Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells

Blum, Walter; Pecze, László; Felley‐Bosco, Emanuela; Wu, Licun; Perrot, Marc de; Schwaller, Beat

doi:10.1016/j.stemcr.2017.02.005

Cited by 29 publications

(39 citation statements)

References 34 publications

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“…These values are almost identical to the ones previously observed after transduction with the Hotta construct (10,16), i.e. 4.8% and 7.1%, respectively (7). Sufficiently high expression levels of endogenous Sox2 and Oct4 drive eGFP expression, which allowed to identifying CSC.…”

Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -supporting

confidence: 86%

“…The eGFP-(+) MM cells have also a higher tumor-initiating capacity in vivo, as well as an increased resistance to cisplatin treatment in vitro. They show a higher tumorsphere-and colony-forming capacity and moreover the ability to convert (differentiate) into bulk cancer cells (7).…”

Section: Discussionmentioning

confidence: 99%

“…In longterm MM cell cultures (>2 months) the proportion of eGFP(+) cells varied to some extent, which we attributed to "biological noise"; however no timedependent trends towards either higher or lower proportion of eGFP(+) cells was observed (data not shown). After 2 weeks in culture part of ZL55-SO and RN5-SO were sorted as described above and resulted in ZL55-SO low , ZL55-SO high , RN5-SO low and RN5-SO high cell populations, characterized by either complete absence of eGFP ( low : eGFP(-)) or essentially 100% of eGFP(+) ( high ) cells, respectively as reported before (7). In the population of ZL55-SO high and RN5-SO high cells, mRNA expression levels of the stem cell markers Sox2 and Oct4, as well as other markers (Aldh1, Klf4, Nanog and c-Myc) were elevated as reported before (7).…”

Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -mentioning

confidence: 99%

“…After 2 weeks in culture part of ZL55-SO and RN5-SO were sorted as described above and resulted in ZL55-SO low , ZL55-SO high , RN5-SO low and RN5-SO high cell populations, characterized by either complete absence of eGFP ( low : eGFP(-)) or essentially 100% of eGFP(+) ( high ) cells, respectively as reported before (7). In the population of ZL55-SO high and RN5-SO high cells, mRNA expression levels of the stem cell markers Sox2 and Oct4, as well as other markers (Aldh1, Klf4, Nanog and c-Myc) were elevated as reported before (7). Real-time cell growth curves obtained by live cell imaging of -SO low and -SO high cells revealed that SO high generally grew slower than SO low cells (Fig.…”

Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -mentioning

confidence: 99%

“…Sox2, Oct4 and Nanog, are considered as transcriptional regulators of the core circuitry in the control of the stem cell state (9). In comparison to non-CSC we have shown before that MM CSC possess different properties with respect to several clinically relevant parameters including chemoresistance in vitro and tumor initiating capacities in vivo (7). The Sox2/Oct4-reporter system, initially developed for the convenient identification of induced pluripotent cells (10), has been successfully applied to visualize early stages of cellular reprogramming (11) and in our case in MM cell lines to identify, isolate and visualize CSC by the expression of eGFP (7).…”

mentioning

confidence: 99%

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Biological noise and positional effects influence cell stemness

Blum

Henzi

Schwaller

et al. 2018

Journal of Biological Chemistry

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Biological (or cellular) noise is the random quantitative variability of proteins and other molecules in individual, genetically identical cells. As the result of biological noise in the levels of some transcription factors that determine a cell's differentiation status, differentiated cells may dedifferentiate to a stem cell state given a sufficiently long time period. Here, to provide direct evidence supporting this hypothesis, we used a live-cell monitoring system based on eGFP expression to continuously assess the "stemness" of individual human and murine malignant mesothelioma (MM) cells over a period of up to 3 months. Re-expression of the transcription factors, the top hierarchical stemness markers SRY-box 2 (Sox2) and octamer-binding transcription factor (Oct4), monitored as cells' eGFP expression was observed in a subpopulation of differentiated eGFP(-) MM cells. However, we found that this transition was extremely rare. Of note, when it did occur, neighboring cells that were not direct descendants of a newly emerged eGFP(+) stem cell were more likely than non-neighboring cells to also become an eGFP(+) stem cell. This observation suggested a positional effect and led to a clustered "mosaic" reappearance of eGFP(+) stem cells. Moreover, stem cells reappeared even in cell cultures derived from one single differentiated eGFP(-) cell. On the basis of our experimental in vitro and in vivo findings, we developed a tumor growth model to predict the clustered localization of cancer stem cells within a tumor mass.Regarding the heterogeneity with respect to differentiation, cancer cell populations consist of cancer stem cells (CSC) and a majority of non-CSC or 'bulk' cancer cells. It is hypothesized that essentially the CSC subpopulation possesses the capability of tumor initiation and has the capacity for self-renewal (1,2). Two main theories were initially developed to explain the distribution of CSC within a tumor: the hierarchical and the stochastic model (1). The hierarchical model suggests that the pool of CSC can only be maintained by cells that have CSC characteristics and by definition, the ability to give rise to progeny with unlimited proliferative capacity. Thus, tumors contain: I) proliferating CSC that The cells in such a tumor do not operate in a deterministic, "well-organized" system -any cell has the same intrinsic potential to contribute to tumor growth. Unlike in the hierarchical model, the stochastic model predicts that CSC are not necessarily and exclusively derived from the CSC cell population. Currently, there is no definitive proof in favor of either model of tumor growth. The development of different cancer types may be explained in different ways; leukemia are thought to mostly follow the hierarchical model (3), while breast cancers likely develop according to the stochastic approach (4).Malignant mesotheliomas (MM) are tumors originating from the serosal cells covering the pleural, peritoneal or pericardial cavities. MM are highly aggressive neoplasms most often associated with...

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Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -mentioning

confidence: 99%

Section: Steady-state Equilibrium Between Egfp(+) and Egfp(-) Cells -mentioning

confidence: 99%

mentioning

confidence: 99%

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Biological noise and positional effects influence cell stemness

Blum

Henzi

Schwaller

et al. 2018

Journal of Biological Chemistry

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Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Milosevic

Kopecka

Salaroglio

et al. 2019

Intl Journal of Cancer

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Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM‐initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness‐related pathways determine chemoresistance. Moreover, there are no predictive markers of IC‐associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness‐related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo‐sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5‐knocked‐out (KO) IC clones were resensitized to the drugs in vitro and in patient‐derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β‐catenin/c‐myc axis that also increased IL‐8 and IL‐1β production. IL‐8 and IL‐1β‐KO IC clones reduced the c‐myc‐driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5‐KO clones had lower IL‐8 and IL‐1β secretion, and c‐myc transcriptional activity, suggesting that either Wnt/GSK3β/β‐catenin and IL‐8/IL‐1β signaling drive c‐myc‐mediated transcription of ABCB5. ABCB5 correlated with lower time‐to‐progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first‐line chemotherapy in MPM patients.

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Isoliensinine augments the therapeutic potential of paclitaxel in multidrug‐resistant colon cancer stem cells and induced mitochondria‐mediated cell death

Manogaran,

Anandan,

Vijaya Padma

2023

J Biochem & Molecular Tox

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Previously we have reported the isoliensinine (ISO) potentates the therapeutic potential of cisplatin in cisplatin resistant colorectal cancer stem cells. The present study evaluates the chemo‐sensitizing potential of the combinatorial regimen of ISO and Paclitaxcel (PTX) on multidrug‐resistant (MDR)‐HCT‐15 cells to reduce the dose requirement of both ISO and PTX. The results of the present study suggest that treatment with the combinatorial regimen of ISO and PTX enhanced the cytotoxic effect with resultant increase in apoptosis in MDR‐HCT‐15 cells as evident from the altered cellular morphology, G2/M cell cycle arrest, propidium iodide uptake, Annexin V, increased intracellular Ca2+ accumulation, decreased mitochondrial membrane potential, diminished ATP production, PARP‐1 cleavage, altered expression of ERK1/2, and apoptotic proteins. Treatment with combinatorial regimen of ISO and PTX also modulated the expression of the transcription factors SOX2, OCT4 which determine the stemness of cancer cells. Thus, results of the present study suggest that ISO and PTX combination regimen induces apoptosis in MDR‐HCT‐15 in a synergistic manner.

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Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells

Cited by 29 publications

References 34 publications

Biological noise and positional effects influence cell stemness

Biological noise and positional effects influence cell stemness

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Isoliensinine augments the therapeutic potential of paclitaxel in multidrug‐resistant colon cancer stem cells and induced mitochondria‐mediated cell death

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