Presence Of Cancer Stem Cells Research Articles

Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy

BackgroundOvarian cancer has a high mortality rate mainly due to its resistance to currently used therapies. This resistance has been associated with the presence of cancer stem cells (CSCs), interactions with the microenvironment, and intratumoral heterogeneity. Therefore, the search for new therapeutic targets, particularly those targeting CSCs, is important for improving patient prognosis. HOOK1 has been found to be transcriptionally altered in a substantial percentage of ovarian tumors, but its role in tumor initiation and development is still not fully understood.MethodsThe downregulation of HOOK1 was performed in ovarian cancer cell lines using CRISPR/Cas9 technology, followed by growth in vitro and in vivo assays. Subsequently, migration (Boyden chamber), cell death (Western-Blot and flow cytometry) and stemness properties (clonal heterogeneity analysis, tumorspheres assay and flow cytometry) of the downregulated cell lines were analysed. To gain insights into the specific mechanisms of action of HOOK1 in ovarian cancer, a proteomic analysis was performed, followed by Western-blot and cytotoxicity assays to confirm the results found within the mass spectrometry. Immunofluorescence staining, Western-blotting and flow cytometry were also employed to finish uncovering the role of HOOK1 in ovarian cancer.ResultsIn this study, we observed that reducing the levels of HOOK1 in ovarian cancer cells reduced in vitro growth and migration and prevented tumor formation in vivo. Furthermore, HOOK1 reduction led to a decrease in stem-like capabilities in these cells, which, however, did not seem related to the expression of genes traditionally associated with this phenotype. A proteome study, along with other analysis, showed that the downregulation of HOOK1 also induced an increase in endoplasmic reticulum stress levels in these cells. Finally, the decrease in stem-like properties observed in cells with downregulated HOOK1 could be explained by an increase in cell death in the CSC population within the culture due to endoplasmic reticulum stress by the unfolded protein response.ConclusionHOOK1 contributes to maintaining the tumorigenic and stemness properties of ovarian cancer cells by preserving protein homeostasis and could be considered an alternative therapeutic target, especially in combination with inducers of endoplasmic reticulum or proteotoxic stress such as proteasome inhibitors.

Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review).

The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5‑30 mm, or whole‑brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial‑to‑mesenchymal transition, overexpression of programmed cell death‑ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes‑associated protein‑1, on cerebral metastases originating from lung cancer.

Cancer Stem Cell and Epithelial Mesenchymal Transition (EMT) in Canine Transmissible Venereal Tumour- A Preliminary Study

Cancer Stem Cell and Epithelial Mesenchymal Transition (EMT) in Canine Transmissible Venereal Tumour- A Preliminary Study

Diagnostic and predictive significance of the ferroptosis-related gene TXNIP in lung adenocarcinoma stem cells based on multi-omics

BackgroundLung cancer stands as the foremost cause of cancer-related fatalities globally. The presence of cancer stem cells (CSCs) poses a challenge, rendering current targeted tumor therapies ineffective. This study endeavors to investigate a novel therapeutic approach focusing on ferroptosis and delves into the expression of ferroptosis-related genes within lung CSCs. MethodsWe systematically examined RNA-seq datasets derived from lung tumor cells (LTCs) and lung cancer stem cells (LSCs), as previously investigated in our research. Our focus was on analyzing differentially expressed genes (DEGs) related to ferroptosis. Utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), we conducted functional analysis of these ferroptosis-related DEGs. Additionally, we employed protein‒protein interaction networks to identify hub genes. LC‒MS/MS analysis of LTCs and LSCs was conducted to pinpoint the crucial ferroptosis-related gene–thioredoxin-interacting protein (TXNIP).Further, we delved into the immune cell infiltration landscape of LTCs and LSCs, examining the correlation between TXNIP and lung adenocarcinoma (LUAD) using data from The Cancer Genome Atlas (TCGA) database. To complement these findings, we measured the expression levels of TXNIP, glutathione peroxidase 4(GPX4), nuclear receptor coactivator 4 (NCOA4) in LUAD tissues through immunohistochemistry (IHC) staining. ResultsA total of 651 DEGs were identified, with 17 of them being ferroptosis-related DEGs. These seventeen genes were categorized into four groups: driver genes, suppressor genes, unclassified genes, and inducer genes. Enrichment analysis revealed significant associations with oxidative stress, cell differentiation, tissue development, and cell death processes. The RNA-seq analysis demonstrated consistent gene expression patterns with protein expression, as evidenced by mass spectrometry analysis. Among the identified genes, SFN and TXNIP were singled out as hub genes, with TXNIP showing particularly noteworthy expression. The expression of the ferroptosis-related gene TXNIP exhibited correlations with the presence of an immunosuppressive microenvironment, TNM stages, and the degree of histological differentiation.Also, the ferroptosis-markers GPX4 and NCOA4 displayed correlations with LUAD. This comprehensive analysis underscores the significance of TXNIP in the context of ferroptosis-related processes and their potential implications in cancer development and progression. ConclusionThe investigation conducted in this study systematically delved into the role of the ferroptosis-related gene TXNIP in Lung CSCs. The identification of TXNIP as a potentially valuable biomarker in this context could have significant implications for refining prognostic assessments and optimizing therapeutic strategies for advanced lung cancer.

A novel combined therapeutic strategy of Nano-EN-IR@Lip mediated photothermal therapy and stem cell inhibition for gastric cancer

Recurrence and metastasis of gastric cancer is a major therapeutic challenge for treatment. The presence of cancer stem cells (CSCs) is a major obstacle to the success of current cancer therapy, often leading to treatment resistance and tumor recurrence and metastasis. Therefore, it is important to develop effective strategies to eradicate CSCs. In this study, we developed a combined therapeutic strategy of photothermal therapy (PTT) and gastric cancer stem cells (GCSCs) inhibition by successfully synthesizing nanoliposomes loaded with IR780 (photosensitizer) and EN4 (c-Myc inhibitor). The nanocomposites are biocompatible and exhibit superior photoacoustic (PA) imaging properties. Under laser irradiation, IR780-mediated PTT effectively and rapidly killed tumor cells, while EN4 synergistically inhibited the self-renewal and stemness of GCSCs by suppressing the expression and activity of the pluripotent transcription factor c-Myc, preventing the tumor progression of gastric cancer. This Nano-EN-IR@Lip is expected to be a novel clinical nanomedicine for the integration of gastric cancer diagnosis, treatment and prevention.

Abstract 5114: Deciphering the implications of THOC7 in medulloblastoma: Unraveling its role in tumor growth and progression

Abstract Background: Medulloblastoma (MB) is the most common malignant brain cancer in children. Despite the progress made in treating MB, the 5-year survival rate for high-risk tumors remains poor and risk of recurrence within 2 years of treatment is still high. Unfortunately, patients who do survive have reduced quality of life because of the highly toxic side effects of radiation and chemotherapy. Those facts underline the importance of identifying new drivers of MB and understanding the mechanism by which those drivers may promote MB. Using CRISPR-based dependency analysis, we discovered THO Complex Subunit 7 Homolog (THOC7) as one of the highly differentially expressed genes that may uniquely provide survival advantage to MB cells. THOC7 is a component of the THO subcomplex of the TREX complex, which is known to couple mRNA transcription, processing and nuclear export associated with spliced mRNA. Methods: To understand the role of THOC7 in MB, we silenced the expression of THOC7 using siRNAs in multiple MB cell lines. The knockdown efficiency was confirmed by western blot and qPCR. The effect of THOC7 silencing on the viability of MB cells was assessed by short-term viability and long-term colony formation assays. The effect of THOC7 silencing on MB cell proliferation was measured using an IncuCyte. To assess whether THOC7 may affect MB progression, we performed Transwell migration assay. To understand the mechanism by which THOC7 may play a role in medulloblastomogenesis, we measured the effect of THOC7 silencing on the cell cycle progression and apoptosis. As presence of cancer stem cells is linked to relapse and makes MB refractory to radiation therapy, we asked whether THOC7 may support MB stem cell proliferation using neurosphere assay. Results: Our analysis revealed that MB is highly addicted to THOC7. Importantly, higher expression of THOC7 is strongly correlated with lower overall survival of MB patients. We showed that depletion of THOC7 inhibited the short- and long-term viability as well as proliferation of MB cells. In addition, silencing of THOC7 inhibited migration/invasion of MB cells. THOC7 depletion led to cell cycle arrest and increased apoptosis of MB cells. Furthermore, our neurosphere assay demonstrated that silencing of THOC7 blocked the MB stem cell proliferation. Conclusion: Our results suggest that THOC7 may be a novel driver of MB growth and progression. Inhibition of MB stem cell proliferation in THOC7 depleted cells indicates that THOC7 inhibition may sensitize refractory MB to radiation therapy. Experiments are currently underway to understand the mechanism by which THOC7 may support MB growth and progression. In conclusion, our results showing no effect of THOC7 silencing on normal cell viability suggest that approaches aimed at silencing THOC7 may be a safe and viable approach for treating MB. Citation Format: Shahad M. Abdulsahib, Santosh Timilsina, Saif Nirzhor, Daisy Medina, Prabhakar V. Pitta, Panneerdoss Subbarayalu, Manjeet K. Rao. Deciphering the implications of THOC7 in medulloblastoma: Unraveling its role in tumor growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5114.

Characteristics of Cancer Stem Cells and Their Potential Role in Endometrial Cancer.

Endometrial cancer is one of most common types of gynaecological tumours in developing countries. It has been suggested that cancer stem cells play an important role in the development of endometrial cancer. These are a subset of highly tumorigenic cells with similar features to normal stem cells (unlimited proliferation, multi-potential differentiation, self-renewal, aggressiveness, invasion, recurrence, and chemo- and endocrine therapy resistance). Wnt/β-catenin, Hedghog, and Notch1 are the most frequently activated pathways in endometrial cancer stem cells. The presence of cancer stem cells is associated with the resistance to chemotherapy caused by different mechanisms. Various markers, including CD24, CD40, CD44, CD9, CD133, and CD 166, have been identified on the surface of these cells. A higher expression of such markers translates into enhanced tumorigenicity. However, there is no strong evidence showing that any of these identified markers can be used as the universal marker for endometrial cancer stem cells. Growing data from genomic and proteomic profiling shed some light on the understanding of the molecular basis of cancers in humans and the role of cancer stem cells. However, there is much left to discover. Therefore, more studies are needed to fully uncover their functional mechanisms in order to prevent the development and recurrence of cancer, as well as to enhance treatment effectiveness.

Abstract B010: PITAR, a p53 inactivating TRIM28 associated RNA, executes an alternate way of p53 inactivation

Abstract B010: PITAR, a <i>p</i>53 inactivating TRIM28 associated RNA, executes an alternate way of p53 inactivation

Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors.

Hypoxia in solid tumors is an important source of chemoresistance that can determine poor patient prognosis. Such chemoresistance relies on the presence of cancer stem cells (CSCs), and hypoxia promotes their generation through transcriptional activation by HIF transcription factors. We used ovarian cancer (OC) cell lines, xenograft models, OC patient samples, transcriptional databases, induced pluripotent stem cells (iPSCs) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). Here, we show that hypoxia induces CSC formation and chemoresistance in ovarian cancer through transcriptional activation of the PLD2 gene. Mechanistically, HIF-1α activates PLD2 transcription through hypoxia response elements, and both hypoxia and PLD2 overexpression lead to increased accessibility around stemness genes, detected by ATAC-seq, at sites bound by AP-1 transcription factors. This in turn provokes a rewiring of stemness genes, including the overexpression of SOX2, SOX9 or NOTCH1. PLD2 overexpression also leads to decreased patient survival, enhanced tumor growth and CSC formation, and increased iPSCs reprograming, confirming its role in dedifferentiation to a stem-like phenotype. Importantly, hypoxia-induced stemness is dependent on PLD2 expression, demonstrating that PLD2 is a major determinant of de-differentiation of ovarian cancer cells to stem-like cells in hypoxic conditions. Finally, we demonstrate that high PLD2 expression increases chemoresistance to cisplatin and carboplatin treatments, both in vitro and in vivo, while its pharmacological inhibition restores sensitivity. Altogether, our work highlights the importance of the HIF-1α-PLD2 axis for CSC generation and chemoresistance in OC and proposes an alternative treatment for patients with high PLD2 expression.

A10 PROLINE METABOLISM AFFECTS CANCER STEM CELLS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Esophageal squamous cell carcinoma (ESCC) is highly deadly with a 5-year survival rate of only 16%, partly due to treatment resistance. Resistance is associated, among others, with the presence of cancer stem cells (CSC). Previous work in the laboratory has shown that prolonged exposure to anticancer treatments such as radiation and/or 5-FU leads to increased number of CSCs. Interestingly, disruption of amino acid metabolism, especially decreased proline levels, has been observed in treated cells. Proline is a non-essential amino acid that can either be uptake from the environment or synthesized from glutamate or ornithine. However, its role in cancer cells remains poorly understood and controversial. Aims Therefore, my project aims at determining the role of proline metabolism in CSC abundance and tumoral properties in ESCC. Methods Using ESCC cell lines, TE11 and TE15, we stimulated proline metabolism by adding proline to the media or inhibited its catabolism using L-THFA. L-THFA forces proline accumulation in the cell. We then conducted flow cytometry to quantify CSC proportion, proliferation assay, spheroid formation assay and spheroids included in collagen for migration and invasion assay. Results First, the stimulation of proline metabolism decreased the proportion of CSCs in flow cytometry. These results align with our initial observations, where CSC-enriched cells exhibited reduced proline levels. Second, the inhibition of proline catabolism by L-THFA had the opposite effect, namely an increase in the proportion of CSC. Interestingly, these changes in the proportion of CSCs induced by proline or L-THFA translated into changes in clonogenic potential, a capacity typically associated with stem cells. Indeed, limiting dilution spheroids formation assays showed that proline decreased while L-THFA increased the number of formed spheroids. Since spheroids formation is linked to the presence of CSC, this provides new evidence of the impact of proline metabolism on CSC characteristics. Finally, L-THFA treatments drastically increased migratory and invasive abilities in 3D spheroid models compared to untreated or proline-treated conditions. Conclusions In conclusion, our results suggest that proline metabolism is implicated in the enrichment of cancer stem cells as well as in their functions. Funding Agencies CAG, CIHRinnovation.ca ; Centre de recherche CHUS ; FMSS ; Canada Research Chairs

A57 LONG-TERM EXPOSURE TO ANTICANCER TREATMENTS INCREASES AUTOPHAGY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background The most common type of esophageal cancer, esophageal squamous cell carcinoma (ESCC), has a 5-year survival rate of only 15%. This low survival rate is to some extent attributed to a high relapse rate, which is, in part, linked to the presence of cancer stem cells (CSC). CSC are a subpopulation of tumor cells that show reduced sensitivity to conventional anticancer therapies, increased potency and self-renewal capacities. With that in mind, ESCC cell lines were exposed in a prolonged manner to anticancer treatments (radiotherapy, 5-FU chemotherapy, and combined therapy) in our laboratory. As expected, an increase in the proportion of CSC (CD44highCD24high) was observed by flow cytometry following the treatments. In pursuit of innovative therapeutic approaches, we conducted an in-depth investigation of the proteomic profiles of these cell lines by mass spectrometry (MS), seeking to unveil novel biological mechanisms. Interestingly, many proteins associated with metabolism and autophagy were modulated. Several alterations were observed by a metabolomic approach as well, namely an increase in intracellular lactate concentration. Recently, a novel role for lactate has been described: lactylation, which is a post-translational modification. Lactylome of those cell lines revealed alteration in proteins related to autophagy and those results led to my research project. Aims Investigate the role of lactylation in autophagy of ESCC. Methods Human ESCC cell lines (including the cell lines exposed to anticancer treatments) will be used as cell culture models. Cell and organoid cultures, mass spectrometry, qPCR, WB, and proliferation assay were used. Results MS analysis of proteins related to autophagy (i.e. RAB1B, CK2, SNX6 et GABARAP) suggests differential regulation of autophagy in cell lines exposed to prolonged treatments. A strong contribution of the 5-FU treatment to the autophagic modification is observable in the double-treated cells. Thus, we confirmed an increase in the LC3BII/I ratio by WB in the cell lines exposed to anticancer treatments. LC3BII/I WB used in combination with Bafilomycin A1 treatment for inhibition of autophagosome and lysosome fusion is a commonly used read-out for autophagic flux. To further study the link between lactylation, autophagy and CSC, we screened 10 human ESCC cell lines for their LC3BII/I ratio. Four cell lines were selected: TE1, TE2, HCE4 and TE5. Using Bafilomycin A1, we confirmed that the autophagic flux in those cell lines was not blocked. Those cell lines will now be used to perform lactylome analysis of sorted CSC cells. Conclusions In brief, our results showed that the autophagic flux is increased in cells exposed to prolonged treatments. This suggests that autophagy could play a role in ESCC response to treatment. Funding Agencies CIHRTRIANGLE, Chaires de recherche du Canada, CRCHUS, Université de Sherbrooke

Platelet Membrane Biomimetic Manganese Carbonate Nanoparticles Promote Breast Cancer Stem Cell Clearance for Sensitized Radiotherapy.

The presence of cancer stem cells (CSCs) significantly limits the therapeutic efficacy of radiotherapy (RT). Efficient elimination of potential CSCs is crucial for enhancing the effectiveness of RT. In this study, we developed a biomimetic hybrid nano-system (PMC) composed of MnCO3 as the inner core and platelet membrane (PM) as the outer shell. By exploiting the specific recognition properties of membrane surface proteins, PMC enables precise targeting of CSCs. Sonodynamic therapy (SDT) was employed using manganese carbonate nanoparticles (MnCO3 NPs), which generate abundant reactive oxygen species (ROS) upon ultrasound (US) irradiation, thereby impairing CSC self-renewal capacity and eradicating CSCs. Subsequent RT effectively eliminates common tumor cells. Both in vitro cell experiments and in vivo animal studies demonstrate that SDT mediated by PMC synergistically enhances RT to selectively combat CSCs while inhibiting tumor growth without noticeable side effects. Our findings offer novel insights for enhancing the efficacy and safety profiles of RT.

Effect of Pioglitazone and Cetuximab on Colon Cancer Stem-like Cell (CCSLCs) Properties.

One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents. The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring. The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal-- to-epithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment. Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment.

Analysis of Clinical Success and Molecular Mechanisms of Action of Novel Anti-glioblastoma Drugs: A Review.

Gliomas and glioblastomas (GBM) are common primary malignant brain tumors, which are highly malignant and have a poor prognosis. The presence of cancer stem cells with unrestricted proliferative capacity and ability to generate glial neoplastic cells, the diffuse nature of GBM, and other specific factors of GBM contribute to poor results of drug therapy in patients with GBM. Despite the worldwide efforts to improve the treatment, many novel anti-GBM drugs are active just in vitro, in silico, and in preclinical trials, and they sometimes demonstrate poor or no activity in clinical trials. In this paper, we have casually selected and analyzed the most promising evidence-based results related to glioblastoma treatment at FDA and Clinical Trials.gov databases. It was observed that the most prospective trend in the development of anti-GBM drugs is combination therapy vs. monotherapy. Our analysis of clinical trials has allowed us to predict that the most promising combination therapy that has shown the best results in patient's surveillance should include drugs that block different growth-promoting signals in glioblastoma cells and that are activated by the V600E BRAF mutation. One drug should inhibit signals from the BRAF protein, whereas the second drug in combination should inhibit signals from the MEK protein Methods: The content of this review is based on information obtained from PubMed, ClinicalTrials. gov, and the U.S. Food and Drug Administration (https://www.fda.gov/). In ClinicalTrials.gov, we retrieved studies published from January 1, 2015. In the data search, "Glioblastoma" was used as the keyword. A study was deleted if it studied remedies for concomitant tumor diseases, as well as if it did not include descriptions of treatment methods and/or if GBM was not mentioned. The analysis of the effectiveness of treatment was carried out according to the increasing overall survival in GBM patients, compared to the gold standard for this cancer. GBM patients treated with novel immunotherapy agents and drugs acting on epigenetic factors and receptor tyrosine kinase inhibitors have shown encouraging potential for future development in clinic. However, combinations of drugs have led to more significant improvements in the results and an increase in life expectancy of patients. For example, the combination of nivolumab and ipilimumab showed a 72% increase in life expectancy compared to using nivolumab alone (9.8 vs. 16.85). Combining anti-GBM drugs appears to be a key direction for increasing treatment effectiveness and overall survival. Radiotherapy of GBM can increase the effect of combination drug therapy.

Targeting Cervical Cancer Stem Cells by Phytochemicals.

Cervical cancer (CaCx) poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide. Despite the emergence of advanced treatment strategies, recurrence remains a bottleneck in favorable treatment outcomes and contributes to poor prognosis. The chemo- or radio-therapy resistance coupled with frequent relapse of more aggressive tumors are some key components that contribute to CaCx-related mortality. The onset of therapy resistance and relapse are attributed to a small subset of, slow-proliferating Cancer Stem Cells (CSC). These CSCs possess the properties of tumorigenesis, self-renewal, and multi-lineage differentiation potential. Because of slow cycling, these cells maintain themselves in a semi-quiescent stage and protect themselves from different anti-proliferative anti-cancer drugs. Keeping in view recent advances in their phenotypic and functional characterization, the feasibility of targeting CSC and associated stem cell signaling bears a strong translational value. The presence of CSC has been reported in CaCx (CCSC) which remains a forefront area of research. However, we have yet to identify clinically useful leads that can target CCSC. There is compelling evidence that phytochemicals, because of their advantages over synthetic anticancer drugs, could emerge as potential therapeutic leads to target these CCSCs. The present article examined the potential of phytochemicals with reported anti-CSC properties and evaluated their future in preclinical and clinical applications against CaCx.

The Potential of Epigallocatechin Gallate in Targeting Cancer Stem Cells: A Comprehensive Review.

The dreadful scenario of cancer prevails due to the presence of cancer stem cells (CSCs), which contribute to tumor growth, metastasis, invasion, resistance to chemo- and radiotherapy, and recurrence. CSCs are a small subpopulation of cells within the tumor that are characterized by self-renewal capability and have the potential to manifest heterogeneous lineages of cancer cells that constitute the tumor. The major bioactive green tea polyphenol (-)-epigallocatechin gallate (EGCG) has been fruitful in downgrading cancer stemness signaling and CSC biomarkers in cancer progression. EGCG has been evidenced to maneuver extrinsic and intrinsic apoptotic pathways in order to decrease the viability of CSCs. Cancer stemness is intricately related to epithelial-mesenchymal transition (EMT), metastasis and therapy resistance, and EGCG has been evidenced to regress all these CSC-related effects. By inhibiting CSC characteristics EGCG has also been evidenced to sensitize the tumor cells to radiotherapy and chemotherapy. However, the use of EGCG in in vitro and in vivo cancer models raises concern about its bioavailability, stability and efficacy against spheroids raised from parental cells. Therefore, novel nano formulations of EGCG and adjuvant therapy of EGCG with other phytochemicals or drugs or small molecules may have a better prospect in targeting CSCs. However, extensive clinical research is still awaited to elucidate a full proof impact of EGCG in cancer therapy.

Chemotherapy Resistance in Cancer: Mechanism and Roadmap to Evade Exploring Apoptosis

Chemotherapy resistance indicates the non-responsiveness of cancer cells to the cytotoxic and inhibitory effects of chemo drugs attributed to either intrinsic or extrinsic resistance mechanisms in cancer cells. Studies so far indicate that drug resistance can be triggered by a multitude of factors such as the over-expression of drug efflux pumps, DNA repair mechanisms, modifications in the drug target such as point mutations and gene amplification, over-expression of anti-apoptotic proteins and down-regulation of pro-apoptotic signals, presence of cancer stem cells and immune-suppressive cells, excessive cytokine production, tumor heterogeneity, epigenetic changes, activation of alternate pro-survival signaling pathways, etc. Both host and tumor-related factors can contribute to therapy resistance. Currently, chemo resistance poses the foremost setback in the successful treatment of cancer, and it exerts significant stress on the available medical resources. Besides the costs associated with the treatment, patients go through severe emotional and physical trauma. Chemotherapy resistance is also a major contributor to accelerated metastasis and invasion. Dose-escalation is not always practical since the associated side effects may increase apart from increasing the treatment costs. Several studies are ongoing to address this issue productively, such as therapeutic molecules designed to restore the apoptotic machinery. Site-specific delivery of pro-apoptotic agents such as small molecules, antibodies, peptides, etc. targeting the apoptosis pathway is also thoroughly studied. Moreover, the efficacy of combination strategies is also a topic of research.

Molecular and Cellular Expressions in Breast Cancer Responsible for Drug Resistance

Breast cancer continues to be a prevalent and highly lethal cancer affecting women globally. Despite significant advancements in early detection and the development of specific therapeutic approaches, the issue of medication resistance remains a prominent challenge in managing this intricate ailment. The study offers a comprehensive analysis of the mechanisms behind the development of treatment resistance in breast cancer cells. The objective of this study is to provide a comprehensive understanding of the molecular and cellular mechanisms behind the occurrence of therapeutic ineffectiveness. This study elucidates several molecular subtypes of breast cancer and their pharmacological responses. The significance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in the development of treatment resistance is emphasized. Additional research on the intricacies of innate and acquired drug resistance mechanisms, including genetic modifications, tumor heterogeneity, and the presence of cancer stem cells, has shed light on the multifaceted nature of drug resistance and its dynamic evolution throughout treatment. Furthermore, this study provides a comprehensive analysis of the impact of microenvironmental variables, including hypoxia, immune evasion, and tumor-stroma connections, on the development of drug resistance. The investigation of the interplay between tumor suppressors and oncogenes in the emergence of drug resistance is now underway, yielding valuable insights into prospective targets for therapeutic intervention. Additionally, this study examines the limitations associated with conventional chemotherapy, endocrine therapies, and targeted medicines, while elucidating the mechanisms underlying treatment resistance and proposing potential strategies to overcome it. Emerging therapies like immunotherapies, epigenetic modulators, and new drug delivery methods are looked at to see if they have the potential to get around mechanisms of resistance and improve patient outcomes. This review aims to give clinicians, researchers, and other healthcare workers a full picture of breast cancer’s complex drug resistance mechanisms. By figuring out the molecular complexities and signaling pathways that lead to treatment resistance, we aim to speed up the development of new therapeutic approaches and personalized interventions. This will bring us closer to the long-awaited goal of beating drug resistance and making breast cancer a manageable, treatable condition.

Regulation of cancer stem cells and immunotherapy of glioblastoma (Review).

Glioblastoma (GB) is one of the most adverse diagnoses in oncology. Complex current treatment results in a median survival of 15 months. Resistance to treatment is associated with the presence of cancer stem cells (CSCs). The present review aimed to analyze the mechanisms of CSC plasticity, showing the particular role of β-catenin in regulating vital functions of CSCs, and to describe the molecular mechanisms of Wnt-independent increase of β-catenin levels, which is influenced by the local microenvironment of CSCs. The present review also analyzed the reasons for the low effectiveness of using medication in the regulation of CSCs, and proposed the development of immunotherapy scenarios with tumor cell vaccines, containing heterogenous cancer cells able of producing a multidirectional antineoplastic immune response. Additionally, the possibility of managing lymphopenia by transplanting hematopoietic stem cells from a healthy sibling and using clofazimine or other repurposed drugs that reduce β-catenin concentration in CSCs was discussed in the present study.

SOX2 promotes a cancer stem cell-like phenotype and local spreading in oral squamous cell carcinoma

Emerging evidence shows that oral squamous cell carcinoma (OSCC) invasiveness can be attributed to a small subpopulation of cancer stem cells (CSCs) in the bulk of the tumor. However, the presence of CSCs in the OSCC close resection margins is still poorly unexplored. Here, we found that BMI1, CD44, SOX2, OCT4, UBE2C, CXCR4 CSCs marker genes are significantly upregulated, while IGF1-R, KLF4, ALDH1A1, CD133, FAM3C are downregulated in the tumor core vs healthy mucosa of 24 patients with OSCC. Among these, SOX2 appears also upregulated in the tumor close margin vs healthy mucosa and this significantly correlates with tumor size and lymph node compromise. In vitro analyses in CAL27 and SCC15 tongue squamous cell carcinoma cell lines, show that SOX2 transient knockdown i) promotes the mesenchymal-to-epithelial transition, ii) smooths the invasiveness, iii) attenuates the 3D tumor sphere-forming capacity, and iv) partially increases the sensitivity to cisplatin treatment. Overall, our study highlights that the OSCC close margins can retain CSC-specific markers. Notably, SOX2 may represent a useful CSCs marker to predict a more aggressive phenotype and a suitable target to prevent local invasiveness.