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1
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Giantini-Larsen AM, Pandey A, Garton ALA, Rampichini M, Winston G, Goldberg JL, Magge R, Stieg PE, Souweidane MM, Ramakrishna R. Therapeutic manipulation and bypass of the blood-brain barrier: powerful tools in glioma treatment. Neurooncol Adv 2025; 7:vdae201. [PMID: 39877748 PMCID: PMC11773386 DOI: 10.1093/noajnl/vdae201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025] Open
Abstract
The blood-brain barrier (BBB) remains an obstacle for delivery of chemotherapeutic agents to gliomas. High grade and recurrent gliomas continue to portend a poor prognosis. Multiple methods of bypassing or manipulating the BBB have been explored, including hyperosmolar therapy, convection-enhanced delivery (CED), laser-guided interstitial thermal therapy (LITT), and Magnetic Resonance Guided Focused Ultrasound (MRgFUS) to enhance delivery of chemotherapeutic agents to glial neoplasms. Here, we review these techniques, currently ongoing clinical trials to disrupt or bypass the BBB in gliomas, and the results of completed trials.
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Affiliation(s)
- Alexandra M Giantini-Larsen
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Abhinav Pandey
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Andrew L A Garton
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Margherita Rampichini
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Graham Winston
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Jacob L Goldberg
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Rajiv Magge
- Department of Neurology, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Philip E Stieg
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Mark M Souweidane
- Department of Neurological Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10065, USA
| | - Rohan Ramakrishna
- Corresponding Author: Rohan Ramakrishna, MD, Chief, Neurological Surgery, New York Presbyterian Brooklyn Methodist Hospital, Weill Cornell Medical Center, 525 East 68 Street, New York, NY 10065, USA ()
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2
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Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021; 21:62. [PMID: 33472628 PMCID: PMC7816485 DOI: 10.1186/s12935-020-01719-5] [Citation(s) in RCA: 359] [Impact Index Per Article: 89.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
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Affiliation(s)
- Asieh Emami Nejad
- Department of Biology, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
| | - Simin Najafgholian
- Department of Emergency Medicine, School of Medicine , Arak University of Medical Sciences, Arak, Iran
| | - Alireza Rostami
- Department of Surgery, School of Medicine Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Alireza Sistani
- Department of Emergency Medicine, School of Medicine Valiasr Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaeifar
- Department of Midwifery, Faculty of Nursing and Midwifery , Arak University of Medical Sciences , Arak, Iran
| | - Mojgan Esparvarinha
- Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences , Isfahan, Iran
| | - Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ahmadlou
- Sciences Medical of University Arak, Hospital Amiralmomenin, Center Development Research Clinical, Arak, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Bahman Sadeghi
- Department of Health and Community Medicine, School of Medicine, Arak University of Medical Sciences, Arak, 3848176341, Iran.
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Medical Laboratory Science, Faculty of Medical Science Kermanshah Branch, Islamic Azad University, Imam Khomeini Campus, Farhikhtegan Bld., Shahid J'afari St., Kermanshah, 3848176341, Iran.
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3
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Weng Z, Ma L, Li J, Zhou Q, Peng L, Li H, Chen L, Xin Z, Shi L, Qi S, Lu Y. A reproduceable in situ xenograft model of spinal glioma. J Neurosci Methods 2020; 346:108928. [PMID: 32898574 DOI: 10.1016/j.jneumeth.2020.108928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/30/2020] [Accepted: 08/31/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Spinal glioma is a nervous system tumor that tends to relapse and has no specific prognostic molecular biomarkers. Thus, a stable and reproduceable animal research model of spinal glioma is urgently needed. NEW METHOD We established a new in situ tumor xenograft model of spinal glioma using nude mice. In this study, we implanted tumors into the cervical spinal cord of nude mice to mimic the pathological characteristics of the original tumors. RESULTS Through anatomical experiments, we found that the cervical lamina of mice was thinner, the intervertebral space was much wider, and the adhesion muscles were more easily separated. According to the examination of spinal cord sections, the best puncture point we identified was located 0.9 mm lateral to the posterior median line at the level of the line between the midpoints of the scapulae and at a depth of 0.9 mm. In the nude mouse xenograft experiment, the implanted tumor tissue retained the pathological characteristics of the original tumor. COMPARISON WITH EXISTING METHOD(S) This model used the cervical spinal cord as the puncture site and patient-derived primary tumor cells, which has never been performed before. Tumor cells could be injected directly without damaging the lamina. Thus, we could reduce the risk of man-made spinal cord injury and infection and avoid destroying the stability and integrity of the spine. CONCLUSIONS This study established a stable and reliable animal model of spinal glioma for further molecular research and targeted therapy development.
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Affiliation(s)
- Zhijian Weng
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Department of Neurosurgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, 519000, China
| | - Liyi Ma
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Junjie Li
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Qiang Zhou
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Lin Peng
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Hong Li
- Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Lei Chen
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Zong Xin
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Linyong Shi
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Songtao Qi
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Glioma Center, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Yuntao Lu
- Department of Neurosurgery, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Neurology Research Institution, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China; Nanfang Glioma Center, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
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4
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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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5
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Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood–brain barrier disruption: where are we now, and where we are going. J Neurooncol 2020; 147:261-278. [DOI: 10.1007/s11060-020-03435-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/13/2020] [Indexed: 12/14/2022]
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6
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Gupta PK, Dharanivasan G, Misra R, Gupta S, Verma RS. Nanomedicine in Cancer Stem Cell Therapy. Nanobiomedicine (Rij) 2020. [DOI: 10.1007/978-981-32-9898-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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7
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Askoxylakis V, Arvanitis CD, Wong CSF, Ferraro GB, Jain RK. Emerging strategies for delivering antiangiogenic therapies to primary and metastatic brain tumors. Adv Drug Deliv Rev 2017. [PMID: 28648712 DOI: 10.1016/j.addr.2017.06.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Five-year survival rates have not increased appreciably for patients with primary and metastatic brain tumors. Nearly 17,000 patients die from primary brain tumors, whereas approximately 200,000 cases are diagnosed with brain metastasis every year in the US alone. At the same time, with improved control of systemic disease, the incidence of brain metastasis is increasing. Thus, novel approaches for improving the treatment outcome for these uniformly fatal diseases are needed urgently. In the review, we summarize the challenges in the treatment of these diseases using antiangiogenic therapies alone or in combination with radio-, chemo- and immuno-therapies. We also discuss the emerging strategies to improve the treatment outcome using both pharmacological approaches to normalize the tumor microenvironment and physical approaches (e.g., focused ultrasound) to modulate the blood-tumor-barrier, along with limitations of each approach. Finally, we offer some new avenues of future research.
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Affiliation(s)
- Vasileios Askoxylakis
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), Boston, MA, 02114, USA
| | - Costas D Arvanitis
- School of Mechanical Engineering, Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Christina S F Wong
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), Boston, MA, 02114, USA
| | - Gino B Ferraro
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), Boston, MA, 02114, USA
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), Boston, MA, 02114, USA.
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8
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Müller-Greven G, Carlin CR, Burgett ME, Ahluwalia MS, Lauko A, Nowacki AS, Herting CJ, Qadan MA, Bredel M, Toms SA, Lathia JD, Hambardzumyan D, Sarkaria JN, Hamerlik P, Gladson CL. Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival. Clin Cancer Res 2017; 23:7059-7071. [PMID: 28912141 DOI: 10.1158/1078-0432.ccr-17-0249] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 08/07/2017] [Accepted: 09/07/2017] [Indexed: 12/26/2022]
Abstract
Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors.Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro Bevacizumab internalization, trafficking, and effects on cell survival were analyzed using multilabel confocal microscopy, immunoblotting, and cytotoxicity assays in the presence/absence of inhibitors.Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+ tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival.Conclusions: We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A. Clin Cancer Res; 23(22); 7059-71. ©2017 AACR.
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Affiliation(s)
- Gaëlle Müller-Greven
- Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.,School of Biomedical Sciences, Kent State University, Kent, Ohio
| | - Cathleen R Carlin
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio
| | - Monica E Burgett
- Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.,School of Biomedical Sciences, Kent State University, Kent, Ohio
| | - Manmeet S Ahluwalia
- Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Adam Lauko
- Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio
| | - Amy S Nowacki
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - Cameron J Herting
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - Maha A Qadan
- Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.,School of Biomedical Sciences, Kent State University, Kent, Ohio
| | - Markus Bredel
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Steven A Toms
- Department of Neurosurgery, Geisinger Medical Center, Geisinger, Pennsylvania
| | - Justin D Lathia
- Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Cell and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | | | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Petra Hamerlik
- Brain Tumor Biology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Candece L Gladson
- Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio. .,Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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9
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Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, Shamaileh HA, Yin W, Zhou SF, Zhao X, Duan W. Cancer stem cell targeted therapy: progress amid controversies. Oncotarget 2016; 6:44191-206. [PMID: 26496035 PMCID: PMC4792551 DOI: 10.18632/oncotarget.6176] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/06/2015] [Indexed: 12/12/2022] Open
Abstract
Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.
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Affiliation(s)
- Tao Wang
- School of Nursing, Zhengzhou University, Zhengzhou, China.,School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Sarah Shigdar
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Michael P Gantier
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
| | - Yingchun Hou
- Co-Innovation Center for Qinba Region's Sustainable Development, Shaanxi Normal University, Xi'an, China
| | - Li Wang
- Department of Gynecologic Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Li
- Cancer Care Centre, St George Hospital and St George Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Hadi Al Shamaileh
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Wang Yin
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Xinhan Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
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10
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López-Gómez M, Casado E, Muñoz M, Alcalá S, Moreno-Rubio J, D'Errico G, Jiménez-Gordo AM, Salinas S, Sainz B. Current evidence for cancer stem cells in gastrointestinal tumors and future research perspectives. Crit Rev Oncol Hematol 2016; 107:54-71. [PMID: 27823652 DOI: 10.1016/j.critrevonc.2016.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 06/22/2016] [Accepted: 08/17/2016] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) are a very heterogeneous subpopulation of "stem-like" cancer cells that have been identified in many cancers, including leukemias and solid tumors. It is believed that CSCs drive tumor growth, malignant behavior and are responsible for the initiation of metastatic spread. In addition, CSCs have been implicated in chemotherapy and radiotherapy resistance. Current evidence supports the theory that CSCs share at least two main features of normal stem cells: self-renewal and differentiation, properties that contribute to tumor survival even in the presence of aggressive chemotherapy; however, the mechanism(s) governing the unique biology of CSCs remain unclear. In the field of gastrointestinal cancer, where we face very low survival rates across different tumor types, unraveling the role of CSCs in gastrointestinal tumors should improve our knowledge of cancer biology and chemoresistance, ultimately benefiting patient survival. Towards this end, much effort is being invested in the characterization of CSCs as a means of overcoming drug resistance and controlling metastatic spread. In this review we will cover the concept of CSCs, the current evidence for CSCs in gastrointestinal tumors and future research directions.
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Affiliation(s)
- Miriam López-Gómez
- Medical Oncology Department, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain; Precision Oncology Laboratory, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain.
| | - Enrique Casado
- Medical Oncology Department, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain; Precision Oncology Laboratory, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain
| | - Marta Muñoz
- Pathological Anatomy Department, Infanta Sofía University Hospital, S.S Reyes, Madrid, Spain
| | - Sonia Alcalá
- Department of Biochemistry, Autónoma University of Madrid, Madrid, Spain; Cancer Biology Department, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain; Enfermedades Crónicas y Cáncer Area, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Juan Moreno-Rubio
- Precision Oncology Laboratory, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain
| | - Gabriele D'Errico
- Department of Biochemistry, Autónoma University of Madrid, Madrid, Spain
| | - Ana María Jiménez-Gordo
- Medical Oncology Department, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain; Precision Oncology Laboratory, Infanta Sofía University Hospital, S.S. Reyes, Madrid, Spain
| | - Silvia Salinas
- Pathological Anatomy Department, Infanta Sofía University Hospital, S.S Reyes, Madrid, Spain
| | - Bruno Sainz
- Department of Biochemistry, Autónoma University of Madrid, Madrid, Spain; Cancer Biology Department, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain; Enfermedades Crónicas y Cáncer Area, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
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11
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Areeb Z, Stylli SS, Ware TMB, Harris NC, Shukla L, Shayan R, Paradiso L, Li B, Morokoff AP, Kaye AH, Luwor RB. Inhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib. Med Oncol 2016; 33:53. [DOI: 10.1007/s12032-016-0767-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 04/12/2016] [Indexed: 11/29/2022]
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12
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Hendricks BK, Cohen-Gadol AA, Miller JC. Novel delivery methods bypassing the blood-brain and blood-tumor barriers. Neurosurg Focus 2015; 38:E10. [PMID: 25727219 DOI: 10.3171/2015.1.focus14767] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.
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Affiliation(s)
- Benjamin K Hendricks
- Goodman Campbell Brain and Spine, Indiana University Department of Neurological Surgery; and
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13
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Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M. Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells 2015; 7:1185-1201. [PMID: 26516409 PMCID: PMC4620424 DOI: 10.4252/wjsc.v7.i9.1185] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 08/02/2015] [Accepted: 09/08/2015] [Indexed: 02/07/2023] Open
Abstract
Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers.
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Allard J, Li K, Lopez XM, Blanchard S, Barbot P, Rorive S, Decaestecker C, Pochet R, Bohl D, Lepore AC, Salmon I, Nicaise C. Immunohistochemical toolkit for tracking and quantifying xenotransplanted human stem cells. Regen Med 2015; 9:437-52. [PMID: 25159062 DOI: 10.2217/rme.14.26] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
AIM Biomarker-based tracking of human stem cells xenotransplanted into animal models is crucial for studying their fate in the field of cell therapy or tumor xenografting. MATERIALS & METHODS Using immunohistochemistry and in situ hybridization, we analyzed the expression of three human-specific biomarkers: Ku80, human mitochondria (hMito) and Alu. RESULTS We showed that Ku80, hMito and Alu biomarkers are broadly expressed in human tissues with no or low cross-reactivity toward rat, mouse or pig tissues. In vitro, we demonstrated that their expression is stable over time and does not change along the differentiation of human-derived induced pluripotent stem cells or human glial-restricted precursors. We tracked in vivo these cell populations after transplantation in rodent spinal cords using aforementioned biomarkers and human-specific antibodies detecting apoptotic, proliferating or neural-committed cells. CONCLUSION This study assesses the human-species specificity of Ku80, hMito and Alu, and proposes useful biomarkers for characterizing human stem cells in xenotransplantation paradigms.
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Affiliation(s)
- Justine Allard
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
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A murine model of targeted infusion for intracranial tumors. J Neurooncol 2015; 126:37-45. [PMID: 26376657 DOI: 10.1007/s11060-015-1942-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 09/12/2015] [Indexed: 10/23/2022]
Abstract
Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.
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Luwor RB, Stylli SS, Kaye AH. Using bioluminescence imaging in glioma research. J Clin Neurosci 2015; 22:779-84. [DOI: 10.1016/j.jocn.2014.11.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 11/03/2014] [Indexed: 01/02/2023]
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Malhi S, Gu X. Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach. Expert Opin Drug Deliv 2015; 12:1177-201. [PMID: 25601619 DOI: 10.1517/17425247.2015.998648] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies. AREAS COVERED This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics. EXPERT OPINION The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.
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Affiliation(s)
- Sarandeep Malhi
- University of Manitoba, College of Pharmacy, Faculty of Health Sciences , 750 McDermot Avenue Winnipeg, MB R3E 0H5 , Canada
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The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res 2014; 38:389-401. [DOI: 10.1007/s12272-014-0531-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/08/2014] [Indexed: 12/19/2022]
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19
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Apoptotic death of cancer stem cells for cancer therapy. Int J Mol Sci 2014; 15:8335-51. [PMID: 24823879 PMCID: PMC4057734 DOI: 10.3390/ijms15058335] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/18/2014] [Accepted: 04/18/2014] [Indexed: 01/08/2023] Open
Abstract
Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides.
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Santillan A, Rubin DG, Foley CP, Sondhi D, Crystal RG, Gobin YP, Ballon DJ. Cannulation of the internal carotid artery in mice: a novel technique for intra-arterial delivery of therapeutics. J Neurosci Methods 2013; 222:106-10. [PMID: 24269174 DOI: 10.1016/j.jneumeth.2013.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 08/17/2013] [Accepted: 11/12/2013] [Indexed: 11/19/2022]
Abstract
We have developed a novel minimally invasive technique for the intra-arterial delivery of therapeutics to the mouse brain. CD-1 mice were anesthetized and placed in a lateral decubitus position. A 10mm midline longitudinal incision was made over the thyroid bone. The omohyoid and sternomastoid muscles were retracted to expose the common carotid artery and external carotid artery (ECA). To maximize delivery of administered agents, the superior thyroid artery was ligated or coagulated, and the occipital artery and the pterygopalatine artery (PPA) were temporarily occluded with 6-0 prolene suture. The ECA was carefully dissected and a permanent ligature was placed on its distal segment while a temporary 6-0 prolene ligature was placed on the proximal segment in order to obtain a flow-free segment of vessel. A sterilized 169 μm outer diameter polyimide microcatheter was introduced into the ECA and advanced in retrograde fashion toward the carotid bifurcation. The catheter was then secured and manually rotated so that the microcatheter tip was oriented cephalad in the internal carotid artery (ICA). We were able to achieve reproducible results for selective ipsilateral hemispheric carotid injections of mannitol mediated therapeutics and/or gadolinium-based MRI contrast agent. Survival rates were dependent on the administered agent and ranged from 78 to 90%. This technique allows for reproducible delivery of agents to the ipsilateral cerebral hemisphere by utilizing anterograde catheter placement and temporary ligation of the PPA. This method is cost-effective and associated with a low rate of morbimortality.
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Affiliation(s)
- Alejandro Santillan
- Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, United States; Citigroup Biomedical Imaging Core Facility (CBIC), Weill Medical College of Cornell University, New York, NY, United States.
| | - David G Rubin
- Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, United States; Citigroup Biomedical Imaging Core Facility (CBIC), Weill Medical College of Cornell University, New York, NY, United States.
| | - Conor P Foley
- Citigroup Biomedical Imaging Core Facility (CBIC), Weill Medical College of Cornell University, New York, NY, United States; Department of Radiology, Weill Medical College of Cornell University, New York, NY, United States.
| | - Dolan Sondhi
- Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, United States.
| | - Ronald G Crystal
- Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, United States.
| | - Y Pierre Gobin
- Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, United States; Citigroup Biomedical Imaging Core Facility (CBIC), Weill Medical College of Cornell University, New York, NY, United States.
| | - Douglas J Ballon
- Citigroup Biomedical Imaging Core Facility (CBIC), Weill Medical College of Cornell University, New York, NY, United States; Department of Radiology, Weill Medical College of Cornell University, New York, NY, United States.
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Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013; 34:732-40. [PMID: 23685952 PMCID: PMC3674516 DOI: 10.1038/aps.2013.27] [Citation(s) in RCA: 440] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 03/06/2013] [Indexed: 02/07/2023]
Abstract
Cancer stem cells (CSCs) have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the "Achilles' heel" of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC-targeted therapeutic strategies aiming to eradicate malignancies.
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Affiliation(s)
- Ke Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
| | - Ying-hui Huang
- China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Ji-long Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
- College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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