The impact of endocrine-disrupting chemicals on stem cells: Mechanisms and implications for human health.

Endocrine-disrupting chemicals (EDCs) are compounds, either natural or man-made, that interfere with the normal functioning of the endocrine system. There is increasing evidence that exposure to EDCs can have profound adverse effects on reproduction, metabolic disorders, neurological alterations, and increased risk of hormone-dependent cancer. Stem cells (SCs) are integral to these pathological processes, and it is therefore crucial to understand how EDCs may influence SC functionality. This review examines the literature on different types of EDCs and their effects on various types of SCs, including embryonic, adult, and cancer SCs. Possible molecular mechanisms through which EDCs may influence the phenotype of SCs are also evaluated. Finally, the possible implications of these effects on human health are discussed. The available literature demonstrates that EDCs can influence the biology of SCs in a variety of ways, including by altering hormonal pathways, DNA damage, epigenetic changes, reactive oxygen species production and alterations in the gene expression patterns. These disruptions may lead to a variety of cell fates and diseases later in adulthood including increased risk of endocrine disorders, obesity, infertility, reproductive abnormalities, and cancer. Therefore, the review emphasizes the importance of raising broader awareness regarding the intricate impact of EDCs on human health.

ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy.

Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFß, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Concise review: breast cancer stems cells and their role in metastases.

Background: Breast cancer stem cells (BCSCs) have been suggested to be responsible for the development of Breast cancer (BC). The aim of this study was to evaluate BCSCs and the target organs microenvironment immunophenotyping markers in common BC metastases, and therapeutic targets regarding to the mentioned criteria. Material and methods: This narrative review involved searching international databases; PubMed, Google Scholar using predetermined keywords including breast cancer, breast cancer stem cells, breast cancer metastases, immunophenotyping, immunohistochemistry and metastases. The search results were assessed based on the title, abstract, and full text of the articles, and relevant findings were included in the review. Results: BCSCs express high amounts of aldehyde dehydrogenase 1 (ALDH1), Ganglioside 2 (GD2), CD44 and CD133 but are negative for CD24 marker. CXCR4 and OPN have high expression in the cells and may contribute in BC metastasis to the bone. Nestin, CK5, prominin-1 (CD133) markers in BCSCs have been reported to correlate with brain metastasis. High expression of CD44 in BCSCs and CXCL12 expression in the liver microenvironment may contribute to BC metastasis to the liver. Aberrantly expressed vascular cell adhesion molecule-1 (VCAM-1) that binds to collagen and elastin fibers on pulmonary parenchyma, and CXCR4 of BCSCs and CXCL12 in lung microenvironment may promote the cells homing and metastasis to lung. Conclusion: As in various types of BC metastases different markers that expressed by the cells and target organ microenvironment are responsible, BCSCs immunophenotyping can be used as target markers to predict the disease prognosis and treatment.

Clinical applications of circulating biomarkers in non-small cell lung cancer.

Despite recent advances in cancer diagnostics and treatment, the mortality associated with lung cancer is still the highest in the world. Late-stage diagnosis, often accompanied by metastasis, is a major contributor to the high mortality rates, emphasizing the urgent need for reliable and readily accessible diagnostic tools that can detect biomarkers unique to lung cancer. Circulating factors, such as circulating tumor DNA and extracellular vesicles, from liquid biopsy have been recognized as diagnostic or prognostic markers in lung cancer. Numerous clinical studies are currently underway to investigate the potential of circulating tumor DNA, circulating tumor RNA, exosomes, and exosomal microRNA within the context of lung cancer. Those clinical studies aim to address the poor diagnostics and limited treatment options for lung cancer, with the ultimate goal of developing clinical markers and personalized therapies. In this review, we discuss the roles of each circulating factor, its current research status, and ongoing clinical studies of circulating factors in non-small cell lung cancer. Additionally, we discuss the circulating factors specifically found in lung cancer stem cells and examine approved diagnostic assays designed to detect circulating biomarkers in lung cancer patients.

Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer.

BACKGROUND: Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells. METHODS: Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis. RESULTS: POMs blocked in vitro binding activity of endogenous SOX2. [P2W18O62]6- (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen. CONCLUSIONS: Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer.

Concomitant Delivery of Pirarubicin and Salinomycin Synergistically Enhanced the Efficacy of Cancer Therapy and Reduced the Risk of Cancer Relapse.

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn't show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment.

Cancer Stem Cells: Detection and Characterization from Solid Tumors.

Cancer stem cells (CSCs) have emerged as an attractive research interest due to their prominent role in development of the tumors. CSCs are rare dormant cells that can self-renew and maintain tumor development and heterogeneity. A better understanding of CSCs can improve tumor classification and contribute toward the development of novel therapeutic approaches to fight cancer. Hence, it is of immense importance to comprehend the basic function of CSCs in tumor formation, which can only be possible by devising perfected methodologies to isolate, detect, and characterize them. In this chapter, we outline the key protocols to culture, identify, and isolate CSCs from solid tumors to further advance basic and clinical investigation related to CSCs and their role in tumor biology.

Oncofetal morphogenesis similar to embryonic gut formation by a subpopulation of DLD-1 human colon cancer cells.

Cancer stem cells (CSC) are thought to be responsible for cancer phenotypes and cellular heterogeneity. Here we demonstrate that the human colon cancer cell line DLD1 contains two types of CSC-like cells that undergo distinct morphogenesis in the reconstituted basement membrane gel Matrigel. In our method with cancer cell spheroids, the parent cell line (DLD1-P) developed grape-like budding structures, whereas the other (DLD1-Wm) and its single-cell clones dynamically developed worm-like ones. Gene expression analysis suggested that the former mimicked intestinal crypt-villus morphogenesis, while the latter mimicked embryonic hindgut development. The organoids of DLD1-Wm cells rapidly extended in two opposite directions by expressing dipolar proteolytic activity. The invasive morphogenesis required the expression of MMP-2 and CD133 genes and ROCK activity. These cells also exhibited gastrula-like morphogenesis even in two-dimensional cultures without Matrigel. Moreover, the two DLD1 cell lines showed clear differences in cellular growth, tumor growth and susceptibility to paclitaxel. This study also provides a simple organoid culture method for human cancer cell lines. HT-29 and other cancer cell lines underwent characteristic morphogenesis in direct contact with normal fibroblasts. Such organoid cultures would be useful for investigating the nature of CSCs and for screening anti-cancer drugs. Our results lead to the hypothesis that CSC-like cells with both invasive activity and a fetal phenotype, i.e,. oncofetal CSCs, are generated in some types of colon cancers.

Single-cell sequencing analysis revealed that WDR72 was a novel cancer stem cells related gene in gastric cancer.

Background: Cancer stem cells (CSCs) are pivotal in tumor resistance to chemotherapy and gastric cancer's rapid proliferation and metastasis. We aimed to explore the CSCs-related genes in gastric cancer epithelial cells. Methods: The mRNA expression profile and single-cell sequencing data of gastric cancer were downloaded from the public database. Results: We identified WDR72 as a CSCs-related gene in gastric cancer epithelial cells. WDR72 was highly expressed in gastric cancer tissues, and high expression of WDR72 was associated with inferior prognosis of patients. WDR72 expression had a significant negative correlation with the infiltration of CD8 + T cells and activated memory CD4 + T cells. PD-L1 expression was significantly reduced in gastric cancer patients with high WDR72 expression. WDR72 was correlated with IC50 of multiple small-molecule drugs. Conclusion: We identified a novel CSCs-related gene in gastric cancer epithelial cells, WDR72, which was highly expressed in patients with high stemness scores.

Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development.

Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.

Autophagy-mediated ID1 turnover dictates chemo-resistant fate in ovarian cancer stem cells.

BACKGROUND: The mechanisms enabling dynamic shifts between drug-resistant and drug-sensitive states in cancer cells are still underexplored. This study investigated the role of targeted autophagic protein degradation in regulating ovarian cancer stem cell (CSC) fate decisions and chemo-resistance. METHODS: Autophagy levels were compared between CSC-enriched side population (SP) and non-SP cells (NSP) in multiple ovarian cancer cell lines using immunoblotting, immunofluorescence, and transmission electron microscopy. The impact of autophagy modulation on CSC markers and differentiation was assessed by flow cytometry, immunoblotting and qRT-PCR. In silico modeling and co-immunoprecipitation identified ID1 interacting proteins. Pharmacological and genetic approaches along with Annexin-PI assay, ChIP assay, western blotting, qRT-PCR and ICP-MS were used to evaluate effects on cisplatin sensitivity, apoptosis, SLC31A1 expression, promoter binding, and intracellular platinum accumulation in ID1 depleted backdrop. Patient-derived tumor spheroids were analyzed for autophagy and SLC31A1 levels. RESULTS: Ovarian CSCs exhibited increased basal autophagy compared to non-CSCs. Further autophagy stimulation by serum-starvation and chemical modes triggered proteolysis of the stemness regulator ID1, driving the differentiation of chemo-resistant CSCs into chemo-sensitive non-CSCs. In silico modeling predicted TCF12 as a potent ID1 interactor, which was validated by co-immunoprecipitation. ID1 depletion freed TCF12 to transactivate the cisplatin influx transporter SLC31A1, increasing intracellular cisplatin levels and cytotoxicity. Patient-derived tumor spheroids exhibited a functional association between autophagy, ID1, SLC31A1, and platinum sensitivity. CONCLUSIONS: This study reveals a novel autophagy-ID1-TCF12-SLC31A1 axis where targeted autophagic degradation of ID1 enables rapid remodeling of CSCs to reverse chemo-resistance. Modulating this pathway could counter drug resistance in ovarian cancer.

Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression.

The global incidence of cancer is increasing, with estimates suggesting that there will be 26 million new cases and 17 million deaths per year by 2030. Cancer stem cells (CSCs) and extracellular vesicles (EVs) are key to the resistance and advancement of cancer. They play a crucial role in tumor dynamics and resistance to therapy. CSCs, initially discovered in acute myeloid leukemia, are well-known for their involvement in tumor initiation, progression, and relapse, mostly because of their distinct characteristics, such as resistance to drugs and the ability to self-renew. EVs, which include exosomes, microvesicles, and apoptotic bodies, play a vital role in facilitating communication between cells within the tumor microenvironment (TME). They have a significant impact on cellular behaviors and contribute to genetic and epigenetic changes. This paper analyzes the mutually beneficial association between CSCs and EVs, emphasizing their role in promoting tumor spread and developing resistance mechanisms. This review aims to investigate the interaction between these entities in order to discover new approaches for attacking the complex machinery of cancer cells. It highlights the significance of CSCs and EVs as crucial targets in the advancement of novel cancer treatments, which helps stimulate additional research, promote progress in ideas for cancer treatment, and provide renewed optimism in the effort to reduce the burden of cancer.

Post-translational modifications: The potential ways for killing cancer stem cells.

While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.

A cuproptosis-based nanomedicine suppresses triple negative breast cancers by regulating tumor microenvironment and eliminating cancer stem cells.

Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.

Prostate cancer stem cells and their targeted therapies.

Prostate cancer (PCa) is the most common malignancy among men worldwide. Through androgen receptor signaling inhibitor (ARSI) treatment, patients eventually succumb to castration-resistant prostate cancer (CRPC). For this, the prostate cancer stem cells (PCSCs), as a minor population of tumor cells that can promote tumor relapse, ARSI resistance, and disease progression, are gaining attention. Therefore, specific therapy targeting PCSCs has momentum. This study reviewed the identification and characterization of PCSCs and PCSC-based putative biomarkers and summarized their mechanisms of action. We further discussed clinical trials of novel therapeutic interventions focused on PCSC-related pathways, the PCSC microenvironment, cutting-edge miRNA therapy, and immunotherapy approaches from a mechanistic standpoint. This review provides updated insights into PCSC plasticity, identifying new PCSC biomarkers and optimized treatments for patients with advanced PCa.

1α,25-hydroxyvitamin D/VDR suppresses stem-like properties of ovarian cancer cells by restraining nuclear translocation of ß-catenin.

Several studies have indicated that 1α,25-hydroxyvitamin D [1α,25(OH)2D3] inhibits the proliferation and metastasis of cancer cells through suppressing epithelial-mesenchymal transition. However, its influence on the translocation of ß-catenin remains unclear. In the present study, ovarian cancer stem-like cells (CSCs), including side population (SP) and CD44+/CD117+, were isolated from mouse ovarian surface epithelial (MOSE) cells with malignant transformation. The findings revealed that 1α,25(OH)2D3 obviously reduced the sphere-forming ability, as well as Notch1 and Klf levels. Moreover, the limiting dilution assay demonstrated that 1α,25(OH)2D3 effectively hindered the tumorigenesis of ovarian CSCs in vitro. Notably, treatment with 1α,25(OH)2D3 led to a substantial increase in the cell population of CD44+/CD117+ forming one tumor from ≤ 100 to 445 in orthotopic transplanted model, indicating a pronounced suppression of stemness of ovarian CSCs. Additionally, 1α,25(OH)2D3 robustly promoted the translocation of ß-catenin from the nuclear to the cytoplasm through directly binding to VDR, which resulted in decreased levels of c-Myc and CyclinD1 within late MOSE cells. Taken together, these results strongly supported the role of 1α,25(OH)2D3 in inhibiting stem-like properties in ovarian cancer cells by restraining nuclear translocation of ß-catenin, thereby offering a promising target for cancer therapeutics.

Integrin αV Inhibition by GMI, a Ganoderma Microsporum Immunomodulatory Protein, Abolish Stemness and Migration in EGFR-Mutated Lung Cancer Cells Resistant to Osimertinib.

Integrins, the receptors of the extracellular matrix, are critical in the proliferation and metastasis of cancer cells. GMI, a Ganoderma microsporum immunomodulatory protein, possesses anticancer and antivirus abilities. The object of this study is to investigate the role of GMI in the integrins signaling pathway in lung cancer cells that harbor the EGFR L858R/T790M double mutation and osimertinib-resistance. Liquid chromatography-mass spectrometry and western blot assay were used to investigate the effect of GMI on inhibiting the protein expressions of integrins in H1975 cells. The migration ability and xenograft tumor growth of H1975 were suppressed by GMI. To elucidate the role of the integrin family in lung cancer resistant to osimertinib (AZD-9291, Tagrisso), H1975 cells were used to establish the osimertinib-resistant cells, named H1975/TR cells. The expressions of Integrin αV and stemness markers were much higher in H1975/TR cells than in H1975 cells. GMI suppressed cell viability, tumor spheroid growth, and the expressions of integrin αV and ß1 in H1975/TR cells. Furthermore, GMI suppressed the expressions of stemness markers and formation of tumor spheres via blocking integrin αV signaling cascade. This is the first study to reveal the novel function of GMI in constraining cancer stem cells and migration by abolishing the integrin αV-related signaling pathway in EGFR-mutated and osimertinib-resistant lung cancer cells.

THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway.

Thrombospondin-2 (THBS2), a secreted extracellular matrix protein, plays a crucial role in various biological processes including angiogenesis, tissue remodeling, and inflammation. Our study focuses on its function in human gastric cancer (GC). Through bioinformatics and tumor tissue analysis, we compared THBS2 expression in GC tissues and adjacent tissues, and predicted regulatory upstream and downstream molecules. The direct regulatory effect of miR-29b-3p on THBS2 was evaluated through dual-luciferase reporter assays, showing that miR-29b-3p targets the 3'-UTR of THBS2 mRNA, reducing its expression in GC cells. The influence of THBS2 on tumorigenesis and stemness was examined on protein expression levels via Western blot. In vivo, THBS2's role was investigated through xenograft and metastasis assays in nude mice, demonstrating that downregulation of THBS2 impairs GC tumorigenesis and liver metastasis. Our study identified THBS2 as a highly expressed prognostic factor in GC patients. Functionally, THBS2 promotes GC progression through the Notch signaling pathway by regulating Notch3, NEY1, and HES1 proteins, and sustains cancer stem cell-like characteristics by Notch3, including the expression of CD44, Nanog, OCT4, and SOX2. In sum, our study reveals that THBS2 promotes GC progression and stemness, modulated negatively by miR-29b-3p. This suggests potential therapeutic targets within the THBS2/Notch signaling axis for combating gastric cancer.

The Role of Tumor Stem Cells in Colorectal Cancer Drug Resistance.

Background: Colorectal cancer is a major cause of mortality among the prevalent malignant tumors of the gastrointestinal tract. Although chemotherapy is a standard treatment for colorectal cancer, its efficacy is limited by chemoresistance. Recent studies have investigated targeting tumor stem cells as a potential new therapeutic approach for addressing chemoresistance in colorectal cancer. Colorectal cancer frequently relapses, with tumor stem cells often representing one of the leading causes of treatment failure. Purpose: Understanding drug resistance in colorectal cancer stem cells is crucial for improving treatment outcomes. By focusing on developing targeted therapies that specifically address drug resistance in colorectal cancer stem cells, there is potential to make significant advancements in the treatment of colorectal cancer.This approach may lead to more effective and lasting outcomes in patients battling colorectal cancer. Research Design: In this review, a comprehensive overview of recent research on colorectal cancer stem cell treatment resistance is presented.Results: Elucidating the key underlying mechanisms. This review also highlights the potential benefits of targeted therapies in overcoming colorectal cancer resistance to treatment. Conclusions: CCSCs are key players in drug resistance of CRC, indicating their potential as targets for effective therapy. Elucidating their role in this process could aid in discovering tailored treatment strategies.The significance of signaling pathways, TME, and miRNA in regulating drug resistance in CCSCs is been highlighted.