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1
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Ghosh N, Chatterjee D, Datta A. Tumor heterogeneity and resistance in glioblastoma: the role of stem cells. Apoptosis 2025:10.1007/s10495-025-02123-y. [PMID: 40375039 DOI: 10.1007/s10495-025-02123-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2025] [Indexed: 05/18/2025]
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant brain tumor, characterized by its heterogeneity and the presence of glioblastoma stem cells (GSCs). GSCs are a subpopulation of cells within the tumor that possess self-renewal and differentiation capabilities, contributing to tumor initiation, progression, and recurrence. This review explores the unique biological properties of GSCs, including their molecular markers, signalling pathways, and interactions with the tumor microenvironment. We discuss the mechanisms by which GSCs evade conventional therapies, such as enhanced DNA repair and metabolic plasticity, which complicate treatment outcomes. Furthermore, we highlight recent advancements in identifying novel biomarkers and therapeutic targets that may improve the efficacy of treatments aimed at GSCs. The potential of targeted therapies, including immunotherapy and combination strategies, is also examined to overcome the challenges posed by GSCs. Ultimately, a deeper understanding of GSC biology is essential for developing personalized treatment approaches that can enhance patient outcomes in glioblastoma.
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Affiliation(s)
- Nikita Ghosh
- Department of Neuroscience Technology, School of Allied Health Sciences, Yenepoya, Mangalore, Karnataka, India
| | | | - Aparna Datta
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, India.
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2
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Zhou Q, Xiang J, Qiu N, Wang Y, Piao Y, Shao S, Tang J, Zhou Z, Shen Y. Tumor Abnormality-Oriented Nanomedicine Design. Chem Rev 2023; 123:10920-10989. [PMID: 37713432 DOI: 10.1021/acs.chemrev.3c00062] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.
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Affiliation(s)
- Quan Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jiajia Xiang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Nasha Qiu
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Yechun Wang
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ying Piao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Shiqun Shao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Jianbin Tang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Zhuxian Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Youqing Shen
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- State Key Laboratory of Chemical Engineering, Zhejiang University, Hangzhou 310058, China
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Organization of self-advantageous niche by neural stem/progenitor cells during development via autocrine VEGF-A under hypoxia. Inflamm Regen 2023; 43:8. [PMID: 36726165 PMCID: PMC9893632 DOI: 10.1186/s41232-022-00254-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/27/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Tissue stem cells are confined within a special microenvironment called niche. Stem cells in such a niche are supplied with nutrients and contacted by other cells to maintain their characters and also to keep or expand their population size. Besides, oxygen concentration is a key factor for stem cell niche. Adult neural stem/progenitor cells (NSPCs) are known to reside in a hypoxic niche. Oxygen concentration levels are lower in fetal organs including brain than maternal organs. However, how fetal NSPCs adapt to the hypoxic environment during brain development, particularly before pial and periventricular vessels start to invade the telencephalon, has not fully been elucidated. METHODS NSPCs were prepared from cerebral cortices of embryonic day (E) 11.5 or E14.5 mouse embryos and were enriched by 4-day incubation with FGF2. To evaluate NSPC numbers, neurosphere formation assay was performed. Sparsely plated NSPCs were cultured to form neurospheres under the hypoxic (1% O2) or normoxic condition. VEGF-A secreted from NSPCs in the culture medium was measured by ELISA. VEGF-A expression and Hif-1a in the developing brain was investigated by in situ hybridization and immunohistochemistry. RESULTS Here we show that neurosphere formation of embryonic NSPCs is dramatically increased under hypoxia compared to normoxia. Vegf-A gene expression and its protein secretion were both up-regulated in the NSPCs under hypoxia. Either recombinant VEGF-A or conditioned medium of the hypoxic NSPC culture enhanced the neurosphere forming ability of normoxic NSPCs, which was attenuated by a VEGF-A signaling inhibitor. Furthermore, in the developing brain, VEGF-A was strongly expressed in the VZ where NSPCs are confined. CONCLUSIONS We show that NSPCs secret VEGF-A in an autocrine fashion to efficiently maintain themselves under hypoxic developmental environment. Our results suggest that NSPCs have adaptive potential to respond to hypoxia to organize self-advantageous niche involving VEGF-A when the vascular system is immature.
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Sabu A, Liu TI, Ng SS, Doong RA, Huang YF, Chiu HC. Nanomedicines Targeting Glioma Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2023; 15:158-181. [PMID: 35544684 DOI: 10.1021/acsami.2c03538] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Glioblastoma (GBM), classified as a grade IV glioma, is a rapidly growing, aggressive, and most commonly occurring tumor of the central nervous system. Despite the therapeutic advances, it carries an ominous prognosis, with a median survival of 14.6 months after diagnosis. Accumulating evidence suggests that cancer stem cells in GBM, termed glioma stem cells (GSCs), play a crucial role in tumor propagation, treatment resistance, and tumor recurrence. GSCs, possessing the capacity for self-renewal and multilineage differentiation, are responsible for tumor growth and heterogeneity, leading to primary obstacles to current cancer therapy. In this respect, increasing efforts have been devoted to the development of anti-GSC strategies based on targeting GSC surface markers, blockage of essential signaling pathways of GSCs, and manipulating the tumor microenvironment (GSC niches). In this review, we will discuss the research knowledge regarding GSC-based therapy and the underlying mechanisms for the treatment of GBM. Given the rapid progression in nanotechnology, innovative nanomedicines developed for GSC targeting will also be highlighted from the perspective of rationale, advantages, and limitations. The goal of this review is to provide broader understanding and key considerations toward the future direction of GSC-based nanotheranostics to fight against GBM.
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Affiliation(s)
- Arjun Sabu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Te-I Liu
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 10617, Taiwan
| | - Siew Suan Ng
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Ruey-An Doong
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yu-Fen Huang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Cheng Chiu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
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Akindona FA, Frederico SC, Hancock JC, Gilbert MR. Exploring the origin of the cancer stem cell niche and its role in anti-angiogenic treatment for glioblastoma. Front Oncol 2022; 12:947634. [PMID: 36091174 PMCID: PMC9454306 DOI: 10.3389/fonc.2022.947634] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/08/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.
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Affiliation(s)
- Funto A. Akindona
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
| | - Stephen C. Frederico
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - John C. Hancock
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Mark R. Gilbert
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Mark R. Gilbert,
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Sohn EJ. Differentially expression and function of circular RNAs in ovarian cancer stem cells. J Ovarian Res 2022; 15:97. [PMID: 35978436 PMCID: PMC9382745 DOI: 10.1186/s13048-022-01014-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background Circular RNAs (circRNAs) are noncoding RNAs that regulate miRNA expression; however, their functions in cancer stem cells (CSCs) are not well known. Methods To determine the function of differentially expression of circRNAs associated with ovarian CSCs, circRNA profiling was conducted using a circRNA-based microarray on sphere-forming cells derived from A2780 and SKOV3 epithelial ovarian cancer cells termed A2780-SP and SKOV3-SP compared to monolayer cells such as A2780 and SKOV3 cells, respectively. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the biological functions of the circRNAs expressed in CSCs. Results The circRNA-based microarray data showed that 159 circRNAs were significantly upregulated (fold change > 1.5) and 55 circRNAs were downregulated in ovarian CSCs compared to monolayer cells. GO and KEGG enrichment analysis of differentially expressed circRNAs in ovarian CSCs showed that they were mainly involved in cell cycle, histone modification, cellular protein metabolic process, cell cycle, apoptotic signaling pathway, and ubiquitin-mediated proteolysis in ovarian cancer. In addition, the hsa-circRNA000963-miRNA-mRNA regulatory network was constructed based on potential target of miRNAs. These analyses involved that the biological function of the hsa-circRNA00096/miRNA/mRNA network was involved in signaling pathways regulating pluripotency of stem cells, PI3K-Akt signaling pathway, cell cycle, p53 signaling pathway, Wnt signaling pathway, calcium modulating pathway, and production of miRNAs involved in gene silencing by miRNA. Conclusions Our data demonstrate the expression profiles of circRNAs in ovarian CSCs and suggest that circRNAs may be potential diagnostic and predictive biomarkers of ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-022-01014-z.
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Affiliation(s)
- Eun Jung Sohn
- Pusan National University, Yangsan, 50612, Republic of Korea.
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Nestin-Expressing Cells in the Lung: The Bad and the Good Parts. Cells 2021; 10:cells10123413. [PMID: 34943921 PMCID: PMC8700449 DOI: 10.3390/cells10123413] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/25/2021] [Accepted: 12/01/2021] [Indexed: 12/27/2022] Open
Abstract
Nestin is a member of the intermediate filament family, which is expressed in a variety of stem or progenitor cells as well as in several types of malignancies. Nestin might be involved in tissue homeostasis or repair, but its expression has also been associated with processes that lead to a poor prognosis in various types of cancer. In this article, we review the literature related to the effect of nestin expression in the lung. According to most of the reports in the literature, nestin expression in lung cancer leads to an aggressive phenotype and resistance to chemotherapy as well as radiation treatments due to the upregulation of phenomena such as cell proliferation, angiogenesis, and metastasis. Furthermore, nestin may be involved in the pathogenesis of some non-cancer-related lung diseases. On the other hand, evidence also indicates that nestin-positive cells may have a role in lung homeostasis and be capable of generating various types of lung tissues. More research is necessary to establish the true value of nestin expression as a prognostic factor and therapeutic target in lung cancer in addition to its usefulness in therapeutic approaches for pulmonary diseases.
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Narayanan S, Wu ZX, Wang JQ, Ma H, Acharekar N, Koya J, Yoganathan S, Fang S, Chen ZS, Pan Y. The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance. Int J Biol Sci 2021; 17:2652-2665. [PMID: 34326700 PMCID: PMC8315011 DOI: 10.7150/ijbs.61229] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocytic leukemia. Syk is abundantly present in the cells of hematopoietic lineage that mediates cell proliferation, differentiation, and adhesion. In this current study, we evaluated the efficacy of GS-9973 to overcome multidrug resistance (MDR) due to the overexpression of the ABCG2 transporter in the non-small cell lung cancer (NSCLC) cell line, NCI-H460/MX20. In vitro, 3 μM of GS-9973 reversed the drug resistance of NCI-H460/MX20 cell line to mitoxantrone or doxorubicin. GS-9973, at 3 μM reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein compared to drug-resistant cells incubated with the vehicle. GS-9973 produced a moderate concentration-dependent increase in the ATPase activity of ABCG2 (EC50 = 0.42 µM) and molecular docking data indicated that GS-9973 had a high affinity (-10.226 kcal/mol) for the substrate-binding site of ABCG2. Finally, HPLC analysis proved that the intracellular concentration of GS-9973 is not significantly different in both parental and resistant cell lines. In conclusion, our study suggests that in vitro, GS-9973 in combination with certain anticancer drugs, represent a strategy to overcome ABCG2-mediated MDR cancers.
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Affiliation(s)
- Silpa Narayanan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Hansu Ma
- Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, PR China
| | - Nikita Acharekar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Jagadish Koya
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Sabesan Yoganathan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Shuo Fang
- Department of Oncology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, PR China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yihang Pan
- Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, PR China
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Paul MR, Zage PE. Overview and recent advances in the targeting of medulloblastoma cancer stem cells. Expert Rev Anticancer Ther 2021; 21:957-974. [PMID: 34047251 DOI: 10.1080/14737140.2021.1932472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation.Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature.Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.
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Affiliation(s)
- Megan Rose Paul
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
| | - Peter E Zage
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
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10
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Ni T, Wang H, Zhan D, Tao L, Lv M, Wang W, Chu Z, Zhou Z, Sunagawa M, Liu Y. CD133+/CD166+ human gastric adenocarcinoma cells present the properties of neoplastic stem cells and emerge more malignant features. Life Sci 2021; 269:119021. [PMID: 33450261 DOI: 10.1016/j.lfs.2021.119021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 12/28/2022]
Abstract
AIMS The recurrence and metastasis of gastric cancer has always been an important factor affecting the prognosis of gastric cancer. Cancer stem cells can promote the recurrence and growth of gastric cancer. The identification and isolation of gastric cancer stem cells contribute to the origin, progress and treatment strategy of gastric cancer. The aim of this study was to identify and isolate gastric cancer stem cells, and provide targets for the treatment of gastric cancer. METHODS Magnetic-activated cell sorting was used to isolate CD133+/CD166+ cell populations from human gastric adenocarcinoma cell lines (BGC-823 and SGC-7901). Sphere formation, cell proliferation, resistance to chemotherapy, colony formation, migration invasion and tumorigenicity in vivo of these cell populations were evaluated. Moreover, RT-qPCR and Western blot were used to investigate the expression level of the stem cell markers Nanog, Sox2, Oct-4, and c-Myc. RESULTS CD133+/CD166+ cell subpopulations presented more malignant features than CD133-/CD166-, CD133-/CD166+, CD133+/CD166- cell populations and parental cells. Moreover, the mRNA and protein expression level of Oct-4 and c-Myc were higher in CD133+/CD166+ cells than in parental cells or other cell populations. CONCLUSION The CD133+/CD166+ populations of human gastric cancer cell lines BGC-823 and SGC-7901 have cancer stem cell characteristics.
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Affiliation(s)
- Tengyang Ni
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Haibo Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Dongmei Zhan
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Li Tao
- Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Mengying Lv
- Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Weimin Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Zewen Chu
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Zhen Zhou
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China
| | - Masataka Sunagawa
- Department of Physiology, School of Medicine, Showa University, Tokyo 142, Japan
| | - Yanqing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou 225001, China.
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Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects. Stem Cell Rev Rep 2020; 15:331-355. [PMID: 30993589 DOI: 10.1007/s12015-019-09887-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since last two decades, the major cancer research has focused on understanding the characteristic properties and mechanism of formation of Cancer stem cells (CSCs), due to their ability to initiate tumor growth, self-renewal property and multi-drug resistance. The discovery of the mechanism of acquisition of stem-like properties by carcinoma cells via epithelial-mesenchymal transition (EMT) has paved a way towards a deeper understanding of CSCs and presented a possible avenue for the development of therapeutic strategies. In spite of years of research, various challenges, such as identification of CSC subpopulation, lack of appropriate experimental models, targeting cancer cells and CSCs specifically without harming normal cells, are being faced while dealing with CSCs. Here, we discuss the biology and characteristics of CSCs, mode of acquisition of stemness (via EMT) and development of multi-drug resistance, the role of tumor niche, the process of dissemination and metastasis, therapeutic implications of CSCs and necessity of targeting them. We emphasise various strategies being developed to specifically target CSCs, including those targeting biomarkers, key pathways and microenvironment. Finally, we focus on the challenges that need to be subdued and propose the aspects that need to be addressed in future studies in order to broaden the understanding of CSCs and develop novel strategies to eradicate them in clinical applications. Graphical Abstract Cancer Stem Cells(CSCs) have gained much attention in the last few decades due to their ability to initiate tumor growth and, self-renewal property and multi-drug resistance. Here, we represent the CSC model of cancer, Characteristics of CSCs, acquisition of stemness and metastatic dissemination of cancer, Therapeutic implications of CSCs and Various strategies being employed to target and eradicate CSCs.
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Hassn Mesrati M, Behrooz AB, Y. Abuhamad A, Syahir A. Understanding Glioblastoma Biomarkers: Knocking a Mountain with a Hammer. Cells 2020; 9:E1236. [PMID: 32429463 PMCID: PMC7291262 DOI: 10.3390/cells9051236] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/18/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Gliomas are the most frequent and deadly form of human primary brain tumors. Among them, the most common and aggressive type is the high-grade glioblastoma multiforme (GBM), which rapidly grows and renders patients a very poor prognosis. Meanwhile, cancer stem cells (CSCs) have been determined in gliomas and play vital roles in driving tumor growth due to their competency in self-renewal and proliferation. Studies of gliomas have recognized CSCs via specific markers. This review comprehensively examines the current knowledge of the most significant CSCs markers in gliomas in general and in glioblastoma in particular and specifically focuses on their outlook and importance in gliomas CSCs research. We suggest that CSCs should be the superior therapeutic approach by directly targeting the markers. In addition, we highlight the association of these markers with each other in relation to their cascading pathways, and interactions with functional miRNAs, providing the role of the networks axes in glioblastoma signaling pathways.
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Affiliation(s)
| | | | | | - Amir Syahir
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (M.H.M.); (A.B.B.); (A.Y.A.)
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Tian Y, Wang Z, Wang Y, Yin B, Yuan J, Qiang B, Han W, Peng X. Glioma-derived endothelial cells promote glioma cells migration via extracellular vesicles-mediated transfer of MYO1C. Biochem Biophys Res Commun 2020; 525:S0006-291X(20)30283-7. [PMID: 32081419 DOI: 10.1016/j.bbrc.2020.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/04/2020] [Indexed: 12/11/2022]
Abstract
Extracellular vesicles (EV), as the intercellular information transfer molecules which can regulate the tumor microenvironment, promote migration and tumor progression. Previous studies reported that EV from endothelial cells was used to guide the fate and survival of gliomas, but many researches focus on normal human endothelial cells (NhEC) rather than tumor-derived endothelial cells. Our laboratory isolated human endothelial cells from glioma issue (GhEC). We have previously demonstrated that EV from GhEC and NhEC, which both can promote glioma stem cells (GSC) proliferation and tumorsphere formation in vitro and tumourigenicity in vivo by the transfer of CD9. However, NhEC-EV or GhEC-EV could suppress glioma cells (GC) proliferation in vitro. It demonstrates the undifferentiated impact of EV. Here, we first compared GhEC-EV proteins with NhEC-EV (Screening criteria: GhEC-EV/NhEC-EV, FC > 1.5), and obtained 70 differential expression proteins, most of which were associated with invasion and migration. We found that GhEC or GhEC-EV preferred promoting GC migration than treating with NhEC or NhEC-EV. In terms of mechanism, we further revealed that EV-mediated transfer of MYO1C induced glioma cell LN229 migration. Knockdown of MYO1C in GhEC or GhEC-EV suppressed this effect. Overexpression of MYO1C promoted migration on the contrary. MYO1C was also detected in glioma cerebrospinal fluid (CSF), which is more suitable as a liquid biopsy biomarker and contributes to early diagnosis and monitoring in glioma. Our findings provide a new protein-MYO1C in EV to target tumor blood vessels, and bring a new point-cut to the treatment of gliomablastoma (GBM).
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Affiliation(s)
- Yuan Tian
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Zhixing Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yuxin Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Bin Yin
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Jiangang Yuan
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Boqin Qiang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Wei Han
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China; Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, China.
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14
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Bahmad HF, Poppiti RJ. Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. J Clin Pathol 2020; 73:243-249. [PMID: 32034059 DOI: 10.1136/jclinpath-2019-206246] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.
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Affiliation(s)
- Hisham F Bahmad
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Robert J Poppiti
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA .,Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
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15
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Steinbichler TB, Savic D, Dudás J, Kvitsaridze I, Skvortsov S, Riechelmann H, Skvortsova II. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol 2020; 60:148-156. [PMID: 31521746 DOI: 10.1016/j.semcancer.2019.09.007] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/10/2019] [Accepted: 09/11/2019] [Indexed: 12/19/2022]
Abstract
Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation, but also dormancy and cellular plasticity that allow adaption to new environmental circumstances. These abilities are ideal prerequisites for the successful establishment of metastasis. This review highlights the role of CSCs in every step of the metastatic cascade from cancer cell invasion into blood vessels, survival in the blood stream, attachment and extravasation as well as colonization of the host organ and subsequent establishment of distant macrometastasis.
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Affiliation(s)
| | - Dragana Savic
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - József Dudás
- Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria
| | - Irma Kvitsaridze
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Sergej Skvortsov
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria.
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16
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Moradi F, Babashah S, Sadeghizadeh M, Jalili A, Hajifathali A, Roshandel H. Signaling pathways involved in chronic myeloid leukemia pathogenesis: The importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2019; 22:581-589. [PMID: 31231484 PMCID: PMC6570743 DOI: 10.22038/ijbms.2019.31879.7666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 11/15/2018] [Indexed: 11/06/2022]
Abstract
OBJECTIVES Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously. MATERIALS AND METHODS In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works . RESULTS Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway. CONCLUSION The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value.
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Affiliation(s)
- Foruzan Moradi
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arsalan Jalili
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hajifathali Roshandel
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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17
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Zhu Y, Zhang H, Zhang G, Shi Y, Huang J. Co-expression of CD44/MyD88 is a poor prognostic factor in advanced epithelial ovarian cancer. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:91. [PMID: 31019941 DOI: 10.21037/atm.2019.01.28] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Cluster of differentiation 44 (CD44)/myeloid differentiation factor 88 (MyD88) is the molecular characterization of EOC stem cells. An important characteristic of CD44+/MyD88+ epithelial ovarian cancer (EOC) cells, which differentiate them from the CD44-/MyD88- EOC cells, is the presence of a functional TLR4-MyD88-NFkB pathway. The aim of our study is to investigate the clinical significance of CD44/MyD88 co-expression in EOC. Methods A total of 138 specimens of ovarian tissues was detected CD44 and MyD88 expression by immunocytochemistry, including EOC (N=108), borderline tumors (N=10), benign cysts (N=10) and normal ovarian tissue (N=10). The association of CD44/MyD88 co-expression with clinicopathological factors and outcomes was analyzed. Results The expression of CD44 was showed distinct difference in EOC (53 of 108, 49.1%), in borderline tumors (3 of 10, 30.0%), in benign cysts (2 of 10, 20.0%) and normal ovarian (2 of 10, 20.0%). A total of 41 (38.0%) cancers showed a combined expression of CD44/MyD88. The expression of CD44 and MyD88 had definitely correlativity (r=0.21, P=0.026). CD44/MyD88 co-expression was associated with tumor progression, metastasis, and recurrence in advanced EOC, and an independent prognostic factor for disease-free survival and overall survival. Conclusions CD44/MyD88 co-expression has been shown to contribute to EOC progression and outcome directly and has a promising as a therapeutic target in EOC.
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Affiliation(s)
- Yi Zhu
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.,Department of Ultrasound, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Hongtao Zhang
- Department of Obstetrics and Gynecology, Sichuan Jinxin Women and Children's Hospital, Chengdu 610000, China
| | - Guonan Zhang
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Yu Shi
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jianming Huang
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.,Department of Biochemistry & Molecular Biology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
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18
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Talukdar S, Bhoopathi P, Emdad L, Das S, Sarkar D, Fisher PB. Dormancy and cancer stem cells: An enigma for cancer therapeutic targeting. Adv Cancer Res 2019; 141:43-84. [PMID: 30691685 DOI: 10.1016/bs.acr.2018.12.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Dormancy occurs when cells remain viable but stop proliferating. When most of a cancer population undergoes this phenomenon, the result is called tumor dormancy, and when a single cancer cell undergoes this process, it is termed quiescence. Cancer stem cells (CSCs) share several overlapping characteristics and signaling pathways with dormant cancer cells, including therapy resistance, and an ability to metastasize and evade the immune system. Cancer cells can be broadly grouped into dormancy-competent CSCs (DCCs), cancer-repopulating cells (CRCs), dormancy-incompetent CSCs and disseminated tumor cells (DTCs). The settings in which cancer cells exploit the dormancy phase to survive and adapt are: (i) primary cancer dormancy; (ii) metastatic dormancy; (iii) therapy-induced dormancy; and (iv) immunologic dormancy. Dormancy, therapy resistance and plasticity of CSCs are fundamentally interconnected processes mediated through mechanisms involving reversible genetic alterations. Niches including metastatic, bone marrow, and perivascular are known to harbor dormant cancer cells. Mechanisms of dormancy induction are complex and multi-factorial and can involve angiogenic switching, addictive oncogene inhibition, immunoediting, anoikis, therapy, autophagy, senescence, epigenetic, and biophysical regulation. Therapy can have opposing effects on cancer cells with respect to dormancy; some therapies can induce dormancy, while others can reactivate dormant cells. There is a lack of consensus relative to the value of therapy-induced dormancy, i.e., some researchers view dormancy induction as a beneficial strategy as it can lead to metastasis inhibition, while others argue that reactivating dormant cancer cells and then eliminating them through therapy are a better approach. More focused investigations of intrinsic cell kinetics and environmental dynamics that promote and maintain cancer cells in a dormant state, and the long-term consequences of dormancy are critical for improving current therapeutic treatment outcomes.
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Affiliation(s)
- Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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19
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Barreto dos Santos N, Bonfanti AP, Rocha‐e‐Silva TAAD, da Silva PI, da Cruz‐Höfling MA, Verinaud L, Rapôso C. Venom of the
Phoneutria nigriventer
spider alters the cell cycle, viability, and migration of cancer cells. J Cell Physiol 2018; 234:1398-1415. [DOI: 10.1002/jcp.26935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/12/2018] [Indexed: 01/15/2023]
Affiliation(s)
- Natália Barreto dos Santos
- Departamento de Biologia Estrutural e Funcional Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP) Campinas Brazil
| | - Amanda Pires Bonfanti
- Departamento de Biologia Estrutural e Funcional Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP) Campinas Brazil
| | | | | | - Maria Alice da Cruz‐Höfling
- Departamento de Bioquímica e Biologia Tecidual Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP) Campinas Brazil
| | - Liana Verinaud
- Departamento de Biologia Estrutural e Funcional Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP) Campinas Brazil
| | - Catarina Rapôso
- Departamento de Biologia Estrutural e Funcional Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP) Campinas Brazil
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20
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Iqbal W, Alkarim S, AlHejin A, Mukhtar H, Saini KS. Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. Oncotarget 2018; 7:76337-76353. [PMID: 27486983 PMCID: PMC5342819 DOI: 10.18632/oncotarget.10942] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/13/2016] [Indexed: 12/11/2022] Open
Abstract
Tumor comprises of heterogeneous population of cells where not all the disseminated cancer cells have the prerogative and "in-build genetic cues" to form secondary tumors. Cells with stem like properties complemented by key signaling molecules clearly have shown to exhibit selective growth advantage to form tumors at distant metastatic sites. Thus, defining the role of cancer stem cells (CSC) in tumorigenesis and metastasis is emerging as a major thrust area for therapeutic intervention. Precise relationship and regulatory mechanisms operating in various signal transduction pathways during cancer dissemination, extravasation and angiogenesis still remain largely enigmatic. How the crosstalk amongst circulating tumor cells (CTC), epithelial mesenchymal transition (EMT) process and CSC is coordinated for initiating the metastasis at secondary tissues, and during cancer relapse could be of great therapeutic interest. The signal transduction mechanisms facilitating the dissemination, infiltration of CSC into blood stream, extravasations, progression of metastasis phenotype and angiogenesis, at distant organs, are the key pathologically important vulnerabilities being elucidated. Therefore, current new drug discovery focus has shifted towards finding "key driver genes" operating in parallel signaling pathways, during quiescence, survival and maintenance of stemness in CSC. Understanding these mechanisms could open new horizons for tackling the issue of cancer recurrence and metastasis-the cause of ~90% cancer associated mortality. To design futuristic & targeted therapies, we propose a multi-pronged strategy involving small molecules, RNA interference, vaccines, antibodies and other biotechnological modalities against CSC and the metastatic signal transduction cascade.
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Affiliation(s)
- Waqas Iqbal
- Embryonic and Cancer Stem Cell Research Group, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh Alkarim
- Embryonic and Cancer Stem Cell Research Group, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed AlHejin
- Embryonic and Cancer Stem Cell Research Group, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hasan Mukhtar
- Embryonic and Cancer Stem Cell Research Group, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Dermatology, University of Wisconsin Medical Sciences Center, Madison, WI, USA
| | - Kulvinder S Saini
- Embryonic and Cancer Stem Cell Research Group, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,School of Biotechnology, Eternal University, Baru Sahib, Himachal Pradesh, India
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21
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Radpour R. Tracing and targeting cancer stem cells: New venture for personalized molecular cancer therapy. World J Stem Cells 2017; 9:169-178. [PMID: 29104735 PMCID: PMC5661129 DOI: 10.4252/wjsc.v9.i10.169] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/14/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023] Open
Abstract
Tumors consist of a mixture of heterogeneous cell types. Cancer stem cells (CSCs) are a minor sub-population within the bulk cancer fraction which has been found to reconstitute and propagate the disease and to be frequently resistant to chemotherapy, irradiation, cytotoxic drugs and probably also against immune attack. CSCs are considered as the seeds of tumor recurrence, driving force of tumorigenesis and metastases. This underlines the urgent need for innovative methods to identify and target CSCs. However, the role and existence of CSCs in therapy resistance and cancer recurrence remains a topic of intense debate. The underlying biological properties of the tumor stem cells are extremely dependent on numerous signals, and the targeted inhibition of these stem cell signaling pathways is one of the promising approaches of the new antitumor therapy approaches. This perspective review article summarizes the novel methods of tracing CSCs and discusses the hallmarks of CSC identification influenced by the microenvironment or by having imperfect detection markers. In addition, explains the known molecular mechanisms of therapy resistance in CSCs as reliable and clinically predictive markers that could enable the use of new targeted antitumor therapy in the sense of personalized medicine.
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Affiliation(s)
- Ramin Radpour
- Tumor Immunology and Cancer Stem Cells, Inselspital, Bern University Hospital, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland.
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22
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Cha SY, Choi YH, Hwang S, Jeong JY, An HJ. Clinical Impact of microRNAs Associated With Cancer Stem Cells as a Prognostic Factor in Ovarian Carcinoma. J Cancer 2017; 8:3538-3547. [PMID: 29151939 PMCID: PMC5687169 DOI: 10.7150/jca.20348] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023] Open
Abstract
Background: Ovarian carcinoma is a highly lethal gynecological malignancy due to its frequent relapses and adoption of chemoresistance. To develop new biomarkers for disease progression in ovarian carcinoma, CSCs, which are considered to contribute to disease relapse and metastasis, were isolated from human ovarian carcinoma tissues, and differentially expressed microRNAs (miRNAs) in CSCs were identified and assessed the clinical implication of expression of these miRNAs. Methods: Primary cancer cells derived from human ovarian carcinomas were cultured and spheroid-forming cells (SFCs) were isolated. Profiles of miRNA expression in CSC-like SFCs were identified by miRNA microarray and the results were validated by quantitative real-time RT-PCR (qRT-PCR). We also assessed the correlations between miRNA expression levels and clinicopathological parameters in ovarian carcinomas. Results: Five miRNAs (miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b) were significantly dysregulated in CSC-like SFCs compared with primary cancer cells. The qRT-PCR showed that miR-5703 and miR-1246 expression was significantly higher in ovarian cancer cells than in normal control cells, whereas the miR-424-5p level was significantly lower. Decreased expression of miR-424-5p was significantly associated with distant metastasis in high stage (stage IIII & IV) carcinomas (35.5% vs. 72.2%, respectively, p=0.013) Conclusion: Taken together, miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b are useful markers for enriching ovarian CSCs. Decreased expression of miR-424-5p in ovarian carcinoma might be a putative biomarker for distant metastasis in ovarian carcinoma.
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Affiliation(s)
- So Youn Cha
- Department of Pathology, CHA University, Sungnam, Republic of Korea
| | - Yeon Ho Choi
- Institute for Clinical Research, CHA University, Sungnam, Republic of Korea
| | - Sohyun Hwang
- Department of Biomedical Science, CHA University, Sungnam, Republic of Korea
| | - Ju-Yeon Jeong
- Institute for Clinical Research, CHA University, Sungnam, Republic of Korea
| | - Hee Jung An
- Department of Pathology, CHA University, Sungnam, Republic of Korea.,Institute for Clinical Research, CHA University, Sungnam, Republic of Korea
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23
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Cai W, Chen G, Luo Q, Liu J, Guo X, Zhang T, Ma F, Yuan L, Li B, Cai J. PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells. Mol Cancer Ther 2017; 16:1187-1198. [PMID: 28336807 DOI: 10.1158/1535-7163.mct-16-0750] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/12/2016] [Accepted: 03/03/2017] [Indexed: 12/14/2022]
Abstract
Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187-98. ©2017 AACR.
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Affiliation(s)
- Wangyu Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Gang Chen
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Qicong Luo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Jun Liu
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Xiaofeng Guo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Tian Zhang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Fei Ma
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Liang Yuan
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Boan Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China. .,Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
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Emery IF, Gopalan A, Wood S, Chow KH, Battelli C, George J, Blaszyk H, Florman J, Yun K. Expression and function of ABCG2 and XIAP in glioblastomas. J Neurooncol 2017; 133:47-57. [PMID: 28432589 PMCID: PMC5627495 DOI: 10.1007/s11060-017-2422-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 04/09/2017] [Indexed: 12/16/2022]
Abstract
Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic strategy in GBMs.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Adult
- Aged
- Aged, 80 and over
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Brain Neoplasms/drug therapy
- Brain Neoplasms/metabolism
- Brain Neoplasms/mortality
- Brain Neoplasms/radiotherapy
- Cells, Cultured
- Dacarbazine/analogs & derivatives
- Dacarbazine/therapeutic use
- Diketopiperazines/pharmacology
- Female
- Follow-Up Studies
- Glioblastoma/drug therapy
- Glioblastoma/metabolism
- Glioblastoma/mortality
- Glioblastoma/radiotherapy
- Heterocyclic Compounds, 4 or More Rings/pharmacology
- Humans
- Indoles/pharmacology
- Male
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Middle Aged
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/metabolism
- Neoplasm Transplantation
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Temozolomide
- X-Linked Inhibitor of Apoptosis Protein/metabolism
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Affiliation(s)
- Ivette F Emery
- Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA.
| | - Archana Gopalan
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Stephanie Wood
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Kin-Hoe Chow
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Chiara Battelli
- New England Cancer Specialists, 100 Campus Drive, Suite 108, Scarborough, ME, 04074, USA
| | - Joshy George
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA
| | - Hagen Blaszyk
- Maine Medical Center Department of Pathology, 22 Bramhall Street, Portland, ME, 04102, USA
| | - Jeffrey Florman
- Maine Medical Center Neuroscience Institute, 22 Bramhall Street, Portland, ME, 04102, USA
| | - Kyuson Yun
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
- Peak Center for Brain and Pituitary Tumors, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030, USA.
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25
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Jin WL, Mao XY, Qiu GZ. Targeting Deubiquitinating Enzymes in Glioblastoma Multiforme: Expectations and Challenges. Med Res Rev 2016; 37:627-661. [PMID: 27775833 DOI: 10.1002/med.21421] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 09/06/2016] [Accepted: 09/25/2016] [Indexed: 12/16/2022]
Abstract
Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well-orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways. In recent years, deubiquitinating enzymes (DUBs) have emerged as potential anti-cancer targets due to their targeting several key proteins involved in the regulation of tumorigenesis, apoptosis, senescence, and autophagy. This review attempts to summarize recent studies of GBM-associated DUBs, their roles in various cellular processes, and discuss the relation between DUBs deregulation and gliomagenesis, especially how DUBs regulate glioma stem cells pluripotency, microenvironment, and resistance of radiation and chemotherapy through core stem-cell transcriptional factors. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of DUBs, and attempted to find a potential GBM treatment by DUBs intervention.
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Affiliation(s)
- Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.,National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China
| | - Xiao-Yuan Mao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, P. R. China
| | - Guan-Zhong Qiu
- Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, 250031, P. R. China
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26
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Huang GH, Xu QF, Cui YH, Li N, Bian XW, Lv SQ. Medulloblastoma stem cells: Promising targets in medulloblastoma therapy. Cancer Sci 2016; 107:583-9. [PMID: 27171351 PMCID: PMC4970825 DOI: 10.1111/cas.12925] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/02/2016] [Accepted: 03/04/2016] [Indexed: 12/15/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long‐term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.
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Affiliation(s)
- Guo-Hao Huang
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qing-Fu Xu
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - You-Hong Cui
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ningning Li
- Division of Neuropathology and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Sheng-Qing Lv
- Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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27
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Cancer stem cells, metabolism, and therapeutic significance. Tumour Biol 2016; 37:5735-42. [PMID: 26864589 DOI: 10.1007/s13277-016-4945-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 01/29/2016] [Indexed: 02/08/2023] Open
Abstract
Cancer stem cells (CSCs) have attracted much attention of the research community in the recent years. Due to their highly tumorigenic and drug-resistant properties, CSCs represent important targets for developing novel anticancer agents and therapeutic strategies. CSCs were first described in hematopoietic malignancies and subsequently identified in various types of solid tumors including brain, breast, lung, colon, melanoma, and ovarian cancer. CSCs possess special biological properties including long-term self-renewal capacity, multi-lineage differentiation, and resistance to conventional chemotherapy and radiotherapy. As such, CSCs are considered as a major source of residual disease after therapy leading to disease occurrence. Thus, it is very important to understand the cellular survival mechanisms specific to CSCs and accordingly develop effective therapeutic approaches to eliminate this subpopulation of cancer cells in order to improve the treatment outcome of cancer patients. Possible therapeutic strategies against CSCs include targeting the self-renewal pathways of CSCs, interrupting the interaction between CSCs and their microenvironment, and exploiting the unique metabolic properties of CSCs. In this review article, we will provide an overview of the biological characteristics of CSCs, with a particular focus on their metabolic properties and potential therapeutic strategies to eliminate CSCs.
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28
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Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2016; 16:225-38. [PMID: 25748930 DOI: 10.1016/j.stem.2015.02.015] [Citation(s) in RCA: 1156] [Impact Index Per Article: 128.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets.
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Affiliation(s)
- Vicki Plaks
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Niwen Kong
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Zena Werb
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA.
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29
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Neradil J, Veselska R. Nestin as a marker of cancer stem cells. Cancer Sci 2015; 106:803-11. [PMID: 25940879 PMCID: PMC4520630 DOI: 10.1111/cas.12691] [Citation(s) in RCA: 193] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/14/2015] [Accepted: 04/27/2015] [Indexed: 12/14/2022] Open
Abstract
The crucial role of cancer stem cells (CSCs) in the pathology of malignant diseases has been extensively studied during the last decade. Nestin, a class VI intermediate filament protein, was originally detected in neural stem cells during development. Its expression has also been reported in different tissues under various pathological conditions. Specifically, nestin has been shown to be expressed in transformed cells of various human malignancies, and a correlation between its expression and the clinical course of some diseases has been proved. Furthermore, the coexpression of nestin with other stem cell markers was described as a CSC phenotype that was subsequently verified using tumorigenicity assays. The primary aim of this review is to summarize the recent findings regarding nestin expression in CSCs, its possible role in CSC phenotypes, particularly with respect to capacity for self-renewal, and its utility as a putative marker of CSCs.
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Affiliation(s)
- Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czech Republic.,Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czech Republic.,Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Brno, Czech Republic
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30
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Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med 2015; 5:84-102. [PMID: 25992323 PMCID: PMC4436943 DOI: 10.5493/wjem.v5.i2.84] [Citation(s) in RCA: 243] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 12/05/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancer-related deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of a significant proportion of gastric cancer cases. This review focuses on the participation of the Wnt/β-catenin pathway in gastric cancer by offering an analysis of the relevant literature published in this field. Indeed, it is discussed the role of key factors in Wnt/β-catenin signaling and their downstream effectors regulating processes involved in tumor initiation, tumor growth, metastasis and resistance to therapy. Available data indicate that constitutive Wnt signalling resulting from Helicobacter pylori infection and inactivation of Wnt inhibitors (mainly by inactivating mutations and promoter hypermethylation) play an important role in gastric cancer. Moreover, a number of recent studies confirmed CTNNB1 and APC as driver genes in gastric cancer. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput “omics” approaches will help in the search for Wnt pathway antagonist in the near future.
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31
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Kaur H, Hütt-Cabezas M, Weingart MF, Xu J, Kuwahara Y, Erdreich-Epstein A, Weissman BE, Eberhart CG, Raabe EH. The chromatin-modifying protein HMGA2 promotes atypical teratoid/rhabdoid cell tumorigenicity. J Neuropathol Exp Neurol 2015; 74:177-85. [PMID: 25575139 PMCID: PMC4695975 DOI: 10.1097/nen.0000000000000161] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric central nervous system tumor. The poor prognosis of AT/RT warrants identification of novel therapeutic targets and strategies. High-mobility Group AT-hook 2 (HMGA2) is a developmentally important chromatin-modifying protein that positively regulates tumor growth, self-renewal, and invasion in other cancer types. High-mobility group A2 was recently identified as being upregulated in AT/RT tissue, but the role of HMGA2 in brain tumors remains unknown. We used lentiviral short-hairpin RNA to suppress HMGA2 in AT/RT cell lines and found that loss of HMGA2 led to decreased cell growth, proliferation, and colony formation and increased apoptosis. We also found that suppression of HMGA2 negatively affected in vivo orthotopic xenograft tumor growth, more than doubling median survival of mice from 58 days to 153 days. Our results indicate a role for HMGA2 in AT/RT in vitro and in vivo and demonstrate that HMGA2 is a potential therapeutic target in these lethal pediatric tumors.
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Affiliation(s)
- Harpreet Kaur
- From the Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center (HK, MH-C, MFW, CGE, EHR), Division of Pediatric Oncology (EHR), Johns Hopkins University School of Medicine, Bloomberg Children's Hospital, Baltimore, Maryland; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (YK, BEW); and Division of Hematology, Oncology, and Blood and Bone Marrow Transplant, Children's Hospital Los Angeles (JX, AE-E); and the University of Southern California (AE-E), Los Angeles, California
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32
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Hegedüs C, Hegedüs T, Sarkadi B. The Role of ABC Multidrug Transporters in Resistance to Targeted Anticancer Kinase Inhibitors. RESISTANCE TO TARGETED ANTI-CANCER THERAPEUTICS 2015. [DOI: 10.1007/978-3-319-09801-2_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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33
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Radiation therapy for glioma stem cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 853:85-110. [PMID: 25895709 DOI: 10.1007/978-3-319-16537-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Radiation therapy is the most effective adjuvant treatment modality for virtually all patients with high-grade glioma. Its ability to improve patient survival has been recognized for decades. Cancer stem cells provide new insights into how tumor biology is affected by radiation and the role that this cell population can play in disease recurrence. Glioma stem cells possess a variety of intracellular mechanisms to resist and even flourish in spite of radiation, and their proliferation and maintenance appear tied to supportive stimuli from the tumor microenvironment. This chapter reviews the basis for our current use of radiation to treat high-grade gliomas, and addresses this model in the context of therapeutically resistant stem cells. We discuss the available evidence highlighting current clinical efforts to improve radiosensitivity, and newer targets worthy of further development.
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34
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Dendritic cell c-kit signaling and adaptive immunity: implications for the upper airways. Curr Opin Allergy Clin Immunol 2014; 14:7-12. [PMID: 24300419 DOI: 10.1097/aci.0000000000000019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW Binding of the receptor tyrosine kinase, c-kit, to its ligand, stem cell factor (SCF), mediates numerous biological functions. Important roles for c-kit in hematopoiesis, melanogenesis, erythropoiesis, spermatogenesis, and carcinogenesis are well documented. Similarly, activation of mast cells and eosinophils by c-kit ligation has long been known to result in degranulation with concomitant release of pro-inflammatory mediators including cytokines. This review will highlight a recently discovered function of c-kit in regulating the adaptive immune responses with relevance to allergic diseases. RECENT FINDINGS Recent studies in a number of laboratories including our own highlight the previously unappreciated functions for c-kit in immunological processes. Increased expression of c-kit and its ligand, SCF, on dendritic cells by Th2/Th17-inducing stimuli leads to c-kit activation and immune skewing toward these subsets and away from Th1 responses. Treatment of dendritic cells with inhibitors of c-kit activation such as imatinib mesylate (Gleevec) induces breach of T-cell tolerance, skewing of responses toward Th1, and activation of natural killer cells. SUMMARY Taken together, these observations suggest that the c-kit/SCF axis may be a useful target for redirecting deleterious immune responses in various disease settings, including allergic diseases that are often associated with Th2 and Th17 responses.
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35
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Lemke D, Weiler M, Blaes J, Wiestler B, Jestaedt L, Klein AC, Löw S, Eisele G, Radlwimmer B, Capper D, Schmieder K, Mittelbronn M, Combs SE, Bendszus M, Weller M, Platten M, Wick W. Primary glioblastoma cultures: can profiling of stem cell markers predict radiotherapy sensitivity? J Neurochem 2014; 131:251-64. [DOI: 10.1111/jnc.12802] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 06/21/2014] [Accepted: 06/25/2014] [Indexed: 11/27/2022]
Affiliation(s)
- Dieter Lemke
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
| | - Markus Weiler
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
| | - Jonas Blaes
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Benedikt Wiestler
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
| | - Leonie Jestaedt
- Department of Neuroradiology; University of Heidelberg; Heidelberg Germany
| | - Ann-Catherine Klein
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Sarah Löw
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
| | - Günter Eisele
- Department of Neurology; University Hospital Zurich; Zurich Switzerland
| | - Bernhard Radlwimmer
- German Cancer Consortium (DKTK); Heidelberg Germany
- Division of Molecular Genetics; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - David Capper
- Institute of Neuropathology; University Clinic Heidelberg; Heidelberg Germany
| | - Kirsten Schmieder
- Department for Neurosurgery; Universitätsmedizin of Mannheim; Mannheim Germany
| | - Michel Mittelbronn
- Institute for Brain Research; University of Tübingen; Tübingen Germany
- Institute of Neurology (Edinger Institute); Goethe University; Frankfurt/Main Germany
| | - Stephanie E. Combs
- Department of Radiation Oncology; University of Heidelberg; Heidelberg Germany
| | - Martin Bendszus
- Department of Neuroradiology; University of Heidelberg; Heidelberg Germany
| | - Michael Weller
- Department of Neurology; University Hospital Zurich; Zurich Switzerland
| | - Michael Platten
- German Cancer Consortium (DKTK); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology; DKFZ Heidelberg; Heidelberg Germany
| | - Wolfgang Wick
- German Cancer Consortium (DKTK); Heidelberg Germany
- Clinical Cooperation Unit Neurooncology; German Cancer Research Center (DKFZ); Heidelberg Germany
- Department of Neurooncology; Neurology Clinic and National Center for Tumor Diseases; University of Heidelberg; Heidelberg Germany
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36
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Kong DS. Cancer stem cells in brain tumors and their lineage hierarchy. Int J Stem Cells 2014; 5:12-5. [PMID: 24298350 DOI: 10.15283/ijsc.2012.5.1.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2012] [Indexed: 01/30/2023] Open
Abstract
Despite recent advances in the development of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. The chemo-resistance of this tumor is attributed to tumor heterogeneity. To explain this unique chemo- resistance, the concept of cancer stem cells has been evoked. Cancer stem cells, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Here, the author reviews and discusses the cancer stem cell concept.
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Affiliation(s)
- Doo-Sik Kong
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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37
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Li K, Dan Z, Nie YQ. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment. World J Gastroenterol 2014; 20:5420-5426. [PMID: 24833872 PMCID: PMC4017057 DOI: 10.3748/wjg.v20.i18.5420] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gastric cancer. They may be derived from gastric stem cells in gastric tissues, or bone marrow mesenchymal stem cells. As with other stem cells, GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance, which are resistant to chemotherapy and thus form the basis of drug resistance. Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs, diagnosis and grading of gastric cancer, and research on GCSC-targeted therapy for gastric cancer. Therefore, discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment.
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38
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Bish R, Vogel C. RNA binding protein-mediated post-transcriptional gene regulation in medulloblastoma. Mol Cells 2014; 37:357-64. [PMID: 24608801 PMCID: PMC4044306 DOI: 10.14348/molcells.2014.0008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 05/02/2014] [Indexed: 12/21/2022] Open
Abstract
Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone. Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma.
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Affiliation(s)
- Rebecca Bish
- New York University, Center for Genomics and Systems Biology, New York, NY,
USA
| | - Christine Vogel
- New York University, Center for Genomics and Systems Biology, New York, NY,
USA
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Abstract
Metastasis is powered by disseminated cancer cells that re-create a full-fledged tumor in unwelcoming tissues, away from the primary site. How cancer cells moving from a tumor into the circulation manage to infiltrate distant organs and initiate metastatic growth is of interest to cancer biologists and clinical oncologists alike. Recent findings have started to define the sources, phenotypic properties, hosting niches, and signaling pathways that support the survival, self-renewal, dormancy, and reactivation of cancer cells that initiate metastasis: metastatic stem cells. By dissecting the biology of this process, vulnerabilities are being exposed that could be exploited to prevent metastasis.
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Affiliation(s)
- Thordur Oskarsson
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Joan Massagué
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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40
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Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ 2013; 21:124-35. [PMID: 24096870 DOI: 10.1038/cdd.2013.131] [Citation(s) in RCA: 179] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 07/17/2013] [Accepted: 08/02/2013] [Indexed: 02/07/2023] Open
Abstract
Side population (SP) cells within tumors are a small fraction of cancer cells with stem-like properties that can be identified by flow cytometry analysis based on their high ability to export certain compounds such as Hoechst 33342 and chemotherapeutic agents. The existence of stem-like SP cells in tumors is considered as a key factor contributing to drug resistance, and presents a major challenge in cancer treatment. Although it has been recognized for some time that tumor tissue niches may significantly affect cancer stem cells (CSCs), the role of key nutrients such as glucose in the microenvironment in affecting stem-like cancer cells and their metabolism largely remains elusive. Here we report that SP cells isolated from human cancer cells exhibit higher glycolytic activity compared to non-SP cells. Glucose in the culture environment exerts a profound effect on SP cells as evidenced by its ability to induce a significant increase in the percentage of SP cells in the overall cancer cell population, and glucose starvation causes a rapid depletion of SP cells. Mechanistically, glucose upregulates the SP fraction through ATP-mediated suppression of AMPK and activation of the Akt pathway, leading to elevated expression of the ATP-dependent efflux pump ABCG2. Importantly, inhibition of glycolysis by 3-BrOP significantly reduces SP cells in vitro and impairs their ability to form tumors in vivo. Our data suggest that glucose is an essential regulator of SP cells mediated by the Akt pathway, and targeting glycolysis may eliminate the drug-resistant SP cells with potentially significant benefits in cancer treatment.
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Zhou W, Sun M, Wang DL, Wang Y, Jin F, Zhang YY, Yang L, Wu XL, Wu YZ. Silencing of RegIV by shRNA causes the loss of stemness properties of cancer stem cells in MKN45 gastric cancer cells. Oncol Rep 2013; 30:2685-90. [PMID: 24064664 DOI: 10.3892/or.2013.2745] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/27/2013] [Indexed: 11/05/2022] Open
Abstract
Regenerating islet-derived family member 4 (RegIV) is overexpressed in several types of tumours, including pancreatic and gastric cancer (GC). However, the role it plays in gastric cancer stem cells (GCSCs) remains unknown. The present study tested the hypothesis that the silencing of RegIV by shRNA in GC cells may cause the loss of their stemness properties, indicating the inhibition of growth, proliferation and increased sensitivity to chemoradiation-induced cell death. MKN45 poorly differentiated human GC cells were propagated as mammospheres in stem cell culture conditions. Mammospheres were identified as CSCs using generally acknowledged CSC markers such as CD44. A panel of 21-nucleotide shRNAs were designed to target RegIV gene expression. Several shRNA constructs were identified that led to significant reduction in RegIV mRNA expression. Furthermore, the stemness properties of control mammospheres and RegIV knockdown mammospheres were compared by tumourigenicity assay in vivo and plate colony formation assay in vitro. Finally, we evaluated the treatment response in both mammospheres which underwent chemoradiation. The knockdown expression of RegIV by shRNA deprived CSCs of their stemness properties and increased the effectiveness of cell killing following chemoradiation. Inhibition of endogenous RegIV expression may be a new therapeutic strategy for human GC.
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Affiliation(s)
- Wei Zhou
- Department of Radiotherapy, Chongqing Cancer Institute, Chongqing 400011, P.R. China
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42
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Brain tumor stem cells: Molecular characteristics and their impact on therapy. Mol Aspects Med 2013; 39:82-101. [PMID: 23831316 DOI: 10.1016/j.mam.2013.06.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 06/14/2013] [Indexed: 01/05/2023]
Abstract
Glioblastoma (GBM) is the most prevalent primary brain tumor and ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding brain cancer genetics and modeling these tumors with new targeted therapies being tested, but these advances have not translated into substantially improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, the first-line treatment for glioblastoma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to healthy brain tissue and development of radioresistance. Therapeutic resistance is attributed at least in part to a cell population within the tumor that possesses stem-like characteristics and tumor propagating capabilities, referred to as cancer stem cells. Within GBM, the intratumoral heterogeneity is derived from a combination of regional genetic variance and a cellular hierarchy often regulated by distinct cancer stem cell niches, most notably perivascular and hypoxic regions. With the recent emergence as a key player in tumor biology, cancer stem cells have symbiotic relationships with the tumor microenvironment, oncogenic signaling pathways, and epigenetic modifications. The origins of cancer stem cells and their contributions to brain tumor growth and therapeutic resistance are under active investigation with novel anti-cancer stem cell therapies offering potential new hope for this lethal disease.
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Higgins DM, Wang R, Milligan B, Schroeder M, Carlson B, Pokorny J, Cheshier SH, Meyer FB, Weissman IL, Sarkaria JN, Henley JR. Brain tumor stem cell multipotency correlates with nanog expression and extent of passaging in human glioblastoma xenografts. Oncotarget 2013; 4:792-801. [PMID: 23801022 PMCID: PMC3742839 DOI: 10.18632/oncotarget.1059] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 06/06/2013] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of only 15 months. A subpopulation of cells, the brain tumor stem cells (BTSCs), may be responsible for the malignancy of this disease. Xenografts have proven to be a robust model of human BTSCs, but the effects of long-term passaging have yet to be determined. Here we present a study detailing changes in BTSC multipotency, invasive migration, and proliferation after serial passaging of human GBM xenografts. Immunocytochemistry and tumorsphere formation assays demonstrated the presence of BTSCs in both early generation (EG-BTSCs; less than 15 passages) and late generation (LG-BTSCs; more than 24 passages) xenografts. The EG-BTSCs upregulated expression of lineage markers for neurons and oligodendrocytes upon differentiation, indicating multipotency. In contrast, the LG-BTSCs were restricted to an astrocytic differentiation. Quantitative migration and proliferation assays showed that EG-BTSCs are more migratory and proliferative than LG-BTSCs. However, both populations respond similarly to the chemokine SDF-1 by increasing invasive migration. These differences between the EG- and LG-BTSCs were correlated with a significant decrease in nanog expression as determined by qRT-PCR. Mice implanted intracranially with EG-BTSCs showed shorter survival when compared to LG-BTSCs. Moreover, differentiation prior to implantation of EG-BTSCs, but not LG-BTSCs, led to increased survival. Thus, nanog may identify multipotent BTSCs. Furthermore, limited passaging of xenografts preserves these multipotent BTSCs, which may be an essential underlying feature of GBM lethality.
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Affiliation(s)
- Dominique M. Higgins
- Medical Scientist Training Program, Mayo Clinic: College of Medicine, Rochester, Minnesota, USA
- Mayo Graduate School, Mayo Clinic: College of Medicine, Rochester, Minnesota, USA
| | - Ruisi Wang
- Mayo Graduate School, Mayo Clinic: College of Medicine, Rochester, Minnesota, USA
| | - Brian Milligan
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Mark Schroeder
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Brett Carlson
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Jenny Pokorny
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Samuel H. Cheshier
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University Medical Center, Stanford, CA
| | - Fredric B. Meyer
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Irving L. Weissman
- Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University Medical Center, Stanford, CA
| | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - John R. Henley
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
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44
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Zhao XQ, Dai CL, Ohnuma S, Liang YJ, Deng W, Chen JJ, Zeng MS, Ambudkar SV, Chen ZS, Fu LW. Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2. Eur J Pharm Sci 2013; 49:441-50. [PMID: 23619284 DOI: 10.1016/j.ejps.2013.04.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 03/12/2013] [Accepted: 04/13/2013] [Indexed: 12/22/2022]
Abstract
Tandutinib is a novel inhibitor of tyrosine kinases FLT3, PDGFR and KIT. Our study was to explore the capability of tandutinib to reverse ABC transporter-mediated multidrug resistance. Tandutinib reversed ABCG2-mediated drug resistance in ABCG2-482-R2, ABCG2-482-G2, ABCG2-482-T7 and S1-M1-80 cells and increased the accumulation of doxorubicin, rhodamine 123 and [H(3)] mitoxantrone in ABCG2-overexpressing cells. Importantly, tandutinib selectively sensitized side population cells to mitoxantrone. Taken together, our results advocate the potency of tandutinib as an ABCG2 modulator and stem-like cells targeted agent to increase efficiency of anticancer drugs.
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Affiliation(s)
- Xiao-qin Zhao
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China
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45
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MicroRNAs overexpressed in ovarian ALDH1-positive cells are associated with chemoresistance. J Ovarian Res 2013; 6:18. [PMID: 23522567 PMCID: PMC3637599 DOI: 10.1186/1757-2215-6-18] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 03/13/2013] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ovarian carcinoma is the leading cause of cancer death worldwide among gynecological malignancies, and the majority of cases are related with recurrence and chemoresistance. Cancer stem cells (CSCs) are believed to be one of the causes of recurrent or chemoresistant ovarian cancer, and microRNAs are regulatory molecules newly implicated to control a variety of cellular processes, including CSCs. Therefore, we identified ovarian CSC-specific microRNAs and investigated their clinicopathological implication in ovarian carcinomas. METHODS We isolated ALDH1 (+) cell population using the Aldefluor assay, and examined the differential expression pattern of miRNAs between ALDH1 (+) and ALDH1 (-) cells using a high-throughput microRNA microarray. We further investigated the expression patterns of differentially expressed miRNAs in human ovarian cancer samples using the real-time reverse transcription-polymerase chain reaction and analyzed their clinical impact in patients with ovarian cancer. RESULTS We found that high ALDH1 expression was associated with chemoresistance in in vitro and ex vivo samples (p = 0.024). We identified six miRNAs, including miR-23b, miR-27a, miR-27b, miR-346, miR-424, and miR-503, overexpressed in ALDH1 (+) cells, and they were significantly upregulated in chemoresistant ovarian cancer cells (1.4 ~ 3.5-fold) and tumor samples (2.8 ~ 5.5-fold) compared with chemosensitive group. Upregulation of ALDH1 (p = 0.019) and miR-503 (p = 0.033) correlated with high clinical stage, and upregulation of miR-27a was related with distant metastasis (p = 0.046) in patients with ovarian cancer. CONCLUSION Our findings indicate that ALDH1 is a useful marker for enriching ovarian CSCs, and high expression of ALDH1 and its related miRNAs, particularly miR-23b, miR-27b, miR-424, and miR-503, are significantly implicated in chemoresistance and tumor progression in ovarian cancer.
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SONG KAI, WU JUNHUA, JIANG CHUNPING. Dysregulation of signaling pathways and putative biomarkers in liver cancer stem cells (Review). Oncol Rep 2012; 29:3-12. [DOI: 10.3892/or.2012.2082] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 09/25/2012] [Indexed: 02/06/2023] Open
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47
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[Cancer stem cells and high-throughput screening methods]. Strahlenther Onkol 2012; 188 Suppl 3:316-9. [PMID: 22907581 DOI: 10.1007/s00066-012-0207-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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48
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Células madre: implicaciones en el desarrollo de tumores cerebrales. RADIOLOGIA 2012; 54:221-30. [DOI: 10.1016/j.rx.2011.05.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 05/06/2011] [Indexed: 12/17/2022]
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49
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Matos Rojas I, Bertholdo D, Castillo M. Stem cells: Implications in the development of brain tumors. RADIOLOGIA 2012. [DOI: 10.1016/j.rxeng.2012.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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50
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Botchkina G. Colon cancer stem cells--from basic to clinical application. Cancer Lett 2012; 338:127-40. [PMID: 22537805 DOI: 10.1016/j.canlet.2012.04.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 03/30/2012] [Accepted: 04/15/2012] [Indexed: 12/28/2022]
Abstract
Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed. The emerging necessity for the development of complex, multimodal CSC-targeted treatment strategies, which combine conventional therapeutics with promising pathway-specific modulators, and natural compounds, which can improve the efficacy of conventional anti-cancer therapeutics and decrease their undesirable side effects is presented. Also, novel requirements and criteria necessary for evaluation of the CSC-targeted drug efficacy and relevant experimental models are discussed.
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Affiliation(s)
- Galina Botchkina
- Department of Pathology, Stony Brook University Medical Center, Stony Brook, NY 11794-3400, United States.
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