|
1
|
Alqarni A, Jasim SA, Altalbawy FMA, Kaur H, Kaur I, Rodriguez-Benites C, Deorari M, Alwaily ER, Al-Ani AM, Redhee AH. Challenges and opportunities for cancer stem cell-targeted immunotherapies include immune checkpoint inhibitor, cancer stem cell-dendritic cell vaccine, chimeric antigen receptor immune cells, and modified exosomes. J Biochem Mol Toxicol 2024; 38:e23719. [PMID: 38764138 DOI: 10.1002/jbt.23719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 04/15/2024] [Accepted: 05/06/2024] [Indexed: 05/21/2024]
Abstract
Cancer stem cells (CSCs) are associated with the tumor microenvironment (TME). CSCs induce tumorigenesis, tumor recurrence and progression, and resistance to standard therapies. Indeed, CSCs pose an increasing challenge to current cancer therapy due to their stemness or self-renewal properties. The molecular and cellular interactions between heterogeneous CSCs and surrounding TME components and tumor-supporting immune cells show synergistic effects toward treatment failure. In the immunosuppressive TME, CSCs express various immunoregulatory proteins, growth factors, metabolites and cytokines, and also produce exosomes, a type of extracellular vesicles, to protect themselves from host immune surveillance. Among these, the identification and application of CSC-derived exosomes could be considered for the development of therapeutic approaches to eliminate CSCs or cancer, in addition to targeting the modulators that remodel the composition of the TME, as reviewed in this study. Here, we introduce the role of CSCs and how their interaction with TME complicates immunotherapies, and then present the CSC-based immunotherapy and the limitation of these therapies. We describe the biology and role of tumor/CSC-derived exosomes that induce immune suppression in the TME, and finally, introduce their potentials for the development of CSC-based targeted immunotherapy in the future.
Collapse
Affiliation(s)
- Abdullah Alqarni
- Department of Diagnostics Dental Sciences and Oral Biology, College of Dentistry, King Khalid University, Abha, Saudi Arabia
| | | | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Harpreet Kaur
- School of Basic and Applied Sciences, Shobhit University, Gangoh, India
- Department of Health and Allied Sciences, Arka Jain University, Jamshedpur, India
| | - Irwanjot Kaur
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, India
| | - Carlos Rodriguez-Benites
- Departamento Académico de Física, Facultad de Ciencias Físicas y Matemáticas, Universidad Nacional de Trujillo, Trujillo, Perú
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi Qar, Iraq
| | - Ahmed M Al-Ani
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
| | - Ahmed H Redhee
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| |
Collapse
|
|
2
|
Jalil AT, Abdulhadi MA, Al Jawadri AMH, Talib HA, Al-Azzawi AKJ, Zabibah RS, Ali A. Cancer Stem Cells in Colorectal Cancer: Implications for Targeted Immunotherapies. J Gastrointest Cancer 2023; 54:1046-1057. [PMID: 37247115 DOI: 10.1007/s12029-023-00945-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2023] [Indexed: 05/30/2023]
Abstract
PURPOSE Colorectal cancers are composed of heterogeneous cell populations in the concepts of genetic and functional degrees that among them cancer stem cells are identified with their self-renewal and stemness capability mediating primary tumorigenesis, metastasize, therapeutic resistance, and tumor recurrence. Therefore, understanding the key mechanisms of stemness in colorectal cancer stem cells (CRCSCs) provides opportunities to discover new treatments or improve existing therapeutic regimens. METHODS We review the biological significance of stemness and the results of potential CRCSC-based targeted immunotherapies. Then, we pointed out the barriers to targeting CRCSCs in vivo and highlight new strategies based on synthetic and biogenic nanocarriers for the development of future anti-CRCSC trials. RESULTS The CSCs' surface markers, antigens, neoantigens, and signaling pathways supportive CRCSCs or immune cells that are interacted with CRCSCs could be targeted by immune monotherapy or in formulation with developed nanocarriers to overcome the resistant mechanisms in immune evader CRCSCs. CONCLUSION Identification molecular and cellular cues supporting stemness in CRCSCs and their targeting by nanoimmunotherpy can improve the efficacy of existed therapies or explore novel therapeutic options in future.
Collapse
Affiliation(s)
- Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | | | | | - Hayder Abdullah Talib
- College of Agriculture, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ahmed Ali
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| |
Collapse
|
|
3
|
TRUONG NC, HUYNH NT, PHAM KD, PHAM PV. Roles of cancer stem cells in cancer immune surveillance. MINERVA BIOTECHNOLOGY AND BIOMOLECULAR RESEARCH 2023. [DOI: 10.23736/s2724-542x.23.02944-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
|
|
4
|
Wu B, Shi X, Jiang M, Liu H. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment. Mol Cancer 2023; 22:38. [PMID: 36810098 PMCID: PMC9942413 DOI: 10.1186/s12943-023-01748-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.
Collapse
Affiliation(s)
- Bo Wu
- grid.459742.90000 0004 1798 5889Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Xiang Shi
- grid.459742.90000 0004 1798 5889Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Meixi Jiang
- grid.412644.10000 0004 5909 0696Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032 China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
| |
Collapse
|
|
5
|
Dianat-Moghadam H, Sharifi M, Salehi R, Keshavarz M, Shahgolzari M, Amoozgar Z. Engaging stemness improves cancer immunotherapy. Cancer Lett 2023; 554:216007. [PMID: 36396102 DOI: 10.1016/j.canlet.2022.216007] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022]
Abstract
Intra-tumoral immune cells promote the stemness of cancer stem cells (CSCs) in the tumor microenvironment (TME). CSCs promote tumor progression, relapse, and resistance to immunotherapy. Cancer stemness induces the expression of neoantigens and neo-properties in CSCs, creating an opportunity for targeted immunotherapies. Isolation of stem-like T cells or retaining stemness in T clonotypes strategies produces exhaustion-resistance T cells with superior re-expansion capacity and long-lasting responses after adoptive cell therapies. Stem cells-derived NK cells may be the next generation of NK cell products for immunotherapy. Here, we have reviewed mechanisms by which stemness factors modulated the immunoediting of the TME and summarized the potentials of CSCs in the development of immunotherapy regimens, including CAR-T cells, CAR-NK cells, cancer vaccines, and monoclonal antibodies. We have discussed the natural or genetically engineered stem-like T cells and stem cell-derived NK cells with increased cytotoxicity to tumor cells. Finally, we have provided a perspective on approaches that may improve the therapeutic efficacy of these novel adoptive cell-based products in targeting immunosuppressive TME.
Collapse
Affiliation(s)
- Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mehdi Shahgolzari
- Dental Implants Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Zohreh Amoozgar
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
6
|
Dianat-Moghadam H, Mahari A, Salahlou R, Khalili M, Azizi M, Sadeghzadeh H. Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy. Stem Cell Res Ther 2022; 13:150. [PMID: 35395787 PMCID: PMC8994338 DOI: 10.1186/s13287-022-02829-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.
Collapse
Affiliation(s)
- Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amir Mahari
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Reza Salahlou
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehdi Azizi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hadi Sadeghzadeh
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
7
|
Du XZ, Wen B, Liu L, Wei YT, Zhao K. Role of immune escape in different digestive tumours. World J Clin Cases 2021; 9:10438-10450. [PMID: 35004976 PMCID: PMC8686128 DOI: 10.12998/wjcc.v9.i34.10438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/15/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
A counterbalance between immune cells and tumour cells is key to fighting tumours, and immune escape is an important mechanism for the survival of tumour cells in the body. Tumor cells and their cytokines impair the activity of T cells, NK cells, macrophages and other immune cells through various ways, and change the expression of their own surface antigens so as to avoid the clearance of the immune system. Changes in major histocompatibility complex molecules, high expression of programmed death-ligand 1, and the presence of immunosuppressive cells in the tumor microenvironment (TME) are main means by which tumors impair the function of immune cells. During the development of tumours of the digestive system, different mechanisms acting on tumour cells, the TME, and immune cells lead to immune escape and promote tumour progression. In this paper, the mechanisms of immune escape in tumour cells of the digestive system are reviewed to provide a theoretical basis for the immunotherapy of gastrointestinal tumours.
Collapse
Affiliation(s)
- Xin-Zhu Du
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Bin Wen
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Lin Liu
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Ying-Ting Wei
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Kui Zhao
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| |
Collapse
|
|
8
|
Tsuchiya H, Shiota G. Immune evasion by cancer stem cells. Regen Ther 2021; 17:20-33. [PMID: 33778133 PMCID: PMC7966825 DOI: 10.1016/j.reth.2021.02.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/10/2021] [Accepted: 02/21/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies.
Collapse
Key Words
- ADCC, antibody-dependent cell mediated cytotoxicity
- ALDH, alcohol dehydrogenase
- AML, acute myeloid leukemia
- ARID3B, AT-rich interaction domain-containing protein 3B
- CCR7, C–C motif chemokine receptor 7
- CIK, cytokine-induced killer cell
- CMV, cytomegalovirus
- CSC, cancer stem cell
- CTL, cytotoxic T lymphocytes
- CTLA-4, cytotoxic T-cell-associated antigen-4
- Cancer stem cells
- DC, dendritic cell
- DNMT, DNA methyltransferase
- EMT, epithelial–mesenchymal transition
- ETO, fat mass and obesity associated protein
- EV, extracellular vesicle
- HNSCC, head and neck squamous cell carcinoma
- Immune checkpoints
- Immune evasion
- KDM4, lysine-specific demethylase 4C
- KIR, killer immunoglobulin-like receptor
- LAG3, lymphocyte activation gene 3
- LILR, leukocyte immunoglobulin-like receptor
- LMP, low molecular weight protein
- LOX, lysyl oxidase
- MDSC, myeloid-derived suppressor cell
- MHC, major histocompatibility complex
- MIC, MHC class I polypeptide-related sequence
- NGF, nerve growth factor
- NK cells
- NK, natural killer
- NOD, nonobese diabetic
- NSG, NOD/SCID IL-2 receptor gamma chain null
- OCT4, octamer-binding transcription factor 4
- PD-1, programmed death receptor-1
- PD-L1/2, ligands 1/2
- PI9, protease inhibitor 9
- PSME3, proteasome activator subunit 3
- SCID, severe combined immunodeficient
- SOX2, sex determining region Y-box 2
- T cells
- TAM, tumor-associated macrophage
- TAP, transporter associated with antigen processing
- TCR, T cell receptor
- Treg, regulatory T cell
- ULBP, UL16 binding protein
- uPAR, urokinase-type plasminogen activator receptor
Collapse
Affiliation(s)
- Hiroyuki Tsuchiya
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Goshi Shiota
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| |
Collapse
|
|
9
|
Batzorig U, Wei PL, Wang W, Huang CY, Chang YJ. Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer. Int J Med Sci 2021; 18:2251-2261. [PMID: 33967600 PMCID: PMC8100635 DOI: 10.7150/ijms.56024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/15/2021] [Indexed: 12/02/2022] Open
Abstract
Colorectal cancer (CRC) is a worldwide health problem. Glucose-regulated protein 94 (GRP94) is known as an important endoplasmic reticulum-stress response protein that shows correlation with aggressive cancer behavior. However, the role of GRP94 in CRC is still unclear. Our results showed that silencing GRP94 (GRP94-KD) reduced cell proliferation, invasion and migration of CRC cells and suppressed tumorigenesis in the xenograft mouse model. Rescue assay showed that ETV1 overexpression reversed the effect of GRP94 on cell proliferation and migration. In the molecular mechanism, we found that knockdown of GRP94 inhibited the level of MAPK pathway, including ERK/p-ERK, JNK/p-JNK, and p38/p-p38 signals. Cyclooxygenase-2 and epithelial-mesenchymal transformation biomarkers, such as N-cadherin, vimentin, and β-catenin were suppressed in GRP94 knockdown cells. Treatment of specific inhibitors of MAPK pathway showed that ERK/p-ERK, and p38/p-p38 inhibitors significantly influenced ETV1 expression as compared to JNK/p-JNK inhibitor. Our results indicated that silencing GRP94 repressed the ability of EMT process, cancer cell proliferation, metastasis, and CRC tumorigenesis. Therefore, GRP94 may play an important role in CRC by regulating ETV1 and MAPK pathway.
Collapse
Affiliation(s)
- Uyanga Batzorig
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Po-Li Wei
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.,Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan
| | - Weu Wang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Chien-Yu Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.,Division of Colorectal Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University.,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Jia Chang
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| |
Collapse
|
|
10
|
Becer E, Kabadayı H, Başer KHC, Vatansever HS. Boswellia sacraessential oil manages colon cancer stem cells proliferation and apoptosis: a new perspective for cure. JOURNAL OF ESSENTIAL OIL RESEARCH 2020. [DOI: 10.1080/10412905.2020.1839586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Eda Becer
- Department of Biochemistry, Faculty of Pharmacy, Near East University , Nicosia, Mersin 10, Turkey
- DESAM Institute, Near East University , Nicosia, Mersin 10, Turkey
| | - Hilal Kabadayı
- Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University , Manisa, Turkey
| | - K. Hüsnü Can Başer
- DESAM Institute, Near East University , Nicosia, Mersin 10, Turkey
- Department of Pharmacognosy, Faculty of Pharmacy, Near East University , Nicosia, Mersin 10, Turkey
| | - Hafize Seda Vatansever
- DESAM Institute, Near East University , Nicosia, Mersin 10, Turkey
- Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University , Manisa, Turkey
| |
Collapse
|
|
11
|
Ben Yahia H, Boujelbene N, Babay W, Ben Safta I, Dhouioui S, Zemni I, Ali Ayadi M, Charfi L, Ouzari HI, Rebmann V, Rizzo R, Mrad K, Driss M, Zidi I. Expression analysis of immune-regulatory molecules HLA-G, HLA-E and IDO in endometrial cancer. Hum Immunol 2020; 81:305-313. [PMID: 32273131 DOI: 10.1016/j.humimm.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 03/01/2020] [Accepted: 03/26/2020] [Indexed: 11/17/2022]
Abstract
HLA-G has been widely implicated in advanced cancers through different pathways of immunosuppression allowing tumor escape. Contrarily, HLA-E has a controversial role in the tumor escape from the immune system. IDO catabolic enzyme is known to be up-regulated in many tumors types allowing their immune escape. Based on these considerations, we investigated the expression of HLA-G, HLA-E and IDO molecules in endometrial cancer (EC) and their association with prognostic clinicopathologic parameters. Their expression were checked in tumoral and adjacent endometrial tissues. Both HLA-G and IDO immunostaining were significantly increased in EC tissues compared to normal residual endometrial glands (Mann Whitney U-test, p = 0.0001 and p = 0,020 respectively). However, HLA-E was highly expressed in tumoral tissues as well as in normal residual endometrial glands (respectively, 100% and 81.8%). Increased HLA-G expression levels were observed in high histological grade (grade 3), and in the non-endometrioid type 2 EC. Unexpectedly, patients with IDO Low expression had significantly impaired overall survival compared to patients with IDO High (log-rank p = 0.021). Conversely, HLA-E low expression was associated to an improved overall survival EC (log-rank p = 0.004). We concluded that, HLA-G and IDO are highly expressed in EC compared to adjacent normal endometrial tissues, that might be interesting for the EC outcome.
Collapse
Affiliation(s)
- Hamza Ben Yahia
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nadia Boujelbene
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Wafa Babay
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Ben Safta
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Sabrine Dhouioui
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Zemni
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Mohamed Ali Ayadi
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Lamia Charfi
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Hadda Imene Ouzari
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstr. 179, 45147 Essen, Germany
| | - Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - Karima Mrad
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Maha Driss
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Inès Zidi
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia.
| |
Collapse
|
|
12
|
Ge Z, Wu S, Zhang Z, Ding S. Mechanism of tumor cells escaping from immune surveillance of NK cells. Immunopharmacol Immunotoxicol 2020; 42:187-198. [PMID: 32223464 DOI: 10.1080/08923973.2020.1742733] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Natural killer (NK) cells play an important role in anti-tumor and anti-infection, and perform their immune surveillance function in various ways. However, no matter what kind of cancer, the functional activity of NK cells in the tumor microenvironment (TME) is suppressed. Understanding the relationship between tumor cells and NK cells is very critical for tumor immunotherapy. This review discusses the mechanism of tumor cells escaping the immune surveillance of NK cells. These include a variety of factors that inhibit the activity of NK cells, an imbalance of activating receptors and inhibiting receptors on NK cells, abnormal binding of receptors and ligands, cross-talk of surrounding cell groups and NK cells in the TME, and other factors that affect NK cell activity. An understanding of these factors is necessary to provide new treatment strategies for tumor immunotherapy.
Collapse
Affiliation(s)
- Zhe Ge
- School of Physical Education & Health Care, East China Normal University, Shanghai, China.,Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| | - Shan Wu
- School of Physical Education & Health Care, East China Normal University, Shanghai, China.,Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| | - Zhe Zhang
- School of Physical Education & Health Care, East China Normal University, Shanghai, China.,Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| | - Shuzhe Ding
- School of Physical Education & Health Care, East China Normal University, Shanghai, China.,Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| |
Collapse
|
|
13
|
Özgül Özdemir RB, Özdemir AT, Kırmaz C, Tuğlu Mİ, Şenol Ö, Özverel CS, Berdeli A. The effects of mesenchymal stem cells on the IDO, HLA-G and PD-L1 expression of breast tumor cells MDA-MB-231 and MCF-7. ARCHIVES OF CLINICAL AND EXPERIMENTAL MEDICINE 2019. [DOI: 10.25000/acem.601633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
|
|
14
|
Kanevskiy L, Erokhina S, Kobyzeva P, Streltsova M, Sapozhnikov A, Kovalenko E. Dimorphism of HLA-E and its Disease Association. Int J Mol Sci 2019; 20:ijms20215496. [PMID: 31690066 PMCID: PMC6862560 DOI: 10.3390/ijms20215496] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/25/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER,HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.
Collapse
Affiliation(s)
- Leonid Kanevskiy
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Sofya Erokhina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Polina Kobyzeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Maria Streltsova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Alexander Sapozhnikov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Elena Kovalenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| |
Collapse
|
|
15
|
Ravindranath MH, Filippone EJ, Devarajan A, Asgharzadeh S. Enhancing Natural Killer and CD8 + T Cell-Mediated Anticancer Cytotoxicity and Proliferation of CD8 + T Cells with HLA-E Monospecific Monoclonal Antibodies. Monoclon Antib Immunodiagn Immunother 2019; 38:38-59. [PMID: 31009335 PMCID: PMC6634170 DOI: 10.1089/mab.2018.0043] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 01/13/2019] [Indexed: 12/16/2022] Open
Abstract
Cytotoxic NK/CD8+ T cells interact with MHC-I ligands on tumor cells through either activating or inhibiting receptors. One of the inhibitory receptors is CD94/NKG2A. The NK/CD8+ T cell cytotoxic capability is lost when tumor-associated human leukocyte antigen, HLA-E, binds the CD94/NKG2A receptor, resulting in tumor progression and reduced survival. Failure of cancer patients to respond to natural killer (NK) cell therapies could be due to HLA-E overexpression in tumor tissues. Preventing the inhibitory receptor-ligand interaction by either receptor- or ligand-specific monoclonal antibodies (mAbs) is an innovative passive immunotherapeutic strategy for cancer. Since receptors and ligands can be monomeric or homo- or heterodimeric proteins, the efficacy of mAbs may rely on their ability to distinguish monospecific (private) functional epitopes from nonfunctional common (public) epitopes. We developed monospecific anti-HLA-E mAbs (e.g., TFL-033) that recognize only HLA-E-specific epitopes, but not epitopes shared with other HLA class-I loci as occurs with currently available polyreactive anti-HLA-E mAbs. Interestingly the amino acid sequences in the α1 and α2 helices of HLA-E, critical for the recognition of the mAb TFL-033, are strikingly the same sequences recognized by the CD94/NKG2A inhibitory receptors on NK/CD8+ cells. Such monospecific mAbs can block the CD94/NKG2A interaction with HLA-E to restore NK cell and CD8+ anticancer cell cytotoxicity. Furthermore, the HLA-E monospecific mAbs significantly promoted the proliferation of the CD4-/CD8+ T cells. These monospecific mAbs are also invaluable for the specific demonstration of HLA-E on tumor biopsies, potentially indicating those tumors most likely to respond to such therapy. Thus, they can be used to enhance passive immunotherapy once phased preclinical studies and clinical trials are completed. On principle, we postulate that NK cell passive immunotherapy should capitalize on both of these features of monospecific HLA-E mAbs, that is, the specific determination HLA-E expression on a particular tumor and the enhancement of NK cell/CD8+ cytotoxicity if HLA-E positive.
Collapse
Affiliation(s)
| | - Edward J Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Asokan Devarajan
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Shahab Asgharzadeh
- Department of Pediatrics and Pathology, Children's Hospital, Keck School of Medicine, USC, Los Angeles, California
| |
Collapse
|
|
16
|
Cai Z, Wang L, Han Y, Gao W, Wei X, Gong R, Zhu M, Sun Y, Yu S. Immunoglobulin‑like transcript 4 and human leukocyte antigen‑G interaction promotes the progression of human colorectal cancer. Int J Oncol 2019; 54:1943-1954. [PMID: 30942436 PMCID: PMC6521940 DOI: 10.3892/ijo.2019.4761] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 02/11/2019] [Indexed: 12/14/2022] Open
Abstract
Immunoglobulin‑like transcript (ILT) 4, a negative regulator of immune response in allograft rejection, autoimmunity and infectious diseases, has recently been determined to serve important roles in tumor development. In the present study, the co‑expression of ILT4 and human leukocyte antigen‑G (HLA‑G) in tissues of human primary colorectal cancer (CRC) was revealed, and its association with older age, advanced stage, regional lymph node involvement and poor overall survival time was identified. In CRC cell lines, ILT4 and HLA‑G co‑expression and their autocrine regulation was demonstrated. ILT4 interference affected HLA‑G expression and regulated the cell proliferation, invasion and migration of CRC. HLA‑G fusion protein treatment also increased ILT4 expression in a dose‑dependent manner, thereby activating protein kinase B (AKT) and extracellular signal‑regulated kinase (ERK) signaling, and facilitating the proliferation, migration and invasion of CRC cells. Additionally, the AKT and ERK activation, and CRC cell malignant characteristics induced by HLA‑G may be suppressed by blocking ILT4. The present results indicated that the interaction of ILT4 and its ligand HLA‑G promotes CRC progression through AKT and ERK signal activation, providing a novel strategy of blocking ILT4/HLA‑G for the treatment of CRC.
Collapse
Affiliation(s)
- Zhaoyang Cai
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Lu Wang
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yali Han
- Department of Radiation Oncology, Qilu Hospital of Shan‑dong University, Jinan, Shandong 250012, P.R. China
| | - Wenwen Gao
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Xiaojuan Wei
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Rumei Gong
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Mingliang Zhu
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Shuwen Yu
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| |
Collapse
|
|
17
|
Voutsadakis IA. Expression and function of immune ligand-receptor pairs in NK cells and cancer stem cells: therapeutic implications. Cell Oncol (Dordr) 2018; 41:107-121. [PMID: 29470831 DOI: 10.1007/s13402-018-0373-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The interplay between the immune system and cancer cells has come to the forefront of cancer therapeutics, with novel immune blockade inhibitors being approved for the treatment of an increasing list of cancers. However, the majority of cancer patients still display or develop resistance to these promising drugs. It is possible that cancer stem cells (CSCs) are contributing to this therapeutic resistance. Although CSCs usually represent a small percentage of the total number of cancer cells, they are endowed with the ability of self-renewal and to produce differentiated progeny. Additionally, they have shown the capacity to establish tumors after transplantation to animals, even in small numbers. CSCs have also been found to be resistant to various anti-cancer therapies, including chemotherapy, radiation therapy and, more recently, immunotherapy. This is true despite the sensitivity of CSCs to lysis in vitro by natural killer (NK) cells, the main effector cells of the innate immune system. In this paper the expression of ligands specific for NK cells on CSCs, the intracellular network responsible for the expression of the NK cytotoxicity receptors, and the status of activation of NK cells in the tumor micro-environment are reviewed. The aim of this review is to highlight potential strategies for overcoming CSC immune resistance, thereby enhancing the efficacy of current and future anti-cancer therapies. THERAPEUTIC IMPLICATIONS NK cell activation in the tumor micro-environment through drugs neutralizing inhibitory immune receptors, and combined with other drugs harnessing the potential of the adaptive immune system, could be the most effective approach for attacking both stem cell and non-stem cell cancer populations.
Collapse
Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON, Canada. .,Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada. .,Division of Medical Oncology, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, ON, P6B 0A8, Canada.
| |
Collapse
|
|
18
|
Zhou Y, Xia L, Wang H, Oyang L, Su M, Liu Q, Lin J, Tan S, Tian Y, Liao Q, Cao D. Cancer stem cells in progression of colorectal cancer. Oncotarget 2017; 9:33403-33415. [PMID: 30279970 PMCID: PMC6161799 DOI: 10.18632/oncotarget.23607] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is one of the most common cancers worldwide with high mortality. Distant metastasis and relapse are major causes of patient death. Cancer stem cells (CSCs) play a critical role in the metastasis and relapse of colorectal cancer. CSCs are a subpopulation of cancer cells with unique properties of self-renewal, infinite division and multi-directional differentiation potential. Colorectal CSCs are defined with a group of cell surface markers, such as CD44, CD133, CD24, EpCAM, LGR5 and ALDH. They are highly tumorigenic, chemoresistant and radioresistant and thus are critical in the metastasis and recurrence of colorectal cancer and disease-free survival. This review article updates the colorectal CSCs with a focus on their role in tumor initiation, progression, drug resistance and tumor relapse.
Collapse
Affiliation(s)
- Yujuan Zhou
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Heran Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Min Su
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Qiang Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jingguan Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yutong Tian
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Qianjin Liao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Deliang Cao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.,Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, 62794, USA
| |
Collapse
|
|
19
|
Szaryńska M, Olejniczak A, Kobiela J, Spychalski P, Kmieć Z. Therapeutic strategies against cancer stem cells in human colorectal cancer. Oncol Lett 2017; 14:7653-7668. [PMID: 29250169 PMCID: PMC5727596 DOI: 10.3892/ol.2017.7261] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/01/2017] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types. Conventional therapeutics only act on proliferating and mature cancer cells, while quiescent CSCs survive and often become resistant to chemotherapy. In this review, markers of CRC-CSCs are evaluated and the recently introduced experimental therapies that specifically target these cells by inducing CSC proliferation, differentiation and sensitization to apoptotic signals via molecules including Dickkopf-1, bone morphogenetic protein 4, Kindlin-1, tankyrases, and p21-activated kinase 1, are discussed. In addition, novel strategies aimed at inhibiting some crucial processes engaged in cancer progression regulated by the Wnt, transforming growth factor β and Notch signaling pathways (pyrvinium pamoate, silibinin, PRI-724, P17, and P144 peptides) are also evaluated. Although the metabolic alterations in cancer were first described decades ago, it is only recently that the concept of targeting key regulatory molecules of cell metabolism, such as sirtuin 1 (miR-34a) and AMPK (metformin), has emerged. In conclusion, the discovery of CSCs has resulted in the definition of novel therapeutic targets and the development of novel experimental therapies for CRC. However, further investigations are required in order to apply these novel drugs in human CRC.
Collapse
Affiliation(s)
- Magdalena Szaryńska
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
| | - Agata Olejniczak
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
| | - Jarosław Kobiela
- Department of General, Endocrine and Transplant Surgery, Invasive Medicine Center, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | - Piotr Spychalski
- Department of General, Endocrine and Transplant Surgery, Invasive Medicine Center, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdańsk, 80-210 Gdańsk; Gdańsk, Poland
| |
Collapse
|