Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases.

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Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance

Cells ◽

10.3390/cells9061450 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1450 ◽

Cited By ~ 3

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.

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

Antioxidants ◽

10.3390/antiox8120633 ◽

2019 ◽

Vol 8 (12) ◽

pp. 633 ◽

Cited By ~ 5

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.

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Immunotherapy: Newer Therapeutic Armamentarium against Cancer Stem Cells

Journal of Oncology ◽

10.1155/2020/3963561 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 2

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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Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis

Pharmaceuticals ◽

10.3390/ph14010060 ◽

2021 ◽

Vol 14 (1) ◽

pp. 60

Author(s):

Laura Sofia Carvalho ◽

Nélio Gonçalves ◽

Nuno André Fonseca ◽

João Nuno Moreira

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Clonal Evolution ◽

Therapy Resistance ◽

Cellular Heterogeneity ◽

Multifunctional Protein ◽

Mesenchymal Transition ◽

Cancer Hallmarks

Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies

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Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20051027 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1027 ◽

Cited By ~ 2

Author(s):

Bijaya Upadhyaya ◽

Yi Liu ◽

Moul Dey

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Transcription Factor ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Therapy Resistance ◽

Dependent Manner ◽

Phenethyl Isothiocyanate ◽

Concentration Dependent Manner

Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDHhi CSCs from HeLa parental cells (p < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDHhi hCSCs in a concentration-dependent manner (p < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs (p ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, p < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs.

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

Cells ◽

10.3390/cells9081896 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1896 ◽

Cited By ~ 3

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.

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Natural Compounds Targeting Cancer Stem Cells: A Promising Resource for Chemotherapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190704111714 ◽

2019 ◽

Vol 19 (15) ◽

pp. 1796-1808 ◽

Cited By ~ 2

Author(s):

Plabon K. Das ◽

Tasnim Zahan ◽

Md. Abdur Rakib ◽

Jahan A. Khanam ◽

Suja Pillai ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Signaling Pathways ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Natural Compounds ◽

Biologically Active ◽

Cancer Pathogenesis ◽

Distant Organ

Background:Cancer Stem Cells (CSCs) are the subpopulation of cancer cells which are directly involved in drug resistance, metastases to distant organ and cancer recurrence.Methods:A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "cancer stem cells" and "natural compounds" in the present study. Articles published between 1999 and 2019 were reviewed. All the expositions concerning CSCs associated cancer pathogenesis and therapy resistance, as well as targeting these properties of CSCs by natural compounds were selected for the current study.Results:Natural compounds have always been thought as a rich source of biologically active principles, which target aberrantly activated signaling pathways and other modalities of CSCs, while tethering painful side effects commonly involved in the first-line and second-line chemo-radiotherapies. In this review, we have described the key signaling pathways activated in CSCs to maintain their survival and highlighted how natural compounds interrupt these signaling pathways to minimize therapy resistance, pathogenesis and cancer recurrence properties of CSCs, thereby providing useful strategies to treat cancer or aid in cancer therapy improvement. Like normal stem cells, CSCs rely on different signaling pathways and other properties for their maintenance. Therefore, the success of cancer treatment depends on the development of proper anti-neoplastic drugs capable of intercepting those signaling pathways as well as other properties of CSCs in order to eradicate this evasive subpopulation of cancer cells.Conclusion:Compounds of natural origin might act as an outstanding source to design novel therapies against cancer stem cells.

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

Gut ◽

10.1136/gutjnl-2021-324994 ◽

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.

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Role of Claudin Proteins in Regulating Cancer Stem Cells and Chemoresistance-Potential Implication in Disease Prognosis and Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21010053 ◽

2019 ◽

Vol 21 (1) ◽

pp. 53 ◽

Cited By ~ 1

Author(s):

Saiprasad Gowrikumar ◽

Amar B. Singh ◽

Punita Dhawan

Keyword(s):

Stem Cells ◽

Cell Adhesion ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Therapy Resistance ◽

Cell Phenotype ◽

Potential Implication ◽

Mesenchymal Transition ◽

Cell Cell

Claudins are cell–cell adhesion proteins, which are expressed in tight junctions (TJs), the most common apical cell-cell adhesion. Claudin proteins help to regulate defense and barrier functions, as well as differentiation and polarity in epithelial and endothelial cells. A series of studies have now reported dysregulation of claudin proteins in cancers. However, the precise mechanisms are still not well understood. Nonetheless, studies have clearly demonstrated a causal role of multiple claudins in the regulation of epithelial to mesenchymal transition (EMT), a key feature in the acquisition of a cancer stem cell phenotype in cancer cells. In addition, claudin proteins are known to modulate therapy resistance in cancer cells, a feature associated with cancer stem cells. In this review, we have focused primarily on highlighting the causal link between claudins, cancer stem cells, and therapy resistance. We have also contemplated the significance of claudins as novel targets in improving the efficacy of cancer therapy. Overall, this review provides a much-needed understanding of the emerging role of claudin proteins in cancer malignancy and therapeutic management.

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Targeting Cancer Stem Cells and Non-Stem Cancer Cells: The Potential of Lipid- Based Nanoparticles

Current Pharmaceutical Design ◽

10.2174/1381612823666171115105252 ◽

2018 ◽

Vol 23 (43) ◽

pp. 6563-6572

Author(s):

Ana Filipa Cruz ◽

Nuno Andre Fonseca ◽

Vera Moura ◽

Sergio Simoes ◽

Joao Nuno Moreira

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells

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