Cancer Stem Cell Therapy Research Articles

COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.

Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/β-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness. The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/β-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism. COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/β-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic β-catenin. COLEC10 overexpression promoted the interaction of β-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation. COLEC10 inhibits HCC stemness by downregulating the Wnt/β-catenin pathway, which is a promising target for liver CSC therapy.

Advances in ovarian tumor stem cells and therapy.

Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70-80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer's recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells' sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.

Targeted Therapy of Tumors and Cancer Stem Cells based on Oxidant-Regulated Redox Pathway and its Mechanism.

A malignant tumor is a frequent and common disease that severely threatens human health. Many mechanisms, such as cell signaling pathway, anti-apoptosis mechanism, cell stemness, metabolism, and cell phenotype, have been studied to explain the reasons for chemotherapy, radioresistance, and tumor recurrences in antitumor treatment. Cancer stem cells (CSCs) are important tumor cell subclasses that can potentially organize and regulate stem cell properties. Growing evidence suggests that CSCs can initiate tumors and constitute a significant factor in metastasis, recurrence, and treatment resistance. The inability to completely target and remove CSCs is a considerable obstacle in tumor treatment. Therefore, drugs and therapeutic strategies that can effectively intervene with CSCs are essential for the treatment of different tumor types. However, the current strategies and efficacy of targeted elimination of CSCs are very limited. Oxidative stress has been recognized to play a crucial role in cancer pathophysiology. Moreover, reactive oxygen species (ROS) production and imbalance of the built-in cellular antioxidant defense system are hallmarks of tumor and cancer etiology. The current paper will focus on the regulation and mechanism behind oxidative stress in tumors and cancer stem cells and its tumor therapy applications. Additionally, the article discusses the role of CSCs in causing tumor treatment resistance and recurrence based on a redox perspective. The study also emphasizes that targeted modulation of oxidative stress in CSCs has great potential in tumor therapy, providing novel prospects for tumor therapy.

Cancer biotherapy: review and prospect.

Malignant tumors pose a grave threat to the quality of human life. The prevalence of malignant tumors in China is steadily rising. Presently, clinical interventions encompass surgery, radiotherapy, and pharmaceutical therapy in isolation or combination. Nonetheless, these modalities fail to completely eradicate malignant tumor cells, frequently leading to metastasis and recurrence. Conversely, tumor biotherapy has emerged as an encouraging fourth approach in preventing and managing malignant tumors owing to its safety, efficacy, and minimal adverse effects. Currently, a range of tumor biotherapy techniques are employed, including gene therapy, tumor vaccines, monoclonal antibody therapy, cancer stem cell therapy, cytokine therapy, and adoptive cellular immunotherapy. This study aims to comprehensively review the latest developments in biological treatments for malignant tumors.

Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα “don't eat me” pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

From dietary lignans to cancer therapy: Integrative systems analysis of enterolactone's molecular targets and signaling pathways in combatting cancer stem cells in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates. Cancer stem cells (CSCs) within TNBC contribute significantly to tumor progression, metastasis, and therapy resistance. This study explores Enterolactone (EL), a bioactive phenolic metabolite from dietary lignans, as a potential therapeutic agent against TNBC-CSCs. The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases. A PPI network was constructed in STRING to emphasize top hub targets. Insights were derived from mRNA expression patterns, tumor stage differentials, and survival analysis via UALCAN and GEPIA2. Molecular docking and dynamics simulations were carried out to explore EL's interactions with hub targets. GeneMANIA was employed to expand the target pool, generating two datasets. Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs. Employing network pharmacology, 53 potential EL targets against TNBC-CSCs were identified, highlighting the top 15 hub targets, including ESR1, AKT1, JUN, EGFR, and others. Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR, Wnt-βcatenin, and MAPK, essential for CSC self-renewal, metastasis, and therapy resistance. GO and KEGG analyses illuminated the biological significance of these targets, elucidating EL's potential mechanisms. Analysis of GMFA-ED1 and -ED2 datasets expanded understanding, revealing novel targets of EL against TNBC-CSCs. In conclusion, EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways, offering promising avenues in TNBC.

Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy

Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but are largely impeded by the cell availability and technical challenges in gene transfer. Here, we develop an efficient approach to generate large-scale macrophages from human induced pluripotent stem cells (hiPSCs). Starting with 1 T150 dish of 106 hiPSCs, more than 109 mature macrophages (iMacs) could be generated within 1 month. The generated iMacs exhibit typical macrophage properties such as phagocytosis and polarization. We then generate hiPSCs integrated with an IL12 expression cassette in AAVS1 locus to produce iMacs secreting IL12, a strong pro-immunity cytokine. hiPSCs derived iMacs_IL12 prevent cytotoxic T cell exhaustion and activate T cells to kill different cancer cells. Furthermore, iMACs_IL12 display strong anti-tumor effects in a T cell dependent manner in subcutaneously or systemically xenografted mice of human lung cancer. Therefore, we provide an off-the-shelf strategy to produce large-scale GEMs for cancer therapy.

Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

Head and neck cancer stem cell maintenance relies on mTOR signaling, specifically involving the mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2)

ObjectiveEmerging evidence suggests that the modest response of head and neck squamous cell carcinoma (HNSCC) to treatment is associated with cancer stem cells (CSC). However, the signaling pathways that play a role in HNSCC CSC maintenance and therapy response are not well-understood. In this study, we investigate the response of CSCs to phosphatase and tensin homolog (PTEN) modulation and its potential dependency on the mammalian target of rapamycin (mTOR) signaling. DesignPTEN deficiency was stably induced using short hairpin RNA (shRNA). Downregulation of RPTOR/mTORC1 and RICTOR/mTORC2 was achieved using small interfering RNA (siRNA). CSCs were evaluated through tumorsphere formation and were classified into various subtypes: parasphere, merosphere, and holosphere. We investigated the effect of rapamycin on CSC properties in both control and PTEN-deficient HNSCC cells. ResultsPTEN deficiency led to an accumulation of CSCs and enhanced a favorable response to rapamycin treatment. The viability of HNSCC CSCs was dependent on mTOR signaling. Deficiencies in both mTORC1 and mTORC2 reduced the number of CSCs. However, CSCs with PTEN deficiency had a greater reliance on mTORC1 signaling. Interestingly, when considering CSC subtypes, a deficiency in mTORC2 led to an increased number of paraspheres in both the control and PTEN-deficient groups. ConclusionsLoss of PTEN signaling increased the HNSCC CSC population, which can be targeted by rapamycin. However, the mTORC2 deficiency can induce a problematic selection of paraspheres CSCs subtype.

Effects of curcumin on Wnt/β-catenin, Hedgehog pathways and expression of EMT transcription factors in basal conditions and upon HIF1A and RELA knockdown in HeLa cells

Targeting the HIF1A and NF-κB pathways with pharmacological inhibitors or small interfering RNAs is one of the most promising aspects of cancer stem cell therapy. However, the influence of HIF1A and NF-κB modulators on downstream targets such as components of the Wnt/β-catenin and Hedgehog pathways and EMT is still poorly understood.HeLa cells were treated with 10 and 50 μM curcumin for 24 h, and the function of the Wnt/β-catenin and Hedgehog pathways and EMT transcription factors were subsequently assessed using 14 RNAs expression qPCR-based analysis. We also applied siRNA-dependent HIF1A and RELA knockdown to investigate the influence of these pathways on the expression of the above RNAs along and in combination with curcumin treatment.At the higher concentration under basal conditions, curcumin suppressed most of the targets studied, while causing a significant increase in SNAI1 expression. Knockdown of HIF1A and RELA reduced the expression of Hedgehog pathway targets. In contrast to basal conditions, the expression of EMT transcription factors appeared to be increased after knockdown in response to 50 μM curcumin.Curcumin significantly inhibited Wnt/β-catenin, Hedgehog pathways and EMT transcription factor, while inducing an increase in SNAI1 gene expression, which may be part of cell adaptation systems. Knockdown of HIF1A and RELA revealed the strong dependence of Hedgehog target expression on HIF1A and NF-κB pathways. The activation status of HIF1A and NF-κB pathways determines the expression pattern of EMT transcription factors in HeLa cells.

Phloridzin Docosahexaenoate Inhibits Spheroid Formation by Breast Cancer Stem Cells and Exhibits Cytotoxic Effects against Paclitaxel-Resistant Triple Negative Breast Cancer Cells.

The eradication of cancer stem cells (CSCs) is vital to successful cancer treatment and overall disease-free survival. CSCs are a sub-population of cells within a tumor that are defined by their capacity for continuous self-renewal and recapitulation of new tumors, demonstrated in vitro through spheroid formation. Flavonoids are a group of phytochemicals with potent anti-oxidant and anti-cancer properties. This paper explores the impact of the flavonoid precursor phloridzin (PZ) linked to the ω-3 fatty acid docosahexaenoate (DHA) on the growth of MCF-7 and paclitaxel-resistant MDA-MB-231-TXL breast cancer cell lines. Spheroid formation assays, acid phosphatase assays, and Western blotting were performed using MCF-7 cells, and the cell viability assays, Annexin-V-488/propidium iodide (PI) staining, and 7-aminoactinomycin D (7-AAD) assays were performed using MDA-MB-231-TXL cells. PZ-DHA significantly reduced spheroid formation, as well as the metabolic activity of MCF-7 breast cancer cells in vitro. Treatment with PZ-DHA also suppressed the metabolic activity of MDA-MB-231-TXL cells and led to apoptosis. PZ-DHA did not have an observable effect on the expression of the drug efflux transporters ATP-binding cassette super-family G member 2 (ABCG2) and multidrug resistance-associated protein 1 (MRP1). PZ-DHA is a potential treatment avenue for chemo-resistant breast cancer and a possible novel CSC therapy. Future pre-clinical studies should explore PZ-DHA as a chemo-preventative agent.

Nanoarchitectonics of doxycycline-loaded vitamin E-D-α-tocopheryl polyethylene glycol 1000 succinate micelles for ovarian cancer stem cell treatment.

Aim: This study aim todevelop doxycycline within the D-α-tocopheryl polyethylene glycol 1000 succinate micelle platform as an anticancer stem cell agent. Materials & methods: The optimized nanomicelle formulation was prepared using the solvent casting method and evaluated through physicochemical and biological characterization. Results: Nanomicelles exhibited mean particle sizes of 14.48nm (polydispersity index: 0.22) using dynamic light scattering and 18.22nm using transmission electron micrography. Drug loading and encapsulation efficiency were 2% and 66.73%, respectively. Doxycycline-loaded micelles exhibited sustained release, with 98.5% released in 24h. IC50 values were 20μg/ml for free drug and 5μg/ml for micelles after 48h of cell exposure. A significant 74% reduction in CD44 biomarker and 100% colony formation inhibition were observed. Conclusion: Doxycycline in hemo/biocompatible nanomicelles holds potential for ovarian cancer stem cell therapy.

"Clinical Application of Mesenchymal Stem Cells for Cancer Therapy: A Review of Registered Clinical Trials"

"Clinical Application of Mesenchymal Stem Cells for Cancer Therapy: A Review of Registered Clinical Trials"

Unlocking the secrets of cancer stem cells: Immune checkpoint inhibitors face their formidable foes

In this issue of Cell Stem Cell, Beziaud etal.1 show that immunotherapy induces stem-like properties in models of breast cancer. Strikingly, T-cell-derived IFNγ promotes cancer stem cell (CSC) phenotypes, therapy resistance, and metastasis. Targeting BCAT1 downstream offers promise for enhancing immunotherapy outcomes.

Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics.

Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs' unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs' unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways' ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFβ (transforming growth factor-β)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.

Epigenetic Therapy for Cancer Stem Cells

Epigenetic Therapy for Cancer Stem Cells

Recent advances in aptamer-based therapeutic strategies for targeting cancer stem cells.

Cancer stem cells (CSCs) are believed to be the main cause of chemotherapy resistance and tumor relapse. Various therapeutic strategies to eliminate CSCs have been developed recently. Aptamers, also called "chemical antibodies", can specifically bind with their molecular targets through special tertiary structures. The advantages of aptamers, such as lower immunogenicity and smaller size, make them superior to conventional antibodies. Therefore, aptamers have been used widely as targeting ligands for CSC-targeted therapeutic strategies in different tumor types. To date, various therapeutic cargoes have been conjugated to aptamers to kill CSCs, such as chemotherapy drugs, small interfering RNAs, and microRNAs. Aptamer-based targeted therapies for CSCs have made great progress in recent years, especially the development of multifunctional aptamer-based therapeutic strategies. Besides, cell-systematic evolution of ligands by exponential enrichment has been applied to screen new aptamers that might have a higher binding ability for CSCs. In this review, we focus on recent advances and introduce some new modalities of aptamer-drug conjugates against CSCs. Some considerations of the advantages and limitations of different aptamer-based targeted therapies for CSCs are also discussed.

From laboratory studies to clinical applications mesenchymal stem cells in cancer treatment: Translational oncology

Stem cell-based studies have accelerated to treat various pathologies, particularly neurological, cardiovascular, orthopedic diseases and cancer with the understanding of their therapeutic potential after their discovery. Stem cells have recently aroused great interest as a promising treatment option in the fighting to cancer with extensive study in the fields of cancer biology. Nevertheless, much uncertainty regarding the act of stem cells in cancer development and treatment remains obscure before the clinical use of stem cell investigation. Despite many obstacles, the migration ability of stem cells, the bioactive factors they secrete, and their immune regulatory properties make them advantageous for gene therapy strategies. However, unknowns and a lack of scientific data remain concerning the use of stem cell based therapies. Therefore, more experimental data are needed to confirm the different study results presented by different scientific communities. In this review, we focused on summarizing the available experimental and clinical data on the potential uses of mesenchymal stem cells in cancer therapy.

Microbiota-Derived Natural Products Targeting Cancer Stem Cells: Inside the Gut Pharma Factory.

Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.

Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.