Cancer stem cells - important players in tumor therapy resistance

: Head and Neck Squamous Cell Carcinoma (HNSCC) is categorized as the sixth most common cancer worldwide, with an incidence of more than 830,000 cases per year and a mortality rate of 50%. Tobacco use, alcohol consumption, and Human Papillomavirus infection are the prominent risks for HNSCC. Despite significant developments in the treatment of HNSCC, a high rate of recurrences makes the clinical situation worse and results in poor survival rates. Recent perspectives demonstrate that whereas epithelial transformation plays a crucial role in cancer development, tumor surrounding microenvironment takes part in progression of cancer as well. Cancer Stem Cells (CSCs), which harbor unlimited self-renewal capacity, have a crucial role in the growth of HNSCC and this cell population is responsible for tumor recurrence unless eliminated by targeted therapy. CSCs are not only a promising target for tumor therapy, but also a crucial biomarker to determine the patients at high risk for undetermined results and disease development. Just as the bone marrow which is the niche of hematopoietic and mesenchymal stem cells, is important for stem cells maintenance. Similarly, the concept of microenvironment is also important for the maintenance of CSCs. Apart from the cell-cell interactions, there are many parameters in the cancer microenvironment that affect the development of cancer, such as extracellular regulation, vascularization, microbial flora, pH and oxygenation. The purpose of this review is to introduce HNSCC, explain the role of CSCs and their microenvironment and refer to the conventional and novel targeted therapy for HNSCC and CSCs.

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PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells

Cancers ◽

10.3390/cancers13092168 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2168

Author(s):

Balawant Kumar ◽

Rizwan Ahmad ◽

Swagat Sharma ◽

Saiprasad Gowrikumar ◽

Mark Primeaux ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Cancer Therapy ◽

Cancer Stem Cells ◽

Side Population ◽

Therapy Resistance ◽

Fluorescent Reporter ◽

Combination Treatments ◽

Gsk 3Β ◽

Resistance To Chemotherapy

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

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Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Science Advances ◽

10.1126/sciadv.abe3445 ◽

2021 ◽

Vol 7 (5) ◽

pp. eabe3445

Author(s):

Yicun Wang ◽

Jinhui Wu ◽

Hui Chen ◽

Yang Yang ◽

Chengwu Xiao ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Negative Feedback ◽

Direct Interaction ◽

Therapy Resistance ◽

Negative Regulator ◽

Chemotherapy Response ◽

Genome Wide

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

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Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers

Cancers ◽

10.3390/cancers13205098 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5098

Author(s):

Sarah E. Mudra ◽

Pritam Sadhukhan ◽

M. Talha Ugurlu ◽

Shorna Alam ◽

Mohammad O. Hoque

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Acquired Resistance ◽

Therapy Resistance ◽

Stem Cell Population ◽

Molecular Characteristics ◽

Targeted Agents ◽

Regulatory Pathways ◽

Lineage Differentiation ◽

Solid Malignancies

Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation—represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/β-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance.

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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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A role for cancer stem cells in therapy resistance: Cellular and molecular mechanisms

Seminars in Cancer Biology ◽

10.1016/j.semcancer.2014.06.004 ◽

2015 ◽

Vol 31 ◽

pp. 16-27 ◽

Cited By ~ 190

Author(s):

Monica Cojoc ◽

Katrin Mäbert ◽

Michael H. Muders ◽

Anna Dubrovska

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Therapy Resistance

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Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance

Cancer Research ◽

10.1158/0008-5472.can-14-3225 ◽

2015 ◽

Vol 75 (6) ◽

pp. 924-929 ◽

Cited By ~ 117

Author(s):

Valery Adorno-Cruz ◽

Golam Kibria ◽

Xia Liu ◽

Mary Doherty ◽

Damian J. Junk ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Therapy Resistance

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

International Journal of Breast Cancer ◽

10.1155/2012/209748 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Jenny E. Chu ◽

Alison L. Allan

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Metastatic Disease ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Therapy Resistance ◽

Breast Cancer Metastasis ◽

Specific Pattern ◽

Organ Tropism

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.

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Requirement of splicing factor hnRNP A2B1 of hnRNPs for tumorigenesis of melanoma stem cells

10.21203/rs.3.rs-92870/v1 ◽

2020 ◽

Author(s):

Mengqi Chu ◽

Haitao Wan ◽

Xiaobo Zhang

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Therapy ◽

Cycle Arrest ◽

Genome Wide ◽

A Genome ◽

Rna Immunoprecipitation ◽

Wide Scale

Abstract Background: Cancer stem cells play essential roles in tumorigenesis, thus being the important targets for tumor therapy. The hnRNP family proteins, the important splicing factors, are found to be associated with tumor progression. However, the influence of hnRNPs on cancer stem cells has not been extensively explored.Methods: Quantitative real-time PCR and Western blot were used to examine the gene expression level. RNA immunoprecipitation assay and RNA sequencing were conducted to identify the RNAs interacted with hnRNP A2B1 on a genome-wide scale. The in vivo assays were performed in nude mice.Results: In this study, the results showed that hnRNP A2B1 of 19 hnRNPs was significantly upregulated in melanoma stem cells compared with non-stem cells, suggesting the important role of hnRNP A2B1 in cancer stem cells. The hnRNP A2B1 silencing triggered the cell cycle arrest in G2 phase, leading to apoptosis of melanoma stem cells. The results revealed that hnRNP A2B1 could bind to the precursor mRNAs of pro-apoptosis genes (DAPK1, SYT7 and RNF128) and anti-apoptosis genes (EIF3H, TPPP3 and DOCK2) to regulate the splicing of these 6 genes, thus promoting the expressions of anti-apoptosis genes and suppressing the expressions of pro-apoptosis genes. The in vivo data indicated that hnRNP A2B1 was required for tumorigenesis of melanoma stem cells in vivo by affecting the splicing of TPPP3, DOCK2, EIF3H, RNF128, DAPK1 and SYT7, thus suppressing apoptosis of melanoma stem cells.Conclusions: HnRNP A2B1 was required for tumorigenesis of melanoma stem cells. Therefore our findings presented novel molecular insights into the roles of hnRNPs in cancer stem cells.

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