Targeting Cancer Stem Cells Research Articles

Significant Association of PD‐L1 With CD44 Expression and Patient Survival: Avenues for Immunotherapy and Cancer Stem Cells Downregulation in Pancreatic Cancers

Background: Pancreatic cancers are known for their aggressive nature. This aggressiveness may be attributed to the presence of cancer stem cells (CSCs), which promote relapse, metastasis, and resistance to chemotherapy. Targeting CSCs is essential to reverse this aggressiveness in pancreatic malignancies. Literature highlights the association of PD‐L1 expression with CSCs in various cancers, suggesting immunotherapy as a promising therapeutic approach. This study is aimed at investigating the potential of immunotherapy in pancreatic cancers by examining its association with selected CSC marker expression.Method: A retrospective cohort study was conducted involving 56 patients with confirmed diagnoses of pancreatic cancers at Aga Khan University Hospital from January 2015 to October 2022. After exclusions, based on refusal to provide consent or incomplete follow‐up data, 38 patients were enrolled in the study. Immunohistochemistry was performed on formalin‐fixed paraffin‐embedded (FFPE) tumor tissue samples to assess the expression of CSC markers (CD133, CD44, and L1CAM) and immune checkpoint inhibitor marker (PD‐L1). Statistical analysis was employed to determine associations between marker expression, clinical factors, and overall survival.Results: The study revealed that 86.8% of pancreatic cancer cases exhibited positive PD‐L1 expression. Moreover, a significant association of PD‐L1 expression was observed with the presence of CD44 protein (p = 0.030), as well as with the overall survival of patients (p = 0.023).Conclusion: Our findings show a significant association of PD‐L1 with CD44 marker expression as well as patient survival. This research shows the potential to serve as the foundation for investigating the efficacy of immunotherapy in reducing CD44‐expressing CSCs in pancreatic cancer, potentially enhancing patient outcomes.

Discovering Novel and Old Drug Targets in Oral Cancer Stem Cells Using bio-inspired methods - A Review

Addressing the high mortality rate and limited treatment options for oral cancer is a global public health challenge. To enhance therapeutic approaches, a comprehensive understanding of oral cancer stem cells (OCSCs) is essential. This review employs advanced bio-inspired methods to identify unique pharmacological targets within OCSCs, considering their heterogeneity and resistance to conventional treatments. The Evolutionary Computation Network for Drug Repositioning (ECN-DR) dissects the intricate signaling pathways and molecular networks within OCSCs using bio-inspired techniques. By integrating machine learning, network analysis, and molecular dynamics simulations, this approach identifies potential targets for both new and existing anticancer drugs. Recognizing the key molecular players in OCSCs enables the design of tailored medicines to disrupt these cells, offering more potent and targeted therapy options with fewer side effects. Molecular dynamics simulations, protein-ligand docking studies, and in silico drug screening predict the binding affinity and therapeutic potential of prospective medications against selected OCSC targets. These simulations contribute to a better understanding of targeting specific proteins in oral cancer therapy. Utilizing bio-inspired methods and computational simulations enhances our knowledge of OCSC biology, advancing the prospects of personalized cancer treatment.

Recent Advances in the Targeting of Head and Neck Cancer Stem Cells

Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous cancer with a poor overall response to therapy. One of the reasons for this therapy resistance could be cancer stem cells (CSCs), a small population of cancer cells with self-renewal and tumor-initiating abilities. Tumor cell heterogeneity represents hurdles for therapeutic elimination of CSCs. Different signaling pathway activations, such as Wnt, Notch, and Sonic-Hedgehog (SHh) pathways, lead to the expression of several cancer stem factors that enable the maintenance of CSC features. Identification and isolation of CSCs are based either on markers (CD133, CD44, and aldehyde dehydrogenase (ALDH)), side populations, or their sphere-forming ability. A key challenge in cancer therapy targeting CSCs is overcoming chemotherapy and radiotherapy resistance. However, in novel therapies, various approaches are being employed to address this hurdle such as targeting cell surface markers, other stem cell markers, and different signaling or metabolic pathways, but also, introducing checkpoint inhibitors and natural compounds into the therapy can be beneficial.

Targeting cancer stem cell plasticity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity.

Advances and Challenges in Cancer Stem Cells for Onco-Therapeutics

Six decades have passed since the foundational recognition of the primary properties of the stem cells. Research on stem cells has since remained at the forefront of efforts to combat a spectrum of diseases, most notably cancer. Despite remarkable progress in medical science, a definitive cure for cancer has remained elusive, spurring the pursuit of diverse therapeutic strategies, among which stem cell therapy is a particularly promising avenue. Moreover, the utilization of cancer stem cells as a therapeutic source holds immense potential for addressing intractable diseases. The strategy of targeting cancer stem cells is beset with challenges, including immune rejection and disease relapse. Additionally, the capacity to inadvertently generate cancer stem cells upon transplantation underscores the critical need to eliminate these cells to ensure the efficacy of cell-based therapies. This paper underscores the pivotal role of cancer stem cells in onco-therapeutics and their potential to aid in early cancer diagnosis. With the proliferation of tissue banks and their collection of malignant tissue types, a renewable source of medications to combat cancer is on the horizon. While cancer stem cell-based therapy presents sophisticated and significant challenges, it offers unprecedented opportunities to extend human life. Continued technological advancements in stem cell therapy promise to provide new insights and refine approaches for cancer treatment, ushering in a new era of hope and innovation in the fight against this formidable disease.

Abstract A021: Screening of novel therapeutic markers for ovarian cancer stem cells

Abstract Drug resistance in epithelial ovarian cancer is reportedly attributed to the existence of cancer stem cells, because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells. We screened an FDA-approved compound and clinical libraries, and found several small molecule drugs that target ovarian CSCs. These drugs decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. Since these drugs harbor target proteins, we investigated the expression of the target proteins in ovarian CSC and found the increased level of the protein expression and new therapeutic markers of ovarian CSCs. Downregulation of these genes reduced the stem-cell-like properties of ovarianCSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with chemo agents, synergistic ect was shown in inhibiting the viability and proliferation of ovarian CSCs. Our results suggested that these may be potential therapeutic drugs for preventing ovarian cancer recurrence. Citation Format: Dong Kyu Choi, Sang Hyun Min. Screening of novel therapeutic markers for ovarian cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A021.

Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Vitamin C (VC) is an essential nutrient that is vital for maintaining cellular physiology. Interestingly, it functions as either an antioxidant or a pro-oxidant, depending on the concentration used. At high-doses, VC selectively targets various cancer cell types through its pro-oxidant action, while at low-doses, VC enhances anti-tumor immunity by acting as an antioxidant. This versatility makes VC a promising anti-tumor agent for both standalone and combination therapies. Tumors consist of diverse cancer cell subtypes with distinct phenotypic and functional characteristics. In particular, cancer stem cells (CSCs), which are self-renewing multi-potent cells, are responsible for tumor recurrence, metastasis, chemoresistance, and heightened mortality. CSCs are often associated with the epithelial–mesenchymal transition (EMT), which confers increased motility and invasive capabilities that are characteristic of malignant and drug-resistant cells. Thus, eradicating CSC populations is crucial and has led to extensive efforts aimed at identifying medicines that can target them. Recent studies suggest that VC can selectively target CSCs via epigenetic and metabolic pathways in various cancers. Here, we highlight recent progress that has been made in understanding how VC effectively targets CSC evolution, providing a rationale for the use of VC either alone or in combination with other treatments to improve outcomes.

Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer.

Cancer stem cells (CSCs) found within cancer tissue play a pivotal role in its resistance to therapy and its potential to metastasize, contributing to elevated mortality rates among patients. Significant strides in understanding the molecular foundations of CSCs have led to preclinical investigations and clinical trials focused on CSC regulator β-catenin signaling targeted interventions in malignancies. As part of the ongoing advancements in marine-organism-derived compound development, it was observed that among the six analogs of Renieramycin T (RT), a potential lead alkaloid from the blue sponge Xestospongia sp., the compound DH_32, displayed the most robust anti-cancer activity in lung cancer A549, H23, and H292 cells. In various lung cancer cell lines, DH_32 exhibited the highest efficacy, with IC50 values of 4.06 ± 0.24 μM, 2.07 ± 0.11 μM, and 1.46 ± 0.06 μM in A549, H23, and H292 cells, respectively. In contrast, parental RT compounds had IC50 values of 5.76 ± 0.23 μM, 2.93 ± 0.07 μM, and 1.52 ± 0.05 μM in the same order. Furthermore, at a dosage of 25 nM, DH_32 showed a stronger ability to inhibit colony formation compared to the lead compound, RT. DH_32 was capable of inducing apoptosis in lung cancer cells, as demonstrated by increased PARP cleavage and reduced levels of the proapoptotic protein Bcl2. Our discovery confirms that DH_32 treatment of lung cancer cells led to a reduced level of CD133, which is associated with the suppression of stem-cell-related transcription factors like OCT4. Moreover, DH_32 significantly suppressed the ability of tumor spheroids to form compared to the original RT compound. Additionally, DH_32 inhibited CSCs by promoting the degradation of β-catenin through ubiquitin-proteasomal pathways. In computational molecular docking, a high-affinity interaction was observed between DH_32 (grid score = -35.559 kcal/mol) and β-catenin, indicating a stronger binding interaction compared to the reference compound R9Q (grid score = -29.044 kcal/mol). In summary, DH_32, a newly developed derivative of the right-half analog of RT, effectively inhibited the initiation of lung cancer spheroids and the self-renewal of lung cancer cells through the upstream process of β-catenin ubiquitin-proteasomal degradation.

Satureja bachtiarica Induces Cancer Cell Death in Breast and Glioblastoma Cancer in 2D/3D Models and Suppresses Breast Cancer Stem Cells.

Overcoming drug resistance and specifically targeting cancer stem cells (CSCs) are critical challenges in improving cancer therapy. Nowadays, the use of novel and native medicinal plants can provide new sources for further investigations for this purpose. The aim of this study was to assess the potential of S. bachtiarica, an endemic plant with diverse medicinal applications, in suppressing and targeting cancer and cancer stem cells in glioblastoma and breast cancer. The effect of S. bachtiarica on viability, migration, invasion, and clonogenic potential of MDAMB-231 and U87-MG cells was assessed in both two- and three-dimensional cell culture models. Additionally, we evaluated its effects on the self-renewal capacity of mammospheres. The experimental outcomes indicated that S. bachtiarica decreased the viability and growth rate of cells and spheroids by inducing apoptosis and inhibited colony formation, migration, and invasion of cells and spheroids. Additionally, colony and sphere-forming ability, as well as the expression of genes associated with EMT and stemness were reduced in mammospheres treated with S. bachtiarica. In conclusion, this study provided valuable insights into the anti-cancer effects of S. bachtiarica, particularly in relation to breast CSCs. Therefore, S. bachtiarica may be a potential adjuvant for the treatment of cancer.

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

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

Tumor-associated macrophages: an effective player of the tumor microenvironment.

Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.

Reversing Resistance of Cancer Stem Cells and Enhancing Photodynamic TherapyBased on Hyaluronic Acid Nanomicelles for Preventing Cancer Recurrence and Metastasis.

Photodynamic therapy (PDT) is a promising approach for tumor treatment; however, the therapeutic resistance of cancer stem cells (CSCs) severely limits its efficacy and easily lead to recurrence. Herein, a hyaluronic acid (HA)-Ce6-Olaparib (OLA) micelle (HCCO) is developed, which combines the CSC targeting of HA, the PDT effect of Ce6, and the DNA damage repair inhibition of OLA. More importantly, HCCO induces immunogenic cell death (ICD) effects, promotes dendritic cells maturation, and alleviates myeloid-derived suppressor cells (MDSCs) infiltration to reverse CSC resistance. As a result, HCCO not only significantly inhibits the growth of 4T1 breast cancer cells and CSCs in vitro, but also effectively inhibits tumor recurrence and metastasis in vivo. This study provides a novel strategy for preventing tumor recurrence and metastasis by the combination of inhibiting DNA damage repair, reversing CSC resistance, and enhancing PDT.

Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability

Hepatocellular carcinoma (HCC) is one of the global health concerns. Hepatitis B virus (HBV) is one of the major causes of HCC. Poor clinical outcome of HCC patients is attributed to a small population of cancer cells known as cancer stem cells (CSCs). In this work, we studied the effect of inhibiting the enhancer of zeste homologue 2 (EZH2), a histone methyltransferase known to be overexpressed in CSCs, using tazemetostat (Taz). The effect of Taz was assessed in the HCC cell line (HEPG2) and Hepatitis B virus-transfected HEPG2 (HBV/HEPG2) cells. MTT assay showed a significant decrease in HEPG2 cells viability after 48 h treatment with either 0.5, 1, 4 or 6 μM Taz. HEPG2 and HBV/HEPG2 cells were incubated with either 0.5 or 1 μM Taz for 48 h, and then, the cells and supernatants were collected for protein expression analysis of EZH2, CD13, epithelial cell adhesion molecule (EpCAM) and β-catenin using enzyme-linked immunosorbent assay (ELISA). Taz showed a significant dose-dependent inhibition of EZH2, CD13 and β-catenin in HEPG2 and HBV/HEPG2 cells. Also, EpCAM protein levels were significantly decreased in HBV/HEPG2 but not in HEPG2 cell line alone. Our results indicate that Taz inhibition of EZH2 leads to downregulation of β-catenin signaling and eventually decreased expression of CD13 and EpCAM, which are characteristic for CSCs. The present study suggests that Taz could be a promising treatment for HCC including HBV-induced HCC that might be used in combination with radio/chemotherapy to target CSCs and prevent tumor relapse.

Talazoparib enhances the quinacrine-mediated apoptosis in patient-derived oral mucosa CSCs by inhibiting BER pathway through the modulation of GCN5 and P300.

The presence of cancer stem cells (CSCs) in the tumor microenvironment (TME) is majorly responsible for the development and recurrence of cancer. Earlier reports suggested that upon DNA damage, poly-(ADP-ribose) polymerase-1 (PARP-1) helps in chromatin modulation and DNA repair process, thereby promoting CSC survival. But whether a combination of DNA damaging agents along with PARP inhibitors can modulate chromatin assembly, inhibit DNA repair processes, and subsequently target CSCs is not known. Hence, we have investigated the effect of nontoxic bioactive compound quinacrine (QC) and a potent PARP inhibitor Talazoparib in patient-derived oral mucosa CSCs (OM-CSCs) and in vivo xenograft mice preclinical model systems. Data showed that QC + Talazoparib inhibited the PARP-1-mediated chromatin remodelers' recruitment and deregulated HAT activity of GCN5 (general control nonderepressible-5) and P300 at DNA damage site, thereby preventing the access of repair proteins to the damaged DNA. Additionally, this combination treatment inhibited topoisomerase activity, induced topological stress, and induced apoptosis in OM-CSCs. Similar results were observed in an in vivo xenograft mice model system. Collectively, the data suggested that QC + Talazoparib treatment inhibited BER pathway, induced genomic instability and triggered apoptosis in OM-CSCs through the deregulation of PARP-1-mediated chromatin remodelers (GCN5 and P300) activity. Schematic representation of QC + Talazoparib-induced apoptosis in oral mucosa CSCs. (1) Induction of DNA damage takes place after QC treatment (2) PARP1-mediated PARylation at the site of DNA damage, which recruits multiple chromatin remodelers (3) Acetylation at the histone tails relax the structure of chromatin and recruits the BER pathway proteins at the site of DNA damage. (4) BER pathway activated at the site of DNA damage. (5) CSCs survive after successful repair of DNA damage. (6) Treatment of QC-treated CSCs with PARP inhibitor Talazoparib (7) Inhibition of PARylation results in failure of chromatin remodelers to interact with PARP1. (8) Inhibition of acetylation status leads to chromatin compaction. (9) BER pathway proteins are not recruited at the site of DNA damage, resulting in inhibition of BER pathway and accumulation of unrepaired DNA damage, leading to apoptosis and cell death.

Revolutionizing colorectal cancer treatment: unleashing the potential of miRNAs in targeting cancer stem cells.

Colorectal cancer (CRC) is a significant contributor to cancer mortality worldwide, and the presence of cancer stem cells (CSC) represents a major challenge for achieving effective treatment. miRNAs have emerged as critical regulators of gene expression, and recent studies have highlighted their role in regulating stemness and therapeutic resistance in CRC stem cells. This review highlights the mechanisms of CSC development, therapy resistance and the potential of miRNAs as therapeutic targets for CRC. It emphasizes the promise of miRNAs as a novel approach to CRC treatment and calls for further research to explore effective miRNA-based therapies and strategies for delivering miRNAs to CSCs in vivo.

Cellular Effects of Selected Unsymmetrical Bisacridines on the Multicellular Tumor Spheroids of HCT116 Colon and A549 Lung Cancer Cells in Comparison to Monolayer Cultures.

Multicellular tumor spheroids are a good tool for testing new anticancer drugs, including those that may target cancer stem cells (CSCs), which are responsible for cancer progression, metastasis, and recurrence. Therefore, we applied this model in our studies of highly active antitumor unsymmetrical bisacridines (UAs). We investigated the cellular response induced by UAs in 2D and 3D cultures of HCT116 colon and A549 lung cancer cells, with an additional focus on their impact on the CSC-like population. We showed that UAs affected the viability of the studied cells, as well as their spherogenic potential in the 2D and 3D cultures. Furthermore, we proved that the most promising UAs (C-2045 and C-2053) induced apoptosis in the HCT116 and A549 spheres to a similar, or even higher, extent than what was found in monolayer conditions. Next, we identified the population of the CSC-like cells in the 2D and 3D cultures of the studied cell lines by determining the levels of CD166, CD133, CD44, and EpCAM markers. We showed that the selected UAs affected the CSC-like population in both of the cell lines, and that A549 was affected more profoundly in 3D than in 2D cultures. Thus, the UAs exhibited high antitumor properties in both the 2D and 3D conditions, which makes them promising candidates for future therapeutic applications.

Iridium nanozyme-mediated photoacoustic imaging-guided NIR-II photothermal therapy and tumor microenvironment regulation for targeted eradication of cancer stem cells

Cancer stem cells (CSCs) are found in many solid tumors, which play decisive roles in the occurrence, recurrence and metastasis of tumors. However, drugs are difficult to kill CSCs due to their limited number and location in oxygen-deprived tissue far from the blood vessels. Meanwhile, the survival and stemness maintenance of CSCs strongly depend on the tumor microenvironment (TME). Herein, we developed a CD44 antibody modified iridium nanosheet with enzyme-like activity (defined as Ir Nts-Ab) that effectively eradicates CSCs for cancer therapy. We observe that Ir Nts-Ab can enrich tumor tissues to remove excessive reactive oxygen species and produce oxygen, thus alleviating hypoxia and the inflammatory TME to reduce the proportion of CSCs and inhibit metastasis. In addition, Ir Nts-Ab targets CSCs and normal cancer cells with near infrared II-region photothermal therapy (NIR-II PTT), and is easily taken up by CSCs due to recognition of the CD44 proteins. Moreover, photoacoustic imaging helps monitor drug accumulation and hypoxic TME improvement in tumor tissue. Importantly, Ir Nts-Ab has good biological safety, making it suitable for biomedical applications. This iridium nanozyme based on TME regulation as well as NIR-II PTT will be a promising strategy for the treatment of cancer. Statement of significanceCancer stem cells (CSCs) are key factors that make tumors difficult to eradicate, and strongly depend on the hypoxic tumor microenvironment (TME), which plays a crucial role in the occurrence and metastasis of tumors. Herein, an antibody modified iridium nanosheet (definition as Ir Nts-Ab) was developed for targeted eradication of CSCs by photoacoustic imaging guided photothermal therapy (PTT) and TME regulation. Ir Nts-Ab with catalase-like activity could inhibit HIF-1α by producing oxygen, thus effectively reducing the proportion of CSCs and inhibiting tumor metastasis. Additionally, Ir Nts-Ab achieved the eradication of CSCs by PTT, and eliminated reactive oxygen species to decrease the inflammatory response, resulting in reduced tumor metastasis, which was promising for the cure of solid tumors in the clinics.

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p-STAT3 in prostate cancer.

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with the capability of self-renewal and drug resistance, leading to tumor progression and disease relapse. Our study aimed to investigate the antitumor effect of berbamine, extracted from berberis amurensis, on prostate CSCs. Sphere formation was used to collect prostate CSCs. The viability, proliferation, invasion, migration, and apoptosis assays were used to evaluate the antitumor effect of berbamine on prostate CSCs. Prostate CSC markers were analyzed by flow cytometry and qRT-PCR. Small RNA sequencing analysis was conducted to analyse miRNAs. Exosomes were extracted using the ExoQuick-TC kit and verified by testing exosomal markers using western blot. Berbamine targets prostate CSCs. Additionally, berbamine enhanced the antitumor effect of cabazitaxel, a second-line chemotherapeutic drug for advanced prostate cancer, and re-sensitized Cabazitaxel-resistant PCa cells (CabaR-DU145) to cabazitaxel by inhibiting ABCG2, CXCR4, IGF2BP1, and p-STAT3. Berbamine enhanced the expression of let-7 miRNA family and miR-26b and influenced the downstream targets IGF2BP1 and p-STAT3, respectively. Silencing CXCR4 and ABCG2 downregulated the expression of IGF2BP1 and p-STAT3, respectively. Importantly, berbamine enhanced also levels of exosomal let-7 family and miR-26b, suggesting that berbamine possibly influences the expression of let-7 family and miR-26b through exosome delivery. Exosomes derived from berbamine-treated CabaR-DU145 cells re-sensitized the cells to cabazitaxel. Berbamine enhanced the toxic activity of cabazitaxel and reversed cabazitaxel resistance potentially through CXCR4/exosomal let-7/IGF2BP1 and ABCG2/exosomal miR-26b/p-STAT3 axes.

Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance.

The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.

BIRC5: A novel therapeutic target for lung cancer stem cells and glioma stem cells

Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) is also known as survivin. BIRC5, a member of the apoptosis inhibitor (IAP) family, negatively regulates apoptosis or programmed cell death by inhibiting caspase activation. Due to these properties, overexpression of BIRC5 enables specific survival and division associated with cancer malignancies. In addition, BIRC5 is highly expressed in stem cells, but not present at all in terminally differentiated cells. On this basis, there is speculation that BIRC5 may be involved in the regulation of cancer stem cells (CSCs), but few study results have been reported. In addition, the molecular mechanisms of BIRC5 regulation are not yet well understood. Through the present study, it was confirmed that BIRC5 is a key factor regulating CSCs and epithelial to mesenchymal transition (EMT). BIRC5 was simultaneously overexpressed in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs), and when the expression was suppressed, the characteristics of CSCs disappeared. In addition, plasminogen activator inhibitor-1 (PAI-1), a secreted factor regulated by BIRC5, is involved in signaling mechanisms that regulate cancer stem cells and EMT, and PAI-1 forms an autocrine chain. Based on these results, BIRC5 is proposed as a novel therapeutic target protein for LCSCs and GSCs.