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Targeted therapy against cancer stem cells. Therapeutics aimed at the general population of cancer cells has a limited impact on cancer stem cells (CSCs). In time, their regenerative and proliferative capabilities are responsible for the relapse. On the contrary, therapy aimed at the CSC population determines a destruction of the population responsible for differentiation and proliferation which in turn produces a much more pronounced and stable tumoral regression. The CSCs are displayed as the green, larger cells while the non-stem cells are depicted as the smaller, red with the skull and bones in the middle.
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Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal develo...
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Context 1
... is known that cancer therapy targeting the tumor cell bulk can produce a partial regression of the tumor, followed by the appearance of new tumor clones, developed from existing CSC population. Therefore, identification and targeting of neoplastic stem cells represents a major challenge in modern cancer therapy and researchers are trying to find new molecular therapies directed specifically against these cells (Figure 2). Thus, molecular therapies against CSCs were reported to be more effective, as they induce tumor regression by reducing the occurrence of new cancer cells (Figure 2) [49,65]. ...
Context 2
... identification and targeting of neoplastic stem cells represents a major challenge in modern cancer therapy and researchers are trying to find new molecular therapies directed specifically against these cells (Figure 2). Thus, molecular therapies against CSCs were reported to be more effective, as they induce tumor regression by reducing the occurrence of new cancer cells (Figure 2) [49,65]. ...
Citations
... By mimicking cancer behavior and offering insights into effective drug development, microfluidic models hold promise for enhancing our understanding of cancer biology [124]. Given that cancer cell motility is influenced by extracellular matrix components and the CSC phenomenon is implicated in therapeutic resistance, microfluidic models like tumors-on-chips could revolutionize CSC research [125][126][127][128][129][130]. ...
Autophagy is a globally conserved cellular activity that plays a critical role in maintaining cellular homeostasis through the breakdown and recycling of cellular constituents. In recent years, there has been much emphasis given to its complex role in cancer stem cells (CSCs) and stem cell treatment. This study examines the molecular processes that support autophagy and how it is regulated in the context of CSCs and stem cell treatment. Although autophagy plays a dual role in the management of CSCs, affecting their removal as well as their maintenance, the intricate interaction between the several signaling channels that control cellular survival and death as part of the molecular mechanism of autophagy has not been well elucidated. Given that CSCs have a role in the development, progression, and resistance to treatment of tumors, it is imperative to comprehend their biological activities. CSCs are important for cancer biology because they also show a tissue regeneration model that helps with organoid regeneration. In other words, the manipulation of autophagy is a viable therapeutic approach in the treatment of cancer and stem cell therapy. Both synthetic and natural substances that target autophagy pathways have demonstrated promise in improving stem cell-based therapies and eliminating CSCs. Nevertheless, there are difficulties associated with the limitations of autophagy in CSC regulation, including resistance mechanisms and off-target effects. Thus, the regulation of autophagy offers a versatile strategy for focusing on CSCs and enhancing the results of stem cell therapy. Therefore, understanding the complex interactions between autophagy and CSC biology would be essential for creating therapeutic treatments that work in both regenerative medicine and cancer treatment.
... Cancer stem cells (CSCs) are a small subpopulation of highly resistant tumor cells with characteristics of self-renewal, infinite proliferation, and potential for multi-directional differentiation. The exact origin of cancer stem cells remains unknown; the theory of their existence was first shown in breast cancer cells [62,63]. The main consequences of CSCs are recurrence after primary treatment, tumor cell heterogeneity, metastasis, minimal residual disease, and drug resistance. ...
Cancer immunotherapy is a rapidly developing field of medicine that aims to use the host’s immune mechanisms to inhibit and eliminate cancer cells. Antibodies targeting CTLA-4, PD-1, and its ligand PD-L1 are used in various cancer therapies. However, the most thoroughly researched pathway targeting PD-1/PD-L1 has many limitations, and multiple malignancies resist its effects. Human endogenous retrovirus-H Long repeat-associating 2 (HHLA2, known as B7H5/B7H7/B7y) is the youngest known molecule from the B7 family. HHLA2/TMIGD2/KIRD3DL3 is one of the critical pathways in modulating the immune response. Recent studies have demonstrated that HHLA2 has a double effect in modulating the immune system. The connection of HHLA2 with TMIGD2 induces T cell growth and cytokine production via an AKT-dependent signaling cascade. On the other hand, the binding of HHLA2 and KIR3DL3 leads to the inhibition of T cells and mediates tumor resistance against NK cells. This review aimed to summarize novel information about HHLA2, focusing on immunological mechanisms and clinical features of the HHLA2/KIR3DL3/TMIGD2 pathway in the context of potential strategies for malignancy treatment.
... CSCs are a small subpopulation of cancer cells that have the ability to self-renew and differentiate into multiple cell types, similar to normal stem cells [27,28]. CSCs are thought to be responsible for tumor initiation, proliferation, and resistance to conventional cancer treatments [29,30]. Therefore, targeting CSCs is an important strategy for developing effective cancer therapies. ...
Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite the advances in GBM treatment, outcomes remain poor, with a 2-year survival rate of less than 5%. Hyperbaric oxygen (HBO) therapy is an intermittent, high-concentration, short-term oxygen therapy used to increase cellular oxygen content. In this study, we evaluated the effects of HBO therapy, alone or combined with other treatment modalities, on GBM in vitro and in vivo. In the in vitro analysis, we used a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess the effects of HBO therapy alone, a colony formation assay to analyze the effects of HBO therapy combined with radiotherapy and with temozolomide (TMZ), and a neurosphere assay to assess GBM stemness. In the in vivo analysis, we used immunohistochemical staining and in vivo bioluminescence imaging to assess GBM stemness and the therapeutic effect of HBO therapy alone or combined with TMZ or radiotherapy, respectively. HBO therapy did not affect GBM cell viability, but it did reduce the analyzed tumors’ ability to form cancer stem cells. In addition, HBO therapy increased GBM sensitivity to TMZ and radiotherapy both in vitro and in vivo. HBO therapy did not enhance tumor growth and exhibited adjuvant effects to chemotherapy and radiotherapy through inhibiting GBM stemness. In conclusion, HBO therapy shows promise as an adjuvant treatment for GBM by reducing cancer stem cell formation and enhancing sensitivity to chemotherapy and radiotherapy.
... Although several new drugs have improved survival in patients with MM over the past decade, patients often develop recurrent and/or refractory MM, and long-term disease-free survival remains poor (3). Numerous studies have shown that primary tumors and MM contain a subpopulation of cancer stem cells (CSCs) with stem-like characteristics, including the capacity for self-renewal and tumorigenicity (4). Additionally, a distinct subset of side population (SP) cells with CSC-like properties that highly express ATP-binding cassette (ABC) transporters are also found in MM, which may alter drug resistance. ...
Drug resistance remains a major challenge for multiple myeloma (MM) treatment, and side population (SP) cells may play a key role in this resistance. The function of connexin 43 (Cx43)-mediated gap junction intercellular communication (GJ-IC) in MM cells is poorly understood. Bone marrow mesenchymal stem cells (BMSCs) from different sources were isolated and cultured. SP cells of MM cell line RPMI 8266 were separated by flow cytometry. Real-time reverse transcriptase-polymerase chain reaction and Western blot were used to detect Cx43 mRNA and protein expression in BMSCs, RPMI 8266 and SP cells from different sources. The effects of BMSCs from different sources on SP cell cycle, in vitro colony formation ability, stem cell-related gene expression and drug resistance, and the addition of 18α glycyrrhetinic acid (18αGA) as a pathway inhibitor were observed. Here, we demonstrate that MM cells expressed Cx43 and contained a high percentage of SP cells. We observed an increase in the survival and proliferative capacity of SP cells compared with RPMI 8226 cells, but treatment with 18αGA decreased SP cell survival and proliferation (all P<0.05). MM cells were sensitive to dexamethasone- and bortezomib-induced apoptosis; however, this sensitivity was significantly decreased when MM cells were co-cultured with BMSCs, and 18αGA partly recovered this cytotoxicity (all P<0.05). Collectively, our data suggest that GJ-IC between BMSCs and MM cells is one of the important regulatory mechanisms underlying MM cells survival, proliferation, and drug sensitivity.
... The causes of recurrence are complex and include the absence of a clear tumor margin useful for a complete resection, the presence of migrating cancer cells into the surrounding normal tissue, high proliferative index, chemotherapy and radiotherapy resistance of the cancer stem cells (CSCs), and cerebrospinal fluid (CSF) dissemination. CSCs, also known as tumor-initiating cells (TICs), are suggested to be responsible for cancer relapse and drug resistance due to their ability to self-renew and to differentiate into a heterogeneous population of cancer cells [4,5]. Therefore, the surgical removal of the entire tumor mass is impossible. ...
... Studies showed that circulating endothelial cells, tumorassociated macrophages (TAMs), Tie-2 monocytes, myeloid-derived suppressor cells (MD-SCs), neutrophiles, and GSCs are involved in the formation of new vessels [63][64][65][66]. GBMs are characterized by increased angiogenesis (process of stimulating the formation of new vessels from pre-existing ones) [2,4,5,9,13]. ...
Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.
... Crucial to new therapeutic strategy planning is CSC analysis and targeting because this cell subpopulation is a key factor in chemotherapeutic agent and radiotherapy resistances, contributes to posttreatment relapse, and is involved in tumor metastasis (14)(15)(16)(17)(18)(19)(20)(21). The fact that conventional chemotherapies preferentially target actively-cycling cells, as opposed to CSCs, may implicate these observed treatment failures. ...
Purpose: The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSC) was explored, as CSCs are considered responsible for chemoresistance and relapses. Experimental Design: Putative mCSCs were visualized by engineering patient-derived melanoma cells (MC) with a lenti-viral vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays. We explored the sensitivity of eGFP þ mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence, in vitro. First, we treated MCs in vitro with fotemustine or dabrafenib (BRAF-mutated cases); then, surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed in vivo in two distinct immunodeficient murine models.
... In most cancers, there is a side population of cells characterized by self-renewal ability, differentiation potential, high tumorigenicity, and therapy resistance, known as cancer stem cells (CSCs) [4,5]. Unfortunately, the presence of CSCs in ESCC can consequently lead to therapeutic failures [6]. ...
... Given that NK1R is considered highly involved in the formation and growth of many carcinomas, intense research is being done to block this receptor with NK1R antagonists for possible anticancer uses [19]. In most of the cancers, there is a side population of cells characterized by self-renewal ability, differentiation potential, high carcinogenicity, and therapy resistance, known as cancer stem cells [4,5]. ESCC, as world's sixth leading cause of cancer mortality, is histologically the main form of esophageal cancer. ...
The antagonists of the neurokinin-1 receptor (NK1R) are known for their anti-inflammatory, anxiolytic, antiemetic, and anticancer activities. Aprepitant, a nonpeptide NK1R antagonist, is used in nausea and vomiting, the most common side effects of cancer chemotherapy in patients. It has been established that NK1R activation by substance P (SP), which links cancer promotion and progression to a neurokinin-mediated environment, became one mechanism that corresponds to the mitogenesis of tumor cells. Therefore, this study is aimed at explaining and evaluating the anticancer impacts of aprepitant on esophageal squamous cancer cell (ESCC) spheres by using in vitro experiments, such as resazurin, ROS, annexin-V binding, RT-PCR, and Western blot analysis. As a result, we showed that aprepitant had strong antiproliferative and cytotoxic effects on ESCC cell spheres. Also, aprepitant caused significant G2-M cell cycle arrest depending on concentration increase. Further, exposure of cells to this agent resulted in caspase -8/-9-dependent apoptotic pathway activation by modifying the expression of genes involved in apoptosis. Besides, treatment of the cells by aprepitant abrogates of the PI3K/Akt pathway, as shown by reducing the level of Akt, induces apoptotic cell death. In summary, pharmacological inhibition of NK1R with aprepitant seems to have a significant chance of treating ESCC as a single agent or in conjunction with other chemotherapeutic drugs.
... Many medicinal plants have anticancer properties due to secondary metabolites synthesized from various phytochemical compounds such as alkaloids, flavonoids, terpenoids, etc. Such metabolites can sensitize cancer cells and cancer stem cells (CSCs) to chemotherapeutic agents by targeting multiple signaling pathways and modulating stemness properties [5]. One such medicinal plant product, the benzo phenanthridine alkaloid Sanguinarine (SNG), is isolated from the species Sanguinaria canadensis and Fumaria [6]. ...
Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies.
... GBM stem cells (GSCs) represent another cell type in GBM that appear to be important for tumour growth, since they have been reported to be implicated in drug resistance and recurrence after therapy (46). This suggests that GSCs may be suitable targets for the development of novel therapeutic strategies (47). ...
Due to its localisation, rapid onset, high relapse rate and resistance to most currently available treatment methods, glioblastoma multiforme (GBM) is considered to be the deadliest type of all gliomas. Although surgical resection, chemotherapy and radiotherapy are among the therapeutic strategies used for the treatment of GBM, the survival rates achieved are not satisfactory, and there is an urgent need for novel effective therapeutic options. In addition to single-target therapy, multi-target therapies are currently under development. Furthermore, drugs are being optimised to improve their ability to cross the blood-brain barrier. In the present review, the main strategies applied for GBM treatment in terms of the most recent therapeutic agents and approaches that are currently under pre-clinical and clinical testing were discussed. In addition, the most recently reported experimental data following the testing of novel therapies, including stem cell therapy, immunotherapy, gene therapy, genomic correction and precision medicine, were reviewed, and their advantages and drawbacks were also summarised.
... Similar to normal stem cells (SCs), CSCs proliferate by undergoing symmetrical cell divisions, securing their self-renewal and differentiation potentials [32,33]. Non-CSCs are nontumorigenic heterogeneous cancer cells, hierarchically generated from CSCs through asymmetrical cell divisions [34,35]. The frequency of CSCs is variable from 0.1 % or less up to 40 % [36][37][38][39], and non-CSCs certainly form the bulk of a tumor. ...
Accumulating evidence strongly indicates that the presence of cancer stem cells (CSCs) leads to the emergence of worse clinical scenarios, such as chemo- and radiotherapy resistance, metastasis, and cancer recurrence. CSCs are a highly tumorigenic population characterized by self-renewal capacity and differentiation potential. Thus, CSCs establish a hierarchical intratumor organization that enables tumor adaptation to evade the immune response and resist anticancer therapy. YY1 functions as a transcription factor, RNA-binding protein, and 3D chromatin regulator. Thus, YY1 has multiple effects and regulates several molecular processes. Emerging evidence indicates that the development of lethal YY1-mediated cancer phenotypes is associated with the presence of or enrichment in cancer stem-like cells. Therefore, it is necessary to investigate whether and to what extent YY1 regulates the CSC phenotype. Since CSCs mirror the phenotypic behavior of stem cells, we initially describe the roles played by YY1 in embryonic and adult stem cells. Next, we scrutinize evidence supporting the contributions of YY1 in CSCs from a number of various cancer types. Finally, we identify new areas for further investigation into the YY1-CSCs axis, including the participation of YY1 in the CSC niche.
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