Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the...Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the mechanism of JR in HCC treatment.Methods The chemical constituents of JR were detected using liquid chromatography-mass spectrometry.The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid(mRNA)microarray chip assay,followed by experimental validation in human HCC cells(SMMC-7721 and Huh7)in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo.HCC cell characteristics of proliferation,migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide,wound healing and Transwell assays,respectively.Image-i^(TM)Hypoxia Reagent was added to reveal hypoxic conditions.Stem cell sphere formation assay was used to detect the stemness.Epithelial-mesenchymal transition(EMT)markers like E-cadherin,vimentin andα-smooth muscle actin,and pluripotent transcription factors including nanog homeobox,octamer-binding transcription factor 4,and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction.Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway.Results According to network pharmacology and mRNA microarray chip analysis,JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway.In vitro and in vivo experiments showed that JR significantly decreased hypoxia,and suppressed HCC cell features of proliferation,migration and invasion;furthermore,the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR.Results based on the co-administration of JR and an agonist(LiCl)or inhibitor(IWR-1-endo)verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway.Conclusion JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions.展开更多
Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hy...Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.展开更多
Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy ...Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.展开更多
The recent discovery of cancer cell plasticity,i.e.their ability to reprogram into cancer stem cells(CSCs)either naturally or under chemotherapy and/or radiotherapy,has changed,once again,the way we consider cancer tr...The recent discovery of cancer cell plasticity,i.e.their ability to reprogram into cancer stem cells(CSCs)either naturally or under chemotherapy and/or radiotherapy,has changed,once again,the way we consider cancer treatment.If cancer stemness is a reversible epigenetic state rather than a genetic identity,opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs.However,the systematic use of DNA methyltransferase and histone deacetylase inhibitors,alone or in combination,in advanced solid tumors including colorectal cancers,regardless of their molecular subtypes,does not seem to be the best strategy.In this review,we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells.We raise questions about the relevant use of currently available epigenetic inhibitors(epidrugs)while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms.These markers include the three cluster of differentiation CD133,CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and.Finally,we describe current treatment strategies using epidrugs,and we hypothesize that,using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression,we could identify better candidates for epienzyme targeting.展开更多
BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the cl...BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the clinical relevance and prognostic significance of Niemann-Pick type C2(NPC2)in gastric cancer(GC)remained largely unexplored.AIM To identify stemness-associated genes in GC.METHODS In this study,epithelial cells were categorized as either tumor or normal epithelial cells using the infer copy number variation method.Stemness scores were calculated for both cell types.The hierarchical Weighted Gene Co-expression Network Analysis identified two gene modules with the strongest association with stemness.Prognostically significant stemness-related genes were pinpointed using univariate Cox regression based on The Cancer Genome Atlas dataset.A predictive model related to stemness was constructed using Least Absolute Shrinkage and Selection Operator regression followed by multivariate Cox analysis.RESULTS Functional roles of NPC2 were validated using single-cell and bulk RNA sequencing data.Further experimental validation revealed that elevated NPC2 expression promoted tumor cell stemness,invasiveness,migratory ability,and resistance to standard chemotherapeutic agents.Importantly,high NPC2 expression correlated with poorer overall survival in GC patients.CONCLUSION In summary,the proposed model offers prognostic insights that outperform traditional clinical staging and may inform more tailored therapeutic approaches for gastric cancer management.展开更多
Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic featur...Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic features that contribute to maintaining their self-renewal and stemness.Phospholipids are essential components of cell membranes and play fundamental roles in cellular activities.CSCs have abnormal phospholipid metabolism,which affects their self-renewal,differentiation,invasion,and drug resistance.Compared with non-CSCs,the phospholipid metabolism of CSCs mainly focused on significantly increased fatty acid(FAs)and phospholipids synthesis,phospho-lipid unsaturation,and lipolysis-fatty acid oxidation(FAO).In brief,FA and phospholipid metabolism in the anabolic and catabolic pathways are strictly regulated in CSCs to maintain self-renewal and stemness activity.In this review,we summarize the alterations in phospholipid metabolism in CSCs and their impacts on the stemness of CSCs,and we put forward the potential applications of targeting phospholipid metabolism for CSCs,to provide directions for the development of drugs targeting the phospholipid metabolism.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC ...BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.展开更多
Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referr...Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.展开更多
Cancer progression involves the gradual loss of a differentiated phenotype and the acquisition of progenitor and stem cell-like features,which are potential culprits of immunotherapy resistance.Although the state-of-t...Cancer progression involves the gradual loss of a differentiated phenotype and the acquisition of progenitor and stem cell-like features,which are potential culprits of immunotherapy resistance.Although the state-of-the-art predictive computational methods have facilitated the prediction of cancer stemness,there remains a lack of efficient resources to accommodate various usage requirements.Here,we present the Cancer Stemness Online,an integrated resource for efficiently scoring cancer stemness potential at both bulk and single-cell levels.This resource integrates eight robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting stemness scores.Downstream analyses were performed from five distinct aspects:identifying the signature genes of cancer stemness;exploring the associations with cancer hallmarks and cellular states;exploring the associations with immune response and the communications with immune cells;investigating the contributions to patient survival;and performing a robustness analysis of cancer stemness among different methods.Moreover,the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users.Both the tables and diverse visualizations of the analytical results are available for download.Together,Cancer Stemness Online is a powerful resource for scoring cancer stemness and expanding downstream functional interpretation,including immune response and cancer hallmarks.Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline.展开更多
The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative(R0)surgery,failures in the clinical development of targeted and immune therapies,...The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative(R0)surgery,failures in the clinical development of targeted and immune therapies,and the pervasive acquisition of chemotherapeutic resistance.Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy,with both attributes related to tumor cell stemness.These malignant characteristics mutually enhance each other,leading to rapid cancer progression.Over the past two decades,numerous studies have produced evidence of the pivotal role of glycogen synthase kinase(GSK)3β in the progression of over 25 different cancer types,including pancreatic cancer.In this review,we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion,as well as its contribution to gemcitabine resistance in pancreatic cancer.Importantly,we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance,tumor cell invasion,and stemness in pancreatic cancer.We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anticancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.展开更多
Objective:Previous studies indicated that aberrant circular RNA(circRNA)expression affects gene expression regulatory networks,leading to the aberrant activation of tumor pathways and promoting tumor cell growth.Howev...Objective:Previous studies indicated that aberrant circular RNA(circRNA)expression affects gene expression regulatory networks,leading to the aberrant activation of tumor pathways and promoting tumor cell growth.However,the expression,clinical significance,and effects on cell propagation,invasion,and dissemination of circRNA_001896 in cervical cancer(CC)tissues remain unclear.Methods:The Gene Expression Omnibus(GEO)datasets(GSE113696 and GSE102686)were used to examine differential circRNA expression in CC and adjacent tissues.The expression of circRNA_001896 was detected in 72 CC patients usingfluorescence quantitative PCR.Correlation analysis with clinical pathological features was performed through COX multivariate and univariate analysis.The effect of circRNA_001896 downregulation on CC cell propagation was examined using the cell counting kit-8(CCK-8)test,clonogenic,3D sphere formation,and in vivo tumorigenesis assays.Results:Intersection of the GSE113696 and GSE102686 datasets revealed an increased expression of four circRNAs,including circRNA_001896,in CC tissues.Fluorescence quantitative PCR confirmed circRNA_001896 as a circular RNA.High expression of circRNA_001896 was considerably associated with lymph node metastasis,International Federation of Gynecologists and Obstetricians(FIGO)stage,tumor diameter,and survival period in CC patients.Proportional hazards model(COX)univariate and multivariate analyses revealed that circRNA_001896 expressions are a distinct risk factor affecting CC patients’prognosis.Cellular functional experiments showed that downregulating circRNA_001896 substantially suppressed CC cell growth,colony formation,and 3D sphere-forming ability.In vivo,tumorigenesis analysis in nude mice demonstrated that downregulating circRNA_001896 remarkably reduced the in vivo proliferation capacity of CC cells.Conclusion:CircRNA_001896 is highly expressed in CC tissues and is substantially related to lymph node metastasis,FIGO stage,tumor size,and survival period in patients.Moreover,downregulating circRNA_001896 significantly inhibits both in vivo and in vitro propagation of CC cells.Therefore,circRNA_001896 might be used as a biomarker for targeted therapy in cervical cancer.展开更多
BACKGROUND Colorectal cancer stem cells(CCSCs)are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer(CRC)patients.CCSCs are generally accepted to be important sou...BACKGROUND Colorectal cancer stem cells(CCSCs)are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer(CRC)patients.CCSCs are generally accepted to be important sources of CRC and are responsible for the progression,metastasis,and therapeutic resistance of CRC.Therefore,targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC.AIM To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism.METHODS CCSCs were enriched from CRC cell lines by in conditioned serum-free medium.Western blot,Aldefluor,transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs.The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis,colony formation,sphere formation,flow cytometry,and western blotting assessments in vitro and tumor growth,immunohistochemistry and immunofluorescence assessments in vivo.RESULTS Compared with parental cells,sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumori-genesis,demonstrating that the CRC sphere cells displayed CSC features.VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells,as indicated by their proliferation,migration and clonality in vitro,and suppressed the tumor of CCSC-derived xenograft tumors in vivo.Besides,VX-509 suppressed the CSC character-istics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition(EMT)signaling in vitro.Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differen-tially expressed genes and CSC-related database information.VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression.Moreover,VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression.CONCLUSION VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal,and inhibits the dedifferentiated self-renewal of CCSCs.展开更多
Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene ...Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene expression were quantified by Western blotting and quantitative real-time polymerase chain reaction,the proportion of BCSCs was examined by flow cytometry,and the self-renewal and proliferation of BCSCs were verified by serial sphere formation and soft agar.Results:Increasing expression of UBE2T was drastically found in breast cancer than that in adjacent tissues.Furthermore,UBE2T overexpression significantly increased the proportion of BCSCs in breast cancer cells and promoted their self-renewal and proliferation.Silent UBE2T exhibited the opposite functions.UBE2T increased the levels of the mammalian target of rapamycin and the phosphorylated mammalian target of rapamycin.Mammalian target of rapamycin(mTOR)inhibitor rapamycin inhibited the function of UBE2T in BCSCs.Conclusion:UBE2T plays a role in BCSCs through mTOR pathway and may suggest a novel therapeutic strategy for breast cancer.展开更多
Objective:To explore the effect and mechanism of prostaglandins D2(PGD2)on the stemness of gastric cancer stem cells(GCSCs).Methods:7901-GCSCs were enriched by serum-free culture method;then the positivity rate of CD4...Objective:To explore the effect and mechanism of prostaglandins D2(PGD2)on the stemness of gastric cancer stem cells(GCSCs).Methods:7901-GCSCs were enriched by serum-free culture method;then the positivity rate of CD44,a stemness marker,was detected by flow cytometry in serum-free cultured 7901-GCSCs;the sphere-forming ability was detected by the sphere-forming assay after stimulation with different concentrations of PGD2(2.5,5,10)μg/mL,and the expression of stemness-related indicators(OCT4,CD44)and autophagyrelated proteins(LC3,Beclin-1)after PGD2 stimulation was detected by the western blot assay in different concentrations.The expression of stemness-related indexes(OCT4,CD44)and autophagy-related proteins(LC3,Beclin-1)were detected by Western blot assay after stimulation with different concentrations of PGD2.The expression of autophagy-related proteins after stimulation with different concentrations of CQ(2.5,5,10)μM was detected by Western blot experiment.The protein expression of autophagy-related proteins(LC3,Beclin-1)and stemness-related indexes(OCT4,CD44)was detected by Western blot experiment after PGD2 as well as PGD2+CQ treatment.Results:Flow cytometry results showed that the expression of CD44 positivity was increased in serum-free cultured 7901-GCSCs compared with gastric cancer cells SGC-7901(P<0.05),which fulfilled the needs of subsequent experiments.The results of stem cell spheroid formation assay showed that the spheroid formation ability of 7901-GCSCs in the PGD2 group was significantly weakened compared with that of the DMSO group(P<0.05).Western blot results showed that the protein expression of stemness-related indexes(OCT4,CD44)was down-regulated in the 7901-GCSCs in the PGD2 group compared with that of the DMSO group(P<0.05),and the expression of autophagy-related proteins(LC3,Beclin-1)expression increased(P<0.05).Compared with the DMSO group,the expression of autophagy-related proteins(LC3,Beclin-1)was decreased in the CQ group(P<0.05).Western blot results also showed that the expression of cellular autophagy-related proteins and stemness-related indexes in the PGD2+CQ group was not significantly changed compared with that of the DMSO group(ns:the difference was not significant),suggesting that the CQ could block the effect of PGD2 on the expression of stemness markers in 7901-GCSCs.7901-GCSCs stemness inhibition.Conclusion:PGD2 may affect the stemness of 7901-GCSCs by regulating autophagy.展开更多
Currently, breast cancer is the most common malignant tumour in Chinese women with a high incidence rate, and recurrence and metastasis are the main reasons affecting survival. Breast Cancer Stem Cells (BCSCs) are ste...Currently, breast cancer is the most common malignant tumour in Chinese women with a high incidence rate, and recurrence and metastasis are the main reasons affecting survival. Breast Cancer Stem Cells (BCSCs) are stem cells capable of continuous regeneration in vivo with strong self-renewal ability and multidirectional differentiation potential, which are highly tumourigenic and insensitive to radiotherapy and chemotherapy, and are highly susceptible to breast cancer recurrence. Therefore, exploring the stemness of BCSCs and their mechanism associated with recurrence is important for developing new therapeutic strategies, improving therapeutic efficacy, and improving patient prognosis.展开更多
Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that...Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that impacts colon cancer(CC)cells and its underlying mechanisms remain poorly understood.Methods:The cytotoxic effect of OA alone or OA-5-Fluorouracil(5-FU)combination on normal and CC cells was analyzed by methyl thiazolyl diphenyl-tetrazolium bromide(MTT).Then,the impact of OA on CC cell lines(LoVo and HT-29)proliferation and stemness were measured using colon formation and tumorsphere formation assays.Octamer-binding transcription factor 4(Oct4),Prominin-1(CD133),Nanog,and transcription factor SOX-2(SOX2)are cell stemness-related indicators whose expression was assessed usingfluorescence qPCR assay,Western blotting,and immunohistochemistry.The effect of OA on the proliferative potency of CC cells was evaluated using an in vivo model.Results:The stem-like characteristics and clone production of colon cancer cells were markedly reduced by OA alone or in combination with OA-5-FU.Moreover,OA increases the susceptibility of CC cells to 5-FU by blocking the cell stemness-related markers(CD133,Nanog,SOX2,and Oct4)expression levels both in vitro and in vivo,as well as by inactivating the activator of transcription 3(STAT3 signaling)and Janus kinase 2/signal transducer(JAK2).Conclusion:Thesefindings imply that oleanolic acid,both in vitro and in vivo,suppresses the JAK2/STAT3 pathway,which in turn reverses chemoresistance and decreases colon cancer cell stemness.Therefore,by reducing the recommended amount of 5-FU,this strategy may improve chemotherapeutic effectiveness and minimize undesired side effects.展开更多
Cancer stem cells(CSCs)constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation,progression,metastasis,and relapse.Their ability to evade conventional treatments,...Cancer stem cells(CSCs)constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation,progression,metastasis,and relapse.Their ability to evade conventional treatments,adapt to metabolic stress,and interact with the tumor microenvironment makes them critical targets for innovative therapeutic strategies.Recent advances in single-cell sequencing,spatial transcriptomics,and multiomics integration have significantly improved our understanding of CSC heterogeneity and metabolic adaptability.Metabolic plasticity allows CSCs to switch between glycolysis,oxidative phosphorylation,and alternative fuel sources such as glutamine and fatty acids,enabling them to survive under diverse environmental conditions.Moreover,interactions with stromal cells,immune components,and vascular endothelial cells facilitate metabolic symbiosis,further promoting CSC survival and drug resistance.Despite substantial progress,major hurdles remain,including the lack of universally reliable CSC biomarkers and the challenge of targeting CSCs without affecting normal stem cells.The development of 3D organoid models,CRISPR-based functional screens,and AI-driven multiomics analysis is paving the way for precision-targeted CSC therapies.Emerging strategies such as dual metabolic inhibition,synthetic biology-based interventions,and immune-based approaches hold promise for overcoming CSC-mediated therapy resistance.Moving forward,an integrative approach combining metabolic reprogramming,immunomodulation,and targeted inhibition of CSC vulnerabilities is essential for developing effective CSC-directed therapies.This review discusses the latest advancements in CSC biology,highlights key challenges,and explores future perspectives on translating these findings into clinical applications.展开更多
Malignant tumors are heterogeneous diseases characterized by uncontrolled cell proliferation,invasion,metastasis,and/or recurrence of their malignancies.In particular,cancer stem cells(CSCs)within these tumors might b...Malignant tumors are heterogeneous diseases characterized by uncontrolled cell proliferation,invasion,metastasis,and/or recurrence of their malignancies.In particular,cancer stem cells(CSCs)within these tumors might be responsible for the property of invasiveness and/or therapies-resistance.CSCs are a self-renewing,awfully tumorigenic subpopulation of cancer cells,which are notorious for strong chemoresistance and are frequently responsible the aggravated invasion,metastasis,and/or recurrence.Developing targeting therapies against CSCs,therefore,may be deliberated a more encouraging mission for the greater cancer therapy.Innovation for a more potent anti-CSC treatment has been required as soon as possible.Interestingly,vitamin D could modulate the inflammatory condition of the tumor microenvironment(TME)by successfully affecting CSCs,which has an imperative role in determining the malignant phenotype of CSCs.In addition,vitamin D may also contribute to the regulation of the malignant behaviors of CSCs.Consistently,vitamin D could have potential applications for the significant inhibition of several tumor growths within various cancer therapies.The biological significance of vitamin D for CSCs regulation may be involved in the function of APRO family proteins.Therefore,vitamin D could be one of the innovative therapeutic modalities for the development of novel CSCs related tumor therapies.展开更多
Hematological cancer stem cells(HCSCs)is a subpopulation of cells within hematological cancers that,through their characteristics,enhance malignancy and render their therapy more challenging.By uncovering the underlyi...Hematological cancer stem cells(HCSCs)is a subpopulation of cells within hematological cancers that,through their characteristics,enhance malignancy and render their therapy more challenging.By uncovering the underlying mechanisms behind characteristic properties such as self-renewal,immune evasion,and conventional therapy resistance,as well as the major differences between other cancers and physiological cells,new and alternative targets can be assessed for use in existing and novel immunotherapeutic interventions.Through the evaluation of the existing literature,one can realize that there have already been several studies addressing the use of stem cell transplantation(SCT),monoclonal antibodies(mAbs),cell therapies,cancer vaccines,and oncolytic viruses,with varying degrees of success.As such,this study aims to combine existing information and clinical evidence to assess and bring to the spotlight targets related toHCSCs that can be considered for the improvement of therapeutic interventions.展开更多
There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which a...There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.展开更多
基金This study was supported by the National Natural Science Foundation of China(No.81803929 and 82074138)the Natural Science Foundation of Shanghai(No.21ZR1479500).
文摘Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the mechanism of JR in HCC treatment.Methods The chemical constituents of JR were detected using liquid chromatography-mass spectrometry.The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid(mRNA)microarray chip assay,followed by experimental validation in human HCC cells(SMMC-7721 and Huh7)in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo.HCC cell characteristics of proliferation,migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide,wound healing and Transwell assays,respectively.Image-i^(TM)Hypoxia Reagent was added to reveal hypoxic conditions.Stem cell sphere formation assay was used to detect the stemness.Epithelial-mesenchymal transition(EMT)markers like E-cadherin,vimentin andα-smooth muscle actin,and pluripotent transcription factors including nanog homeobox,octamer-binding transcription factor 4,and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction.Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway.Results According to network pharmacology and mRNA microarray chip analysis,JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway.In vitro and in vivo experiments showed that JR significantly decreased hypoxia,and suppressed HCC cell features of proliferation,migration and invasion;furthermore,the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR.Results based on the co-administration of JR and an agonist(LiCl)or inhibitor(IWR-1-endo)verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway.Conclusion JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions.
基金supported by the National Natural Science Foundation of China(No.82104977)Youth Start-up Foundation of Changhai Hospital(No.2019QNB05)。
文摘Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81602599,31400752,81771781,and U1804281)the National Key Research and Development Program of China(Grant No.2016YFC1303501)。
文摘Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.
基金Supported by"Institut National de la Sante et de la Recherche Médicale"(Inserm)"Centre National de la Recherche Scientifique"(CNRS)"la Ligue Nationale contre le Cancer"(Committees 59,60 and 62)
文摘The recent discovery of cancer cell plasticity,i.e.their ability to reprogram into cancer stem cells(CSCs)either naturally or under chemotherapy and/or radiotherapy,has changed,once again,the way we consider cancer treatment.If cancer stemness is a reversible epigenetic state rather than a genetic identity,opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs.However,the systematic use of DNA methyltransferase and histone deacetylase inhibitors,alone or in combination,in advanced solid tumors including colorectal cancers,regardless of their molecular subtypes,does not seem to be the best strategy.In this review,we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells.We raise questions about the relevant use of currently available epigenetic inhibitors(epidrugs)while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms.These markers include the three cluster of differentiation CD133,CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and.Finally,we describe current treatment strategies using epidrugs,and we hypothesize that,using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression,we could identify better candidates for epienzyme targeting.
文摘BACKGROUND Tumors characterized by high cellular stemness often have unfavorable clinical outcomes,primarily due to their heightened potential for metastasis and resistance to chemotherapy.Among the model genes,the clinical relevance and prognostic significance of Niemann-Pick type C2(NPC2)in gastric cancer(GC)remained largely unexplored.AIM To identify stemness-associated genes in GC.METHODS In this study,epithelial cells were categorized as either tumor or normal epithelial cells using the infer copy number variation method.Stemness scores were calculated for both cell types.The hierarchical Weighted Gene Co-expression Network Analysis identified two gene modules with the strongest association with stemness.Prognostically significant stemness-related genes were pinpointed using univariate Cox regression based on The Cancer Genome Atlas dataset.A predictive model related to stemness was constructed using Least Absolute Shrinkage and Selection Operator regression followed by multivariate Cox analysis.RESULTS Functional roles of NPC2 were validated using single-cell and bulk RNA sequencing data.Further experimental validation revealed that elevated NPC2 expression promoted tumor cell stemness,invasiveness,migratory ability,and resistance to standard chemotherapeutic agents.Importantly,high NPC2 expression correlated with poorer overall survival in GC patients.CONCLUSION In summary,the proposed model offers prognostic insights that outperform traditional clinical staging and may inform more tailored therapeutic approaches for gastric cancer management.
基金supported by grants from National Natural Science Foundation of China(81902784,81771086)by the Fund of Sichuan Provincial Department of science and technology(2024YFFK0393,2022YFS0039)+1 种基金the Research and Develop Program,West China Hospital of Stomatology,Sichuan University(LCYJ2023-DL-2,RD-02-202002)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-004)。
文摘Cancer Stem Cells(CSCs)are cancer cells with self-renewal and tumorigenesis abilities.CSCs in tumor tissues are the leading cause of tumor progression,recurrence,and drug resistance.CSCs have distinct metabolic features that contribute to maintaining their self-renewal and stemness.Phospholipids are essential components of cell membranes and play fundamental roles in cellular activities.CSCs have abnormal phospholipid metabolism,which affects their self-renewal,differentiation,invasion,and drug resistance.Compared with non-CSCs,the phospholipid metabolism of CSCs mainly focused on significantly increased fatty acid(FAs)and phospholipids synthesis,phospho-lipid unsaturation,and lipolysis-fatty acid oxidation(FAO).In brief,FA and phospholipid metabolism in the anabolic and catabolic pathways are strictly regulated in CSCs to maintain self-renewal and stemness activity.In this review,we summarize the alterations in phospholipid metabolism in CSCs and their impacts on the stemness of CSCs,and we put forward the potential applications of targeting phospholipid metabolism for CSCs,to provide directions for the development of drugs targeting the phospholipid metabolism.
基金Supported by Inner Mongolia Natural Science Foundation and the 3rd Affiliated of Inner Medical University,No.2021MS08067.
文摘BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.
基金supported by a fellowship from the American Italian Cancer Foundation(AICF)(#223565-01)supported by the Italian Ministry of Health,Ricerca Finalizzata 2021 Giovani Ricercatori,ID.GR-2021-12375316+19 种基金funded by the CERCA Program/Generalitat de Catalunya,MCIN/AEI/10.13039/501100011033the European Development Regional Fund,“A way to make Europe”EDRF(project PID2021-125282OB-I00)Departament de Recerca i Universitats/Generalitat de Catalunya(2021 SGR 01494)“La Caixa”Research Foundation and the Cellex Foundation(CEL007)supported(as a PI unless otherwise indicated)by one NIH R01 grant(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)by a grant from the STARR Cancer Consortium(#I16--0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291,PI:Deasy,Formenti,Weichselbaum)by the 2019 Laura Ziskin Prize in Translational Research(#ZP--6177,PI:Formenti)from the Stand Up to Cancer(SU2C)by a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PI:Demaria,Formenti),a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center(New York,US)by startup funds from the Dept.of Radiation Oncology at Weill Cornell Medicine(New York,US)by startup funds from Fox Chase Cancer Center(Philadelphia,US)by donations from Promontory(New York,US)the Luke Heller TECPR2 Foundation(Boston,US),supported by funding from Associazione Italiana per la Ricerca sul Cancro AIRC,IG 2022 ID.27685CARESS Fondazione Piemontese per la Ricerca sul Cancro(FRPC)5×1000 Intramural Grantthe European Union–Next Generation EU–PNRR M6C2-Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN(ID.PNRR-POC-2023-12378288)funds from the Italian Institute for Genomic Medicine and Compagnia di San Paolo.
文摘Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.
基金supported by the National Natural Science Foundation of China(Grant Nos.32322020,32170676,and 32060152)the Heilongjiang Provincial Natural Science Foundation of China(Key Program)(Grant No.ZD2023C007)the Heilongjiang Touyan Innovation Team Program,China.
文摘Cancer progression involves the gradual loss of a differentiated phenotype and the acquisition of progenitor and stem cell-like features,which are potential culprits of immunotherapy resistance.Although the state-of-the-art predictive computational methods have facilitated the prediction of cancer stemness,there remains a lack of efficient resources to accommodate various usage requirements.Here,we present the Cancer Stemness Online,an integrated resource for efficiently scoring cancer stemness potential at both bulk and single-cell levels.This resource integrates eight robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting stemness scores.Downstream analyses were performed from five distinct aspects:identifying the signature genes of cancer stemness;exploring the associations with cancer hallmarks and cellular states;exploring the associations with immune response and the communications with immune cells;investigating the contributions to patient survival;and performing a robustness analysis of cancer stemness among different methods.Moreover,the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users.Both the tables and diverse visualizations of the analytical results are available for download.Together,Cancer Stemness Online is a powerful resource for scoring cancer stemness and expanding downstream functional interpretation,including immune response and cancer hallmarks.Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline.
基金supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Science,Sports,Technology and Culture and from the Japan Society for the Promotion of Science(to UM:23K14644,TD:22K07227,T.Miyashita:23K08163,and T.Minamoto:22H03144).
文摘The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative(R0)surgery,failures in the clinical development of targeted and immune therapies,and the pervasive acquisition of chemotherapeutic resistance.Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy,with both attributes related to tumor cell stemness.These malignant characteristics mutually enhance each other,leading to rapid cancer progression.Over the past two decades,numerous studies have produced evidence of the pivotal role of glycogen synthase kinase(GSK)3β in the progression of over 25 different cancer types,including pancreatic cancer.In this review,we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion,as well as its contribution to gemcitabine resistance in pancreatic cancer.Importantly,we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance,tumor cell invasion,and stemness in pancreatic cancer.We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anticancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.
基金This study was supported by the Nantong Science and Technology Plan Project(No.JC22022107).
文摘Objective:Previous studies indicated that aberrant circular RNA(circRNA)expression affects gene expression regulatory networks,leading to the aberrant activation of tumor pathways and promoting tumor cell growth.However,the expression,clinical significance,and effects on cell propagation,invasion,and dissemination of circRNA_001896 in cervical cancer(CC)tissues remain unclear.Methods:The Gene Expression Omnibus(GEO)datasets(GSE113696 and GSE102686)were used to examine differential circRNA expression in CC and adjacent tissues.The expression of circRNA_001896 was detected in 72 CC patients usingfluorescence quantitative PCR.Correlation analysis with clinical pathological features was performed through COX multivariate and univariate analysis.The effect of circRNA_001896 downregulation on CC cell propagation was examined using the cell counting kit-8(CCK-8)test,clonogenic,3D sphere formation,and in vivo tumorigenesis assays.Results:Intersection of the GSE113696 and GSE102686 datasets revealed an increased expression of four circRNAs,including circRNA_001896,in CC tissues.Fluorescence quantitative PCR confirmed circRNA_001896 as a circular RNA.High expression of circRNA_001896 was considerably associated with lymph node metastasis,International Federation of Gynecologists and Obstetricians(FIGO)stage,tumor diameter,and survival period in CC patients.Proportional hazards model(COX)univariate and multivariate analyses revealed that circRNA_001896 expressions are a distinct risk factor affecting CC patients’prognosis.Cellular functional experiments showed that downregulating circRNA_001896 substantially suppressed CC cell growth,colony formation,and 3D sphere-forming ability.In vivo,tumorigenesis analysis in nude mice demonstrated that downregulating circRNA_001896 remarkably reduced the in vivo proliferation capacity of CC cells.Conclusion:CircRNA_001896 is highly expressed in CC tissues and is substantially related to lymph node metastasis,FIGO stage,tumor size,and survival period in patients.Moreover,downregulating circRNA_001896 significantly inhibits both in vivo and in vitro propagation of CC cells.Therefore,circRNA_001896 might be used as a biomarker for targeted therapy in cervical cancer.
基金National Natural Science Foundation of China,No.82074298Chengdu Science and Technology Bureau Project,No.2021-YF05-01726-SN“Xinglin Scholars”Research Promotion Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022007.
文摘BACKGROUND Colorectal cancer stem cells(CCSCs)are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer(CRC)patients.CCSCs are generally accepted to be important sources of CRC and are responsible for the progression,metastasis,and therapeutic resistance of CRC.Therefore,targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC.AIM To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism.METHODS CCSCs were enriched from CRC cell lines by in conditioned serum-free medium.Western blot,Aldefluor,transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs.The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis,colony formation,sphere formation,flow cytometry,and western blotting assessments in vitro and tumor growth,immunohistochemistry and immunofluorescence assessments in vivo.RESULTS Compared with parental cells,sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumori-genesis,demonstrating that the CRC sphere cells displayed CSC features.VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells,as indicated by their proliferation,migration and clonality in vitro,and suppressed the tumor of CCSC-derived xenograft tumors in vivo.Besides,VX-509 suppressed the CSC character-istics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition(EMT)signaling in vitro.Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differen-tially expressed genes and CSC-related database information.VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression.Moreover,VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression.CONCLUSION VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal,and inhibits the dedifferentiated self-renewal of CCSCs.
基金This research was partly supported by the Fundamental Research Funds of Shandong University(21510078614097)the Shandong Natural Science Foundation General Project(ZR2022MC093).
文摘Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene expression were quantified by Western blotting and quantitative real-time polymerase chain reaction,the proportion of BCSCs was examined by flow cytometry,and the self-renewal and proliferation of BCSCs were verified by serial sphere formation and soft agar.Results:Increasing expression of UBE2T was drastically found in breast cancer than that in adjacent tissues.Furthermore,UBE2T overexpression significantly increased the proportion of BCSCs in breast cancer cells and promoted their self-renewal and proliferation.Silent UBE2T exhibited the opposite functions.UBE2T increased the levels of the mammalian target of rapamycin and the phosphorylated mammalian target of rapamycin.Mammalian target of rapamycin(mTOR)inhibitor rapamycin inhibited the function of UBE2T in BCSCs.Conclusion:UBE2T plays a role in BCSCs through mTOR pathway and may suggest a novel therapeutic strategy for breast cancer.
基金Natural Science Foundation of Anhui Province(No.1908085MH258)Scientific Research and Innovation Project of Bengbu Medical College(No.Byycxz21004)。
文摘Objective:To explore the effect and mechanism of prostaglandins D2(PGD2)on the stemness of gastric cancer stem cells(GCSCs).Methods:7901-GCSCs were enriched by serum-free culture method;then the positivity rate of CD44,a stemness marker,was detected by flow cytometry in serum-free cultured 7901-GCSCs;the sphere-forming ability was detected by the sphere-forming assay after stimulation with different concentrations of PGD2(2.5,5,10)μg/mL,and the expression of stemness-related indicators(OCT4,CD44)and autophagyrelated proteins(LC3,Beclin-1)after PGD2 stimulation was detected by the western blot assay in different concentrations.The expression of stemness-related indexes(OCT4,CD44)and autophagy-related proteins(LC3,Beclin-1)were detected by Western blot assay after stimulation with different concentrations of PGD2.The expression of autophagy-related proteins after stimulation with different concentrations of CQ(2.5,5,10)μM was detected by Western blot experiment.The protein expression of autophagy-related proteins(LC3,Beclin-1)and stemness-related indexes(OCT4,CD44)was detected by Western blot experiment after PGD2 as well as PGD2+CQ treatment.Results:Flow cytometry results showed that the expression of CD44 positivity was increased in serum-free cultured 7901-GCSCs compared with gastric cancer cells SGC-7901(P<0.05),which fulfilled the needs of subsequent experiments.The results of stem cell spheroid formation assay showed that the spheroid formation ability of 7901-GCSCs in the PGD2 group was significantly weakened compared with that of the DMSO group(P<0.05).Western blot results showed that the protein expression of stemness-related indexes(OCT4,CD44)was down-regulated in the 7901-GCSCs in the PGD2 group compared with that of the DMSO group(P<0.05),and the expression of autophagy-related proteins(LC3,Beclin-1)expression increased(P<0.05).Compared with the DMSO group,the expression of autophagy-related proteins(LC3,Beclin-1)was decreased in the CQ group(P<0.05).Western blot results also showed that the expression of cellular autophagy-related proteins and stemness-related indexes in the PGD2+CQ group was not significantly changed compared with that of the DMSO group(ns:the difference was not significant),suggesting that the CQ could block the effect of PGD2 on the expression of stemness markers in 7901-GCSCs.7901-GCSCs stemness inhibition.Conclusion:PGD2 may affect the stemness of 7901-GCSCs by regulating autophagy.
文摘Currently, breast cancer is the most common malignant tumour in Chinese women with a high incidence rate, and recurrence and metastasis are the main reasons affecting survival. Breast Cancer Stem Cells (BCSCs) are stem cells capable of continuous regeneration in vivo with strong self-renewal ability and multidirectional differentiation potential, which are highly tumourigenic and insensitive to radiotherapy and chemotherapy, and are highly susceptible to breast cancer recurrence. Therefore, exploring the stemness of BCSCs and their mechanism associated with recurrence is important for developing new therapeutic strategies, improving therapeutic efficacy, and improving patient prognosis.
基金The work was supported by grants from the Scientific Research Projects of Medical and Health Institutions of Longhua District,Shenzhen(2021016)Shenzhen Basic Research Project(JCYJ20210324125803008).
文摘Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that impacts colon cancer(CC)cells and its underlying mechanisms remain poorly understood.Methods:The cytotoxic effect of OA alone or OA-5-Fluorouracil(5-FU)combination on normal and CC cells was analyzed by methyl thiazolyl diphenyl-tetrazolium bromide(MTT).Then,the impact of OA on CC cell lines(LoVo and HT-29)proliferation and stemness were measured using colon formation and tumorsphere formation assays.Octamer-binding transcription factor 4(Oct4),Prominin-1(CD133),Nanog,and transcription factor SOX-2(SOX2)are cell stemness-related indicators whose expression was assessed usingfluorescence qPCR assay,Western blotting,and immunohistochemistry.The effect of OA on the proliferative potency of CC cells was evaluated using an in vivo model.Results:The stem-like characteristics and clone production of colon cancer cells were markedly reduced by OA alone or in combination with OA-5-FU.Moreover,OA increases the susceptibility of CC cells to 5-FU by blocking the cell stemness-related markers(CD133,Nanog,SOX2,and Oct4)expression levels both in vitro and in vivo,as well as by inactivating the activator of transcription 3(STAT3 signaling)and Janus kinase 2/signal transducer(JAK2).Conclusion:Thesefindings imply that oleanolic acid,both in vitro and in vivo,suppresses the JAK2/STAT3 pathway,which in turn reverses chemoresistance and decreases colon cancer cell stemness.Therefore,by reducing the recommended amount of 5-FU,this strategy may improve chemotherapeutic effectiveness and minimize undesired side effects.
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(RS-2023-00207904)supported by the Global-Learning&Academic Research Institution for Master’s·PhD students and the Postdocs(LAMP)Program of the National Research Foundation of Korea(NRF)grant funded by the Ministry of Education(No.RS-2023—00301938).
文摘Cancer stem cells(CSCs)constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation,progression,metastasis,and relapse.Their ability to evade conventional treatments,adapt to metabolic stress,and interact with the tumor microenvironment makes them critical targets for innovative therapeutic strategies.Recent advances in single-cell sequencing,spatial transcriptomics,and multiomics integration have significantly improved our understanding of CSC heterogeneity and metabolic adaptability.Metabolic plasticity allows CSCs to switch between glycolysis,oxidative phosphorylation,and alternative fuel sources such as glutamine and fatty acids,enabling them to survive under diverse environmental conditions.Moreover,interactions with stromal cells,immune components,and vascular endothelial cells facilitate metabolic symbiosis,further promoting CSC survival and drug resistance.Despite substantial progress,major hurdles remain,including the lack of universally reliable CSC biomarkers and the challenge of targeting CSCs without affecting normal stem cells.The development of 3D organoid models,CRISPR-based functional screens,and AI-driven multiomics analysis is paving the way for precision-targeted CSC therapies.Emerging strategies such as dual metabolic inhibition,synthetic biology-based interventions,and immune-based approaches hold promise for overcoming CSC-mediated therapy resistance.Moving forward,an integrative approach combining metabolic reprogramming,immunomodulation,and targeted inhibition of CSC vulnerabilities is essential for developing effective CSC-directed therapies.This review discusses the latest advancements in CSC biology,highlights key challenges,and explores future perspectives on translating these findings into clinical applications.
文摘Malignant tumors are heterogeneous diseases characterized by uncontrolled cell proliferation,invasion,metastasis,and/or recurrence of their malignancies.In particular,cancer stem cells(CSCs)within these tumors might be responsible for the property of invasiveness and/or therapies-resistance.CSCs are a self-renewing,awfully tumorigenic subpopulation of cancer cells,which are notorious for strong chemoresistance and are frequently responsible the aggravated invasion,metastasis,and/or recurrence.Developing targeting therapies against CSCs,therefore,may be deliberated a more encouraging mission for the greater cancer therapy.Innovation for a more potent anti-CSC treatment has been required as soon as possible.Interestingly,vitamin D could modulate the inflammatory condition of the tumor microenvironment(TME)by successfully affecting CSCs,which has an imperative role in determining the malignant phenotype of CSCs.In addition,vitamin D may also contribute to the regulation of the malignant behaviors of CSCs.Consistently,vitamin D could have potential applications for the significant inhibition of several tumor growths within various cancer therapies.The biological significance of vitamin D for CSCs regulation may be involved in the function of APRO family proteins.Therefore,vitamin D could be one of the innovative therapeutic modalities for the development of novel CSCs related tumor therapies.
文摘Hematological cancer stem cells(HCSCs)is a subpopulation of cells within hematological cancers that,through their characteristics,enhance malignancy and render their therapy more challenging.By uncovering the underlying mechanisms behind characteristic properties such as self-renewal,immune evasion,and conventional therapy resistance,as well as the major differences between other cancers and physiological cells,new and alternative targets can be assessed for use in existing and novel immunotherapeutic interventions.Through the evaluation of the existing literature,one can realize that there have already been several studies addressing the use of stem cell transplantation(SCT),monoclonal antibodies(mAbs),cell therapies,cancer vaccines,and oncolytic viruses,with varying degrees of success.As such,this study aims to combine existing information and clinical evidence to assess and bring to the spotlight targets related toHCSCs that can be considered for the improvement of therapeutic interventions.
基金sponsored by Shanghai Education Commission Major Project(2017-01-07-00-07-E00052)National Natural Science Foundation of China(No.81773657)+1 种基金Shanghai Sailing Program(No.20YF1404500)Scientific Research Foundation of Huashan Hospital,Fudan University(No.2019QD012).
文摘There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.
