absence of MSCs using transwell culture dish for 7 days. Invasion activity was assessed by using matrigel invasion assay. In addition, real-time PCR experiments were performed to quantitate E-cadherin mRNA levels. RESULTS: When Panc-1 cells were mixed with MSCs and co-injected into NOD/SCID mice, tumorigenic activity was enhanced as compared to single injection of the equivalent number of cancer cells. In vitro co-culturing with MSCs changed the shape of Panc-1-derived SP cells to spindle-like appearance. The cell-to-cell contact underwent loosely, these morphological changes were consistent with EMT. E-cadherin mRNA levels were decreased after co-culturing. In addition, SP cell matrigel invasion activity was enhanced by co-culturing with MSCs. Similar results were observed in SP cells when EMT was induced by incubation in the presence of TGF-beta, a known inducer of EMT. It was surprising that when SP cells were co-incubated with MSCs, most of the cells fell into non-SP fraction by re-analysis of Hoechst33342 staining. This alteration was reversible as the cells recovered SP-phenotype by removing the MSCs. In CONCLUSION, MSC-derived soluble factors may induce EMT which is concordant with augmentation of invasion activity in metastatic SP cells. The SP-phenotype appears to be transient and reversible, which could be regulated by MSC-derived factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4102.
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Abstract Breast cancer in advanced stages tends to develop metastases and / or chemoresistance, in both cases therapeutic options are limited and have low probability of success, which represents the biggest obstacle in reducing mortality from this disease. There is a close connection between the Epithelial-Mesenchymal Transition (EMT) process of cancer cells and the acquisition of invasive and metastatic ability. Numerous EMT mediators have been described in cancer and among them miRNAs play a fundamental role in regulating such process, suggesting that it could be a therapeutic target to address this phenotype. Curcumin (diferuloylmethane) is a derivative compound of Curcuma longa that has therapeutic properties in various cancers as blocking initiation and tumor progression through its anti-inflammatory, antioxidant, proapoptotic, antiangiogenic and antimetastatic effects. The role of curcumin on EMT in non-cancerous breast cells MCF-10F and in breast cancer cell lines MCF-7 and MDA-MB-231 was evaluated. This work shows that in all these cell lines curcumin induced the expression of tumor suppressor microRNA miR-34a and repressed the expression of several genes involved in EMT and metastasis as Axl, Slug, Twist, N-cadherin, vimentin, fibronectin, among others. Consequently, curcumin inhibited the migration and invasiveness in these cells, irrespective of the expression of estrogen and progesterone receptors and p53 mutational status. Blockade of miR-34a by transfection with antagomiR-34a inhibited the effect of curcumin on EMT genes and on the migratory/invasive potential of cells indicating that miR-34a plays a central role in the Curcumin-mediated suppression of EMT and invasion. Therefore, results confirm the suppressive effect of curcumin on EMT and invasion in breast cancer cells, showing that such substance exerts this effect by inducing expression of miRNA miR-34a and consequently the repression of several of its target genes. Supported by Tarapacá University, Arica, Chile (GMC). Citation Format: Marcela Gallardo, Richard Ponce-Cusi, Gloria M. Calaf. Curcumin inhibits epithelial-mesenchymal transition and invasion in breast cancer cells by controlling miR-34a expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1478. doi:10.1158/1538-7445.AM2017-1478
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Epithelial ovarian carcinoma
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Cancer Drug Resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. Both clinical and experimental aspects of drug resistance in cancer are included.
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Background: Breast cancer is the leading cause of cancer-related death in Mexico, with most deaths being related to locally advanced or metastatic disease at diagnosis.Epithelial-mesenchymal transition (EMT) is one of the steps that are indispensable for metastasis.Different factors trigger EMT, like TGF-β, EGF and interleukin 6 (IL-6), among others.EMT is characterized by E-cadherin expression loss and N-cadherin and vimentin expression.In this study, we investigated the role of IL-6 on EMT induction.Methods: MBCDF and MBCD17 primary breast cancer cell cultures were used.E-cadherin expression was measured by Western Blot.Cells were stimulated with IL-6 to induce EMT.STAT3 activation was measured using phospho-specific antibodies, and E-cadherin expression was measured as EMT marker.Results: MBCDF and MBCD17 primary breast cancer cell cultures stimulation with IL-6 induced STAT3-Tyr705 phosphorylation without its total levels being altered; in addition, IL-6 cell-stimulation was shown to induce EMT, as evidenced by E-cadherin loss.Conclusions: The results of the present work suggest that IL-6 induces EMT in primary breast cancer cell cultures through STAT3 phosphorylation.(creativecommons.
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