Metformin regulates breast cancer stem cello ntogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status

Vázquez-Martín, Alejandro; Oliveras‐Ferraros, Cristina; Cufí, Sílvia; Barco, Sonia Del; Martín-Castillo, Begoña; Menendez, Javier A.

doi:10.4161/cc.9.18.13131

Cited by 182 publications

(137 citation statements)

References 70 publications

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“…Metabolic reprogramming of cancer cells has also shown to trigger such an interconversion. 35,36 In keeping with our results, a recent study indicated that TMZ might induce mutations in pretreated tumors. 37 Through the analysis of 4 938 362 mutations from 7042 human cancers, the authors extracted 21 distinct mutational signatures.…”

Section: Discussionsupporting

confidence: 80%

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

et al. 2014

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Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.

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Section: Discussionsupporting

confidence: 80%

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

et al. 2014

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“…The targeting of the EMT phenomenon is, therefore, a promising therapeutic strategy to prevent and circumvent the de novo resistance to trastuzumab-based therapeutic regimens. 36,[79][80][81][82][83][84][85][86][87] the trastuzumab-sensitive SLUG/SNAIL2 KD-JIMT1 cells. Our findings favor a functional heterogeneity in the breast CS-like compartment and suggest that, in addition to the widely recognized CSCs with mesenchymal-like phenotypes, tumor-initiating cells with an epithelia-like morphology and functionality might be considered to understand better the breast cancer responses to molecularly targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

“…It is well-established that there are morphological differences in the mammospheres generated from different cell lines and different sources; e.g., mammospheres generated from CD44 + C24 -/low MDA-MB-231 mesenchymal cells form much looser structures of cell clumps compared with those derived from CD44 -CD24 + MCF-7 luminal cells. We made the unexpected observation that, unlike the loose, grapelike structures generated by mesenchymal breast cancer cells, 57 the mammospheres generated from the CD44 + C24 -/low -enriched basal/HER2+ JIMT1 parental cells were solid structures with a rounded phenotype (Fig. 8).…”

Section: Epithelial-to-mesenchymal Transition (Emt) Confers Primary Rmentioning

confidence: 98%

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

et al. 2012

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“…Additional support for metformin as a therapeutic agent comes from in vivo models where metformin seems to selectively inhibit CD44 þ /CD24 low cancer stem celllike populations (54), repress genes associated with epithelial to mesenchymal transition such as ZEB1 TWIST, SNAi1 (55), and work synergistically with chemotherapy agents (54). In addition, inhibition of glutamine metabolism, at least in prostate models, may synergize with metformin (56).…”

Section: Metforminmentioning

confidence: 99%

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson

2014

Clinical Cancer Research

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Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-ofopportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508-15. Ó2014 AACR.

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Metformin regulates breast cancer stem cello ntogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status

Cited by 182 publications

References 70 publications

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

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