Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers

MicroRNAs(miRNAs)have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells(CSCs).The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells(GCSCs).Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs.This review summarizes the coding process and biological functions of miRNAs and demon-strates their role and efficacy in gastric cancer(GC)metastasis,drug resistance,and apoptosis,especially in the regulatory mechanism of GCSCs.It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis,apart from the initial formation of GC.It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC.We believe that this review may help in designing novel therapeutic approaches for GC.

Prostaglandin D2 regulation of autophagy affects stemness of gastric cancer stem cells

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.

Research progress on lung cancer stem cells in epidermal growth factor receptor–tyrosine kinase inhibitor targeted therapy resistance in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.

Exploring the Pivotal Association of AI in Cancer Stem Cells Detection and Treatment

Cancer stem cells(CSCs),or tumor-initiating cells(TICs),are cancerous cell subpopulations that remain while tumor cells propagate as a unique subset and exhibit multiple applications in several diseases.They are responsible for cancer cell initiation,development,metastasis,proliferation,and recurrence due to their self-renewal and differentiation abilities in many kinds of cells.Artificial intelligence(AI)has gained significant attention because of its vast applications in various fields including agriculture,healthcare,transportation,and robotics,particularly in detecting human diseases such as cancer.The division and metastasis of cancerous cells are not easy to identify at early stages due to their uncontrolled situations.It has provided some real-time pictures of cancer progression and relapse.The purpose of this review paper is to explore new investigations into the role of AI in cancer stem cell progression and metastasis and in regenerative medicines.It describes the association of machine learning and AI with CSCs along with its numerous applications from cancer diagnosis to therapy.This review has also provided key challenges and future directions of AI in cancer stem cell research diagnosis and therapeutic approach.

Therapeutic implications of cancer stem cells in prostate cancer

Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells(PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs;methods for isolation and enrichment of PCSCs;and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.

Cancer stem cells: a target for overcoming therapeutic resistance and relapse

Cancer stem cells(CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

Advances of nanotechnology applied to cancer stem cells

Cancer stem cells(CSCs)are a small proportion of the cells that exist in cancer tissues.They are considered to be the culprit of tumor genesis,development,drug resistance,metastasis and recurrence because of their self-renewal,proliferation,and differentiation potential.The elimination of CSCs is thus the key to cure cancer,and targeting CSCs provides a new method for tumor treatment.Due to the advantages of controlled sustained release,targeting and high biocompatibility,a variety of nanomaterials are used in the diagnosis and treatments targeting CSCs and promote the recognition and removal of tumor cells and CSCs.This article mainly reviews the research progress of nanotechnology in sorting CSCs and nanodrug delivery systems targeting CSCs.Furthermore,we identify the problems and future research directions of nanotechnology in CSC therapy.We hope that this review will provide guidance for the design of nanotechnology as a drug carrier so that it can be used in clinic for cancer therapy as soon as possible.

Molecular signaling in cancer stem cells of tongue squamous cell carcinoma:Therapeutic implications and challenges

Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates.Amongst oral cavity cancers,tongue carcinoma is a very common and aggressive oral cavity carcinoma.Despite the implementation of a multimodality treatment regime including surgical intervention,chemo-radiation as well as targeted therapy,tongue carcinoma shows a poor overall 5-year survival pattern,which is attributed to therapy resistance and recurrence of the disease.The presence of a rare population,i.e.,cancer stem cells(CSCs)within the tumor,are involved in therapy resistance,recurrence,and distant metastasis that results in poor survival patterns.Therapeutic agents targeting CSCs have been in clinical trials,although they are unable to reach into therapy stage which is due to their failure in trials.A more detailed understanding of the CSCs is essential for identifying efficient targets.Molecular signaling pathways,which are differentially regulated in the CSCs,are one of the promising targets to manipulate the CSCs that would provide an improved outcome.In this review,we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.

Targeting the mechano-microenvironment and liver cancer stem cells:a promising therapeutic strategy for liver cancer

Over the past 2 decades,cancer stem cells(CSCs)have been identified as the root cause of cancer occurrence,progression,chemoradioresistance,recurrence,and metastasis.Targeting CSCs is a novel therapeutic strategy for cancer management and treatment.Liver cancer(LC)is a malignant disease that can endanger human health.Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer.In this review,we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells(LCSCs)in liver cancer progression.We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis.Finally,we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer.Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Roles of cancer stem cells in gastrointestinal cancers

Cancer stem cells(CSCs)are the main cause of tumor growth,invasion,metastasis and recurrence.Recently,CSCs have been extensively studied to identify CSCspecific surface markers as well as signaling pathways that play key roles in CSCs self-renewal.The involvement of CSCs in the pathogenesis of gastrointestinal(GI)cancers also highlights these cells as a priority target for therapy.The diagnosis,prognosis and treatment of GI cancer have always been a focus of attention.Therefore,the potential application of CSCs in GI cancers is receiving increasing attention.This review summarizes the role of CSCs in GI cancers,focusing on esophageal cancer,gastric cancer,liver cancer,colorectal cancer,and pancreatic cancer.In addition,we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers,which may provide better guidance for clinical treatment of GI cancers.

Obesity and cancer stem cells:Roles in cancer initiation,progression and therapy resistance

Obesity,the global pandemic since industrialization,is the number one lifestylerelated risk factor for premature death,which increases the incidence and mortality of various diseases and conditions,including cancer.In recent years,the theory of cancer stem cells(CSCs),which have the capacity for self-renewal,metastasis and treatment resistance,has been bolstered by increasing evidence.However,research on how obesity affects CSCs to facilitate cancer initiation,progression and therapy resistance is still in its infancy,although evidence has already begun to accumulate.Regarding the ever-increasing burden of obesity and obesity-related cancer,it is pertinent to summarize evidence about the effects of obesity on CSCs,as elucidating these effects will contribute to the improvement in the management of obesity-related cancers.In this review,we discuss the association between obesity and CSCs,with a particular focus on how obesity promotes cancer initiation,progression and therapy resistance through CSCs and the mechanisms underlying these effects.In addition,the prospect of preventing cancer and targeting the mechanisms linking obesity and CSCs to reduce cancer risk or to improve the survival of patients with cancer is considered.

Ardisia gigantifolia ethanolic extract inhibits cell proliferation and targets cancer stem cells in gastric cancer

Objective:To evaluate the effects of ethanol extract from Ardisia gigantifolia leaves on cell proliferation and cancer stem cell(CSC)number in gastric cancer.Methods:The inhibitory effect of Ardisia gigantifolia extract on the proliferation of MKN45 and MKN74 gastric cancer cells was assessed using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay.Non-adherent culture(3D)model was used to evaluate the effect of the extract on tumorsphere size and number.Moreover,the expression of CD44,ALDH,and p21 was determined by immunofluorescence analysis.Flow cytometric analysis was performed to evaluate cell cycle arrest and the expression of gastric CSC markers CD44 and ALDH.Real-time PCR analysis was also carried out to assess the effect of the extract on the expression of cell cycle-regulated genes.Results:Ardisia gigantifolia extract effectively inhibited cell proliferation with an IC_(50)of 55.7μg/m L in MKN45 cells and 123.6μg/m L in MKN74 cells.The extract also arrested cell cycle in the G_(0)/G_(1)phase as well as significantly reduced the size and number of tumorspheres.The markedly increased expression of p21 was observed at both m RNA and protein levels in the extract-treated adherent cells and tumorspheres.In addition,Ardisia gigantifolia extract significantly reduced the number of CD44-and/or ALDH-expressing gastric CSC.Conclusions:The development of gastric CSC can be inhibited by the ethanol extract of Ardisia gigantifolia.

Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics

Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells(CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.

Reporter gene systems for the identification and characterization of cancer stem cells

Cancer stem cells(CSCs)are tumor cells that share functional characteristics with normal and embryonic stem cells.CSCs have increased tumor-initiating capacity and metastatic potential and lower sensitivity to chemo-and radiotherapy,with important roles in tumor progression and the response to therapy.Thus,a current goal of cancer research is to eliminate CSCs,necessitating an adequate phenotypic and functional characterization of CSCs.Strategies have been developed to identify,enrich,and track CSCs,many of which distinguish CSCs by evaluating the expression of surface markers,the initiation of specific signaling pathways,and the activation of master transcription factors that control stemness in normal cells.We review and discuss the use of reporter gene systems for identifying CSCs.Reporters that are under the control of aldehyde dehydrogenase 1A1,CD133,Notch,Nanog homeobox,Sex-determining region Y-box 2,and POU class 5 homeobox can be used to identify CSCs in many tumor types,track cells in real time,and screen for drugs.Thus,reporter gene systems,in combination with in vitro and in vivo functional assays,can assess changes in the CSCs pool.We present relevant examples of these systems in the evaluation of experimental CSCs-targeting therapeutics,demonstrating their value in CSCs research.

Beyond tumorigenesis: cancer stem cells in metastasis

The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.

Gastric cancer stem cells in gastric carcinogenesis,progression,prevention and treatment

In recent decades,the study of the mechanism of tumorigenesis has brought much progress to cancer treatment.However,cancer stem cell(CSC)theory has changed previous views of tumors,and has provided a new method for treatment of cancer.The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development,resulting in a new effective strategy for cancer treatment.Gastric CSCs(GCSCs)are the basis for the onset of gastric cancer.They may be derived from gastric stem cells in gastric tissues,or bone marrow mesenchymal stem cells.As with other stem cells,GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance,which are resistant to chemotherapy and thus form the basis of drug resistance.Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs,diagnosis and grading of gastric cancer,and research on GCSC-targeted therapy for gastric cancer.Therefore,discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment.

Circulating tumor and cancer stem cells in hepatitis C virusassociated liver disease

AIM: To assess the role of circulating tumor cells (CTCs) and cancer stem cells (CSCs) in hepatitis C virus (HCV)-associated liver disease.

Cancer stem cells in colorectal cancer from pathogenesis to therapy: Controversies and perspectives

Colorectal cancer remains one of the most common and lethal malignancies worldwide despite the use of various therapeutic strategies. A better understanding of the mechanisms responsible for tumor initiation and progression is essential for the development of novel, more powerful therapies. The traditional, so-called &#x0201c;stochastic model&#x0201d; of tumor development, which assumes that each cancer cell is tumorigenic, has been deeply challenged during the past decade by the identification of cancer stem cells (CSCs), a biologically distinct subset of cells within the bulk of tumor mass. This discovery led to the development of the hierarchical model of tumorigenesis which assumes that only CSCs have the ability to initiate tumor growth, both at primary and metastatic sites. This model implies that the elimination of all CSCs is fundamental to eradicate tumors and that failure to do so might be responsible for the occurrence of relapses and/or metastases frequently observed in the clinical management of colorectal cancer patients. Identification and isolation of CSCs is essential for a better understanding of their role in the tumorigenetic process and for the development of CSC-specific therapies. Several methods have been used for this purpose and many efforts have been focused on the identification of specific CSC-surface markers. This review provides an overview of the proposed roles of CSC in human colorectal tumorigenesis focusing on the most important molecules identified as CSC-specific markers in colorectal cancer and on the potential strategies for the development of CSC-targeted therapy.

Oncolytic viruses against cancer stem cells: A promising approach for gastrointestinal cancer

Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell(CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer(liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations.

Effects of Notch-1 Down-regulation on Malignant Behaviors of Breast Cancer Stem Cells

This study examined the effect of Notch-1 signaling on malignant behaviors of breast cancer cells by regulating breast cancer stem cells （BCSCs）. BCSCs were enriched by using serum-free me- dium and knocked out of Notch-1 by using a lentiviral vector. Real-time polymerase chain reaction （RT-PCR） and Western blotting were used to detect the Notch-1 expression levels in breast cancer cell lines and BCSCs, and fl0w cytometry to detect the proportion of BCSCs in BCSC spheres. The BCSC self-renewal, migration, invasion, and tumorigenicity were examined by the tumor microsphere-forming assay and transwell assay and after xenotransplantation. The results showed that the Notch-1 silencing reduced the number of BCSC spheres, the proportion of BCSCs, and the number of cells penetrating through the transwell membrane. It also decreased the size of tumors that were implanted in the nude mice. These results suggest that Notch-1 signaling is intimately linked to the behaviors of BCSCs. Blocking Notch-1 signaling can inhibit the malignant behaviors of BCSCs, which may provide a prom- ising therapeutical approach for breast cancer.