Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties

Paranjape, Anurag N.; Mandal, Tamoghna; Mukherjee, Geetashree; Kumar, Manish; Sengupta, Kundan; Rangarajan, Annapoorni

doi:10.1038/onc.2011.378

Cited by 30 publications

(35 citation statements)

References 38 publications

(45 reference statements)

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“…In fact, simply overexpressing certain oncogenic molecules (e.g., Nanog, CD44, Twist, hTERT, etc) is sufficient to reprogram primary non-tumorigenic cells or bulk cancer cells into stem-like cancer cells [136][137][138][139][140][141]. These latter observations [136][137][138][139][140][141] are consistent with the observations that such 'stemness' molecules are most frequently expressed in undifferentiated tumor cells. Finally, as CSCs constantly interact with their microenvironment, protumorigenic alterations in the microenvironment (e.g., in stromal cells) will likely affect CSC properties and promote plasticity in CSC progeny [142,143].…”

Section: Intrinsic and Induced Plasticity In Csc Progenysupporting

confidence: 79%

“…Experimental EMT and inflammatory cytokines IL-6, IL-8, TGFβ, and TNFα can all promote the manifestation of CSC phenotypes and properties [130][131][132][133][134][135]. In fact, simply overexpressing certain oncogenic molecules (e.g., Nanog, CD44, Twist, hTERT, etc) is sufficient to reprogram primary non-tumorigenic cells or bulk cancer cells into stem-like cancer cells [136][137][138][139][140][141]. These latter observations [136][137][138][139][140][141] are consistent with the observations that such 'stemness' molecules are most frequently expressed in undifferentiated tumor cells.…”

Section: Intrinsic and Induced Plasticity In Csc Progenymentioning

confidence: 99%

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Understanding cancer stem cell heterogeneity and plasticity

2012

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Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

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Section: Intrinsic and Induced Plasticity In Csc Progenysupporting

confidence: 79%

Section: Intrinsic and Induced Plasticity In Csc Progenymentioning

confidence: 99%

Understanding cancer stem cell heterogeneity and plasticity

2012

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“…NBLE and NBLE-derived cells were cultured as described previously [36] in DMEM-F12 with growth factors (10 ng/ml hEGF, 1 mg/ml hydrocortisone, 10 mg/ml insulin, 4 ng/ml heparin) (Sigma Aldrich) and B27 (Invitrogen, Carlsbad, CA, USA). HMLE and HMLE-Bmi1 cells were cultured in DMEM-F12 media with 10 ng/ml hEGF, 0.5 μg/ml hydrocortisone, and 10 μg/ml insulin (Sigma Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

et al. 2014

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BackgroundThe Bmi1 polycomb ring finger oncogene, a transcriptional repressor belonging to the Polycomb group of proteins plays an important role in the regulation of stem cell self-renewal and is elevated in several cancers. In the current study, we have explored the role of Bmi1 in regulating the stemness and drug resistance of breast cancer cells.MethodsUsing real time PCR and immunohistochemistry primary breast tissues were analyzed. Retro- and lentiviruses were utilized to overexpress and knockdown Bmi1, RT-PCR and Western blot was performed to evaluate mRNA and protein expression. Stemness properties were analyzed by flow cytometry and sphere-formation and tumor formation was determined by mouse xenograft experiments. Dual luciferase assay was employed to assess promoter activity and MTT assay was used to analyze drug response.ResultsWe found Bmi1 overexpression in 64% of grade III invasive ductal breast adenocarcinomas compared to normal breast tissues. Bmi1 overexpression in immortalized and transformed breast epithelial cells increased their sphere-forming efficiency, induced epithelial to mesenchymal transition (EMT) with an increase in the expression of stemness-related genes. Knockdown of Bmi1 in tumorigenic breast cells induced epithelial morphology, reduced expression of stemness-related genes, decreased the IC50 values of doxorubicin and abrogated tumor-formation. Bmi1-high tumors showed elevated Nanog expression whereas the tumors with lower Bmi1 showed reduced Nanog levels. Overexpression of Bmi1 increased Nanog levels whereas knockdown of Bmi1 reduced its expression. Dual luciferase promoter-reporter assay revealed Bmi1 positively regulated the Nanog and NFκB promoter activity. RT-PCR analysis showed that Bmi1 overexpression activated the NFκB pathway whereas Bmi1 knockdown reduced the expression of NFκB target genes, suggesting that Bmi1 might regulate Nanog expression through the NFκB pathway.ConclusionsOur study showed that Bmi1 is overexpressed in several high-grade, invasive ductal breast adenocarcinomas, thus supporting its role as a prognostic marker. While Bmi1 overexpression increased self-renewal and promoted EMT, its knockdown reversed EMT, reduced stemness, and rendered cells drug sensitive, thus highlighting a crucial role for Bmi1 in regulating the stemness and drug response of breast cancer cells. Bmi1 may control self-renewal through the regulation of Nanog expression via the NFκB pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-785) contains supplementary material, which is available to authorized users.

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“…Indeed, work from our laboratory has shown that in vitro transformation of normal human mammary epithelial cells (HMECs) growing in suspension as mammospheres (that are enriched in stem/progenitor cells) required fewer genetic elements for transformation (Paranjape et al 2012) compared to those growing in adherent conditions (Elenbaas et al 2001) that favour differentiation.…”

Section: Stem Cells and Cancermentioning

confidence: 99%

Competing views on cancer

et al. 2014

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Despite intense research efforts that have provided enormous insight, cancer continues to be a poorly understood disease. There has been much debate over whether the cancerous state can be said to originate in a single cell or whether it is a reflection of aberrant behaviour on the part of a ‘society of cells’. This article presents, in the form of a debate conducted among the authors, three views of how the problem might be addressed. We do not claim that the views exhaust all possibilities. These views are (a) the tissue organization field theory (TOFT) that is based on a breakdown of tissue organization involving many cells from different embryological layers, (b) the cancer stem cell (CSC) hypothesis that focuses on genetic and epigenetic changes that take place within single cells, and (c) the proposition that rewiring of the cell’s protein interaction networks mediated by intrinsically disordered proteins (IDPs) drives the tumorigenic process. The views are based on different philosophical approaches. In detail, they differ on some points and agree on others. It is left to the reader to decide whether one approach to understanding cancer appears more promising than the other.

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Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties

Cited by 30 publications

References 38 publications

Understanding cancer stem cell heterogeneity and plasticity

Understanding cancer stem cell heterogeneity and plasticity

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

Competing views on cancer

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