scholarly journals Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1450 ◽  
Author(s):  
Patrick Santos ◽  
Fausto Almeida
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Therapy Resistance ◽  
Chemotherapeutic Agents ◽  
Exosomal Mirnas ◽  
Key Factor

Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field.

scholarly journals Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1896 ◽  
Author(s):  
Kevin Dzobo ◽  
Dimakatso Alice Senthebane ◽  
Chelene Ganz ◽  
Nicholas Ekow Thomford ◽  
Ambroise Wonkam ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Treatment Strategies ◽  
Cancer Recurrence ◽  
Therapy Resistance ◽  
Microenvironmental Factors ◽  
Novel Treatment Strategies

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

scholarly journals Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

2020 ◽  
Author(s):  
Dimakatso Alice Senthebane ◽  
Chelene Ganz ◽  
Nicholas Ekow Thomford ◽  
Kevin Dzobo
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Treatment Strategies ◽  
Cancer Recurrence ◽  
Therapy Resistance ◽  
Repair Mechanisms ◽  
Microenvironmental Factors ◽  
Novel Treatment Strategies

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

scholarly journals Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Gut ◽  
2022 ◽  
pp. gutjnl-2021-324994
Author(s):  
Carolina F Ruivo ◽  
Nuno Bastos ◽  
Barbara Adem ◽  
Ines Batista ◽  
Cecilia Duraes ◽  
...  
Keyword(s):  
Stem Cells ◽  
Communication Network ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Biological Significance ◽  
Disease Free Survival ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Increased Risk

ObjectiveIntratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DesignWe have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).ResultsWe demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.ConclusionPDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

scholarly journals Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3191
Author(s):  
Katherine Po Sin Chung ◽  
Rainbow Wing Hei Leung ◽  
Terence Kin Wah Lee
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Current Knowledge ◽  
Special Focus ◽  
Intrinsic Regulation ◽  
Mechanistic Basis ◽  
Novel Therapeutic Strategies

Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

scholarly journals Blood and Cancer: Cancer Stem Cells as Origin of Hematopoietic Cells in Solid Tumor Microenvironments

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1293 ◽  
Author(s):  
Ghmkin Hassan ◽  
Masaharu Seno
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cancer Cells ◽  
Solid Tumor ◽  
Immune Cells ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Tumor Microenvironments

The concepts of hematopoiesis and the generation of blood and immune cells from hematopoietic stem cells are some steady concepts in the field of hematology. However, the knowledge of hematopoietic cells arising from solid tumor cancer stem cells is novel. In the solid tumor microenvironment, hematopoietic cells play pivotal roles in tumor growth and progression. Recent studies have reported that solid tumor cancer cells or cancer stem cells could differentiate into hematopoietic cells. Here, we discuss efforts and research that focused on the presence of hematopoietic cells in tumor microenvironments. We also discuss hematopoiesis from solid tumor cancer stem cells and clarify the notion of differentiation of solid tumor cancer stem cells into non-cancer hematopoietic stem cells.

scholarly journals miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

2020 ◽  
Vol 21 (7) ◽  
pp. 2313 ◽  
Author(s):  
Giuseppina Roscigno ◽  
Assunta Cirella ◽  
Alessandra Affinito ◽  
Cristina Quintavalle ◽  
Iolanda Scognamiglio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Negative Regulator ◽  
Mammosphere Formation ◽  
Incidence And Mortality ◽  
Cells Of The Microenvironment

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

scholarly journals Chronic Oxidative Stress Promotes Molecular Changes Associated with Epithelial Mesenchymal Transition, NRF2, and Breast Cancer Stem Cell Phenotype

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 633 ◽  
Author(s):  
Ana Čipak Gašparović ◽  
Lidija Milković ◽  
Nadia Dandachi ◽  
Stefanie Stanzer ◽  
Iskra Pezdirc ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Chronic Oxidative Stress ◽  
Emt Markers

Oxidative stress plays a role in carcinogenesis, but it also contributes to the modulation of tumor cells and microenvironment caused by chemotherapeutics. One of the consequences of oxidative stress is lipid peroxidation, which can, through reactive aldehydes such as 4-hydroxy-2-nonenal (HNE), affect cell signaling pathways. On the other hand, cancer stem cells (CSC) are now recognized as a major factor of malignancy by causing metastasis, relapse, and therapy resistance. Here, we evaluated whether oxidative stress and HNE modulation of the microenvironment can influence CSC growth, modifications of the epithelial to mesenchymal transition (EMT) markers, the antioxidant system, and the frequency of breast cancer stem cells (BCSC). Our results showed that oxidative changes in the microenvironment of BCSC and particularly chronic oxidative stress caused changes in the proliferation and growth of breast cancer cells. In addition, changes associated with EMT, increase in glutathione (GSH) and Nuclear factor erythroid 2-related factor 2 (NRF2) were observed in breast cancer cells grown on HNE pretreated collagen and under chronic oxidative stress. Our results suggest that chronic oxidative stress can be a bidirectional modulator of BCSC fate. Low levels of HNE can increase differentiation markers in BCSC, while higher levels increased GSH and NRF2 as well as certain EMT markers, thereby increasing therapy resistance.

scholarly journals Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaobo Zheng ◽  
Chune Yu ◽  
Mingqing Xu
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Progression ◽  
Immune Escape ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
The Relationship

Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.

scholarly journals Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

2019 ◽  
Vol 43 (1) ◽  
pp. 123-136 ◽  
Author(s):  
Zhiyong Yang ◽  
Ning Zhao ◽  
Jing Cui ◽  
Heshui Wu ◽  
Jiongxin Xiong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Expression Levels ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Cancer Stem Cells

Abstract Purpose Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. Methods GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. Results BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes. Conclusions Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

scholarly journals Immunotherapy: Newer Therapeutic Armamentarium against Cancer Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Saurabh Pratap Singh ◽  
Richa Singh ◽  
Om Prakash Gupta ◽  
Shalini Gupta ◽  
Madan Lal Brahma Bhatt
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Effective Means ◽  
Treatment Strategies ◽  
Antigen Expression ◽  
Therapy Resistance ◽  
Treatment Modalities ◽  
Self Renewal ◽  
Primary Tumors

Mounting evidence from the literature suggests the existence of a subpopulation of cancer stem cells (CSCs) in almost all types of human cancers. These CSCs possessing a self-renewal capacity inhabit primary tumors and are more defiant to standard antimitotic and molecularly targeted therapies which are used for eliminating actively proliferating and differentiated cancer cells. Clinical relevance of CSCs emerges from the fact that they are the root cause of therapy resistance, relapse, and metastasis. Earlier, surgery, chemotherapy, and radiotherapy were established as cancer treatment modalities, but recently, immunotherapy is also gaining importance in the management of various cancer patients, mostly those of the advanced stage. This review abridges potential off-target effects of inhibiting CSC self-renewal pathways on immune cells and some recent immunological studies specifically targeting CSCs on the basis of their antigen expression profile, even though molecular markers or antigens that have been described till date as expressed by cancer stem cells are not specifically expressed by these cells which is a major limitation to target CSCs. We propose that owing to CSC stemness property to mediate immunotherapy response, we can apply a combination therapy approach by targeting CSCs and tumor microenvironment (TME) along with conventional treatment strategies as an effective means to eradicate cancer cells.

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