Cancer Stem Cell Therapy Resistance Research Articles

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

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

The Interaction between DNMT1 and High-Mannose CD133 Maintains the Slow-Cycling State and Tumorigenic Potential of Glioma Stem Cell.

The quiescent/slow‐cycling state preserves the self‐renewal capacity of cancer stem cells (CSCs) and leads to the therapy resistance of CSCs. The mechanisms maintaining CSCs quiescence remain largely unknown. Here, it is demonstrated that lower expression of MAN1A1 in glioma stem cell (GSC) resulted in the formation of high‐mannose type N‐glycan on CD133. Furthermore, the high‐mannose type N‐glycan of CD133 is necessary for its interaction with DNMT1. Activation of p21 and p27 by the CD133–DNMT1 interaction maintains the slow‐cycling state of GSC, and promotes chemotherapy resistance and tumorigenesis of GSCs. Elimination of the CD133–DNMT1 interaction by a cell‐penetrating peptide or MAN1A1 overexpression inhibits the tumorigenesis of GSCs and increases the sensitivity of GSCs to temozolomide. Analysis of glioma samples reveals that the levels of high‐mannose type N‐glycan are correlated with glioma recurrence. Collectively, the high mannose CD133–DNMT1 interaction maintains the slow‐cycling state and tumorigenic potential of GSC, providing a potential strategy to eliminate quiescent GSCs.

Combinatorial Strategies to Target Molecular and Signaling Pathways to Disarm Cancer Stem Cells.

Cancer is an urgent public health issue with a very huge number of cases all over the world expected to increase by 2040. Despite improved diagnosis and therapeutic protocols, it remains the main leading cause of death in the world. Cancer stem cells (CSCs) constitute a tumor subpopulation defined by ability to self-renewal and to generate the heterogeneous and differentiated cell lineages that form the tumor bulk. These cells represent a major concern in cancer treatment due to resistance to conventional protocols of radiotherapy, chemotherapy and molecular targeted therapy. In fact, although partial or complete tumor regression can be achieved in patients, these responses are often followed by cancer relapse due to the expansion of CSCs population. The aberrant activation of developmental and oncogenic signaling pathways plays a relevant role in promoting CSCs therapy resistance. Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy. Therefore, an urgent need to design alternative combinatorial strategies to replace conventional regimens exists. This review summarizes the preclinical studies which provide a proof of concept of therapeutic efficacy of combinatorial approaches targeting the CSCs.

Novel Therapeutic Strategies for Ovarian Cancer Stem Cells.

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies. Due to the lack of specific symptoms and screening methods, this disease is usually diagnosed only at an advanced and metastatic stage. The gold-standard treatment for OC patients consists of debulking surgery followed by taxane combined with platinum-based chemotherapy. Most patients show complete clinical remission after first-line therapy, but the majority of them ultimately relapse, developing radio- and chemoresistant tumors. It is now proposed that the cause of recurrence and reduced therapy efficacy is the presence of small populations of cancer stem cells (CSCs). These cells are usually resistant against conventional cancer therapies and for this reason, effective targeted therapies for the complete eradication of CSCs are urgently needed. In this review article, we highlight the mechanisms of CSC therapy resistance, epithelial-to-mesenchymal transition, stemness, and novel therapeutic strategies for ovarian CSCs.

ID:3004 Lung cancer stem cell and its therapeutic potential

Cancer stem cells (CSCs), a subpopulation of cancer cells with the ability to self-renew and giving rise to differentiated cancer cells, are thought to play a crucial role in tumour development, invasion, metastasis and recurrence. Treatments for lung cancer remain a challenging due to ineffectiveness of current available therapies to eradicate the quiescent and therapy-resistance of CSCs. Therefore, new treatment regime specifically targeting CSCs are needed to improve the effectiveness of lung cancer treatment. However the identification of lung CSCs especially in non-small cell lung cancer (NSCLC) remains challenging due to highly heterogeneous cell population and no standard markers to distinguish the lung CSCs from their cancer origins. The use of cell surface markers in isolation, identification and characterization of CSCs is one of the important tools as to understand the basic molecular composition and properties of CSCs and the pathways that of these heterogeneous population of cells are involved for future targeted therapy. Our group has identified, isolated and characterized putative lung CSCs from NSCLC cell line based on expression of combination CSCs markers, the CD166/CD44 and CD166/EpCAM using fluorescence activated cell sorting (FACS). The putative lung CSCs, the CD166+CD44+ CD166+EpCAM+ were characterized for multipotent and self-renewal capability using differentiation, clonogenic and spheroid assays. Following microarray gene expression study and bioinformatics analysis, our data has shown that the NF-κB was consistently expressed and shown to play a significant role in maintaining tumorigenicity of CSCs. In order to proof the role of NF-κB, the cells were treated with different concentrations of BMS-345541 (an inhibitor of NF-κB molecule) and the effectiveness of the treatments were evaluated through its ability to reduce self-renewal, expression of stemness genes (Sox2, Oct4, Klf4, Nanog and Sca-1), migration and epithelial to mesenchymal transition process (EMT) activities. The effectiveness of curcumin as drug sensitizer for effective therapy in treating chemoresistance of CSCs, was also investigated. The capability of CD166+/CD44+ and CD166+/EpCAM+ to differentiate into multipotent cell lineages (adipocytes and osteocyte), to form colony and to anchorage independent spheres and expressed stemness genes were shown in this study. The inhibition of NF-κB molecule using BMS-345441 has reduced the sphere forming capability, expression of stemness genes (Sox2, Nanog and Oct4), migration and expression of EMT genes in lung CSCs. Meanwhile, curcumin was found to reduce the cells proliferation activity and induced apoptosis of the cells. In addition, curcumin was also able to sensitize cisplatin, to supress the migration ability and inhibiting self-renewal capability of lung CSCs. Besides, the mRNA level of Sox2, Klf4, Nanog and Oct4 were down-regulated in lung CSCs after treatment with combination of both curcumin and cisplatin. Our findings suggest that NF-κB could be used as a potential targeted gene for lung cancer gene modification whereas curcumin could be used as potential natural compound that was able to sensitize the chemotherapy drug for effective cancer therapy.

Current understanding of cancer stem cells: Review of their radiobiology and role in head and neck cancers.

Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1%-10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a result of preferential killing, but also their capacity to alter divisional dynamics and enlist the support of a complicit microenvironment in therapy resistance and proliferation. The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control.

Cancer stem cell drugs target K-ras signaling in a stemness context.

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.

Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential.

Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties, and therapeutic response in an in vivo primary, syngeneic p53null claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion, and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53null claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity, and metastatic potential in vivo.

The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the "Seed" and the "Soil"?

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.