Metformin targets gastric cancer stem cells

Courtois, Sarah; Durán, Raúl V.; Giraud, Julie; Sifré, Elodie; Izotte, Julien; Mégraud, Françis; Lehours, Philippe; Varon, Christine; Bessède, Emilie

doi:10.1016/j.ejca.2017.07.020

Cited by 69 publications

(55 citation statements)

References 29 publications

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“…Because of CSCs are believed to up-regulation of multiple stemness genes to exert their regulatory effects on specific biological processes [19]. In this case, it was not surprising that we identified that knocked down or over-expression PRR11 affected stemness expression.…”

Section: Discussionmentioning

confidence: 86%

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Hu¹,

Song²,

Yao³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. Methods: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. Results: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. Conclusions: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.

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Section: Discussionmentioning

confidence: 86%

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Hu¹,

Song²,

Yao³

et al. 2018

Cell Physiol Biochem

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“…To evaluate the antitumor activity of VP in vivo , xenograft experiments were performed using MKN45 cells and GC10 PDX cells. Cells were subcutaneously injected into the right flank of NSG immunodeficient mice and tumor development was measured periodically as previously described . When tumor size reached 200 mm 3 , VP in DMSO or DMSO vehicle was subcutaneously injected daily at the tumor periphery.…”

Section: Resultsmentioning

confidence: 99%

“…In all, 100,000 MKN45 GC line and GC10 PDX were suspended in 100 μl of 7 mg/ml ice‐cold Matrigel (Ozyme, Montigny‐le‐Bretonneux, France) and subcutaneously injected into the dorsal flank of 7‐week‐old nonobese diabetic/severe combined immunodeficiency/interleukin‐2Rγ null (NSG) immunodeficient male mice. Tumors were measured three times a week using a caliper and tumor volumes were calculated as reported . When the tumor volumes reached around 200 mm 3 , 50 μl of DMSO (control group) or VP solution was subcutaneously injected per mouse at the tumor periphery daily for 13–17 days, after which the mice were sacrificed.…”

Section: Methodsmentioning

confidence: 99%

“…When the tumor volumes reached around 200 mm 3 , 50 μl of DMSO (control group) or VP solution was subcutaneously injected per mouse at the tumor periphery daily for 13–17 days, after which the mice were sacrificed. Tumors were collected, weighed, fixed in a 3.7% buffered‐formaldehyde solution and embedded in paraffin according to standard procedures as described . Immunodeficient mice were housed in Level 2 animal facility at the University of Bordeaux, with the agreement of the local Ethics Committee on Animal Experiments CEEA50 of Bordeaux (accreditation number 50120151‐A) and the French Committee of Genetic Engineering (authorization number 4608).…”

Section: Methodsmentioning

confidence: 99%

“…Innovative approaches combine systemic chemotherapy agents (including 5‐fluorouracil and cisplatin), which target the bulk of proliferative cells, with the development of new therapies specifically raised against gastric CSC. We previously proved the possibility of targeting gastric CSC self‐renewal properties either by inducing their differentiation or by acting on their metabolism . The study and targeting of specific CSC signaling pathways could lead to new therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

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Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

Giraud

Molina-Castro

Seeneevassen

et al. 2019

Intl Journal of Cancer

Self Cite

105

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Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation‐44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T‐TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration‐approved drug preventing Y/T‐TEAD interaction, on gastric CSC tumorigenic properties. Y/T‐TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient‐derived GC and cell lines. Verteporfin effects on Y/T‐TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient‐derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T‐TEAD molecular signature was enriched in CD44+ patient‐derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T‐TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere‐forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T‐TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ‐TEAD activity could be a promising CSC‐based strategy for the treatment of GC.

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Double‐Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors

Li,

Yang,

Ren

et al. 2024

Advanced Materials

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Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self‐renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC‐enriched tumors is proposed in this study and was realized utilizing our developed double layered hollow mesoporous cuprous oxide nanoparticles (DL‐HMCONs). The high drug loading contents of camptothecin (CPT) and all‐trans retinoic acid (ATRA) demonstrate that our DL‐HMCON can be used as a generic drug delivery system (DDS). ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL‐HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL‐HMCON@HA for CSC‐containing tumors have been demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non‐CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non‐CSCs; and 3) the third release of Cu+ from DL‐HMCON itself triggers the Fenton‐like reaction and GSH depletion, resulting in ferroptosis of non‐CSCs. Our CPT3@ATRA3@DL‐HMCON@HA has been verified to possess high DDST efficacy for CSC‐enriched tumors with high biosafety.This article is protected by copyright. All rights reserved

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Metformin targets gastric cancer stem cells

Cited by 69 publications

References 29 publications

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

Double‐Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors

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