1
|
Li X, Chaouhan HS, Yu S, Wang I, Yu T, Chuang Y, Chen K, Lin F, Chen MY, Hsu C, Sun K, Li C. Hypoxia-Induced Metabolic and Functional Changes in Oral CSCs: Implications for Stemness and Viability Modulation Through BNIP3-Driven Mitophagy. J Cell Mol Med 2025; 29:e70400. [PMID: 39945227 PMCID: PMC11822456 DOI: 10.1111/jcmm.70400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 01/07/2025] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
Oral squamous cell carcinomas (OSCCs), like several solid tumours, contain heterogeneous subpopulations of a small subset of cancer cells, termed cancer stem cells (CSCs), that are highly relevant to cancer metastasis and invasive properties. CSCs have also shown a high capacity to survive against various stressful environments, such as hypoxia. However, the molecular underpinnings behind the high potential of CSCs to survive under this stress remain unclear. The current study aimed to investigate the significance of autophagy systems in oral CSC maintenance and survival under stress conditions. Human OSCC cell lines OECM-1 and OECM-1 CSCs were cultured in different hypoxic time periods for proliferation and cytotoxicity analyses. The stemness property of CSCs is evaluated by sphere formation, transwell and wound healing assays protein expression of stemness, and epithelial-to-mesenchymal transition markers. Mitochondrial functions, including mitochondrial ROS generation, mitochondria dynamics, mitophagy, and mitochondrial metabolism (glycolysis and oxidative phosphorylation [OXPHOS]) were examined by western blotting, immunohistochemistry, and XF-seahorse assays, respectively. Under hypoxia, oral CSCs showed a higher proliferation rate with increased invasion/migration/EMT properties than OECM-1 cells. Further, hypoxia-induced BNIP3-driven mitophagy was activated in OECM-1 CSCs than in OECM-1 cells, which also triggered a metabolic shift towards OXPHOS, and BNIP3/-L silencing by siRNA significantly attenuated OECM-1 CSCs stemness features. TCGA data analyses also revealed a higher BNIP3 expression in head and neck squamous carcinoma patients' tumour samples associated with lower patient survival. Collectively, our results revealed a BNIP3/-L-driven autophagy contributes to the OECM-1 CSCs stemness features under hypoxia, suggesting a novel therapeutic strategy involving BNIP3 and autophagy inhibition in oral CSCs.
Collapse
Affiliation(s)
- Xin Li
- Graduate Institute of Biomedical SciencesChina Medical UniversityTaichungTaiwan
| | | | - Shao‐Hua Yu
- Department of Emergency MedicineChina Medical University HospitalTaichungTaiwan
| | - I‐Kuan Wang
- Division of NephrologyChina Medical University HospitalTaichungTaiwan
- Department of Internal Medicine, School of MedicineChina Medical UniversityTaichungTaiwan
| | - Tung‐Min Yu
- Division of Nephrology, Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan
- School of MedicineChina Medical UniversityTaichungTaiwan
| | - Ya‐Wen Chuang
- Division of Nephrology, Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
| | - Kuen‐Bao Chen
- Department of AnesthesiologyChina Medical University HospitalTaichungTaiwan
| | - Feng‐Yen Lin
- Taipei Heart InstituteTaipei Medical UniversityTaipeiTaiwan
- Division of Cardiology and Cardiovascular Research CenterTaipei Medical University HospitalTaipeiTaiwan
- Department of Internal Medicine, College of Medicine, School of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Michael Yuan‐Chien Chen
- School of DentistryChina Medical UniversityTaichungTaiwan
- Department of DentistryChina Medical University HospitalTaichungTaiwan
| | - Che‐Hao Hsu
- Department of AnesthesiologyTungs' Taichung Metroharbor HospitalTaichungTaiwan
| | - Kuo‐Ting Sun
- School of DentistryChina Medical UniversityTaichungTaiwan
- Department of DentistryChina Medical University HospitalTaichungTaiwan
- Department of Pediatric DentistryChina Medical University HospitalTaichungTaiwan
| | - Chi‐Yuan Li
- Graduate Institute of Biomedical SciencesChina Medical UniversityTaichungTaiwan
- Department of AnesthesiologyChina Medical University HospitalTaichungTaiwan
| |
Collapse
|
2
|
Zhu Z, Ding D, Hu H, He T. Pen2/ErbB4 signaling regulates stemness of pancreatic ductal carcinoma. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167316. [PMID: 38901650 DOI: 10.1016/j.bbadis.2024.167316] [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: 04/17/2024] [Revised: 05/29/2024] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
Cancer stem cells (CSCs) are critical for progression, invasion, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC). Presenilin enhancer 2 (Pen2), a vital component of the gamma-secretase complex, is overexpressed in various cancers and plays a significant role in carcinogenesis. Here, we investigated the association between Pen2 expression and the stem-like properties of PDAC cells. We analyzed Pen2 and its downstream target, Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4), using public databases. The expression of Pen2 in CSC populations, marked by CD133+, CD44+, or epithelial cell adhesion molecule (EpCAM)+, was evaluated. Pen2-positive cells were sorted from Pen2-negative ones in PDAC cells transduced with a vector designed to express green fluorescent protein (GFP) under the Pen2 promoter. Stemness was examined in vitro and in vivo in Pen2-positive versus Pen2-negative cells. Our results showed that Pen2 was significantly upregulated, while ErbB4 was significantly downregulated in PDAC tissues compared to adjacent non-tumorous tissues, with an inverse relationship between Pen2 and Erbb4 levels. PDACs with high Pen2 expression are associated with considerably poorer patient survival. The CSC populations identified by CD133+, CD44+, and EpCAM+ markers displayed significantly higher Pen2 and lower EpCAM levels. Compared to Pen2-negative PDAC cells, Pen2-positive cells formed more tumor spheres, were more invasive and migratory, and showed significantly increased resistance to chemotherapy-induced apoptosis. Altering Pen2 levels reversed these oncogenic effects. In vivo, Pen2-positive cells formed larger tumors in immunodeficient mice. Overall, our findings suggest that Pen2 is highly expressed in CSCs within PDAC cells, being a novel therapeutic target.
Collapse
Affiliation(s)
- Zhongfei Zhu
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Dan Ding
- Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Hao Hu
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Tianlin He
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| |
Collapse
|
3
|
Taylor MA, Kandyba E, Halliwill K, Delrosario R, Khoroshkin M, Goodarzi H, Quigley D, Li YR, Wu D, Bollam SR, Mirzoeva OK, Akhurst RJ, Balmain A. Stem-cell states converge in multistage cutaneous squamous cell carcinoma development. Science 2024; 384:eadi7453. [PMID: 38815020 DOI: 10.1126/science.adi7453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 04/05/2024] [Indexed: 06/01/2024]
Abstract
Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.
Collapse
Affiliation(s)
- Mark A Taylor
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Clinical Research Centre, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Eve Kandyba
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Kyle Halliwill
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- AbbVie, South San Francisco, CA 94080, USA
| | - Reyno Delrosario
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Matvei Khoroshkin
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Hani Goodarzi
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94518, USA
- Department of Urology, University of California San Francisco, San Francisco, CA 94518, USA
- Arc Institute, Palo Alto, CA 94304, USA
| | - David Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Urology, University of California San Francisco, San Francisco, CA 94518, USA
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA 94518, USA
| | - Yun Rose Li
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
- Department of Cancer Genetics & Epigenetics, City of Hope National Medical Center, Duarte, CA 91010, USA
- Division of Quantitative Medicine & Systems Biology, Translational Genomics Research Institute, Phoenix, CA 85004, USA
| | - Di Wu
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Saumya R Bollam
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94518, USA
| | - Olga K Mirzoeva
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Rosemary J Akhurst
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94518, USA
| | - Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94518, USA
| |
Collapse
|
4
|
Supruniuk E, Baczewska M, Żebrowska E, Maciejczyk M, Lauko KK, Dajnowicz-Brzezik P, Milewska P, Knapp P, Zalewska A, Chabowski A. Redox Biomarkers and Matrix Remodeling Molecules in Ovarian Cancer. Antioxidants (Basel) 2024; 13:200. [PMID: 38397798 PMCID: PMC10885995 DOI: 10.3390/antiox13020200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Ovarian cancer (OC) has emerged as the leading cause of death due to gynecological malignancies among women. Oxidative stress and metalloproteinases (MMPs) have been shown to influence signaling pathways and afflict the progression of carcinogenesis. Therefore, the assessment of matrix-remodeling and oxidative stress intensity can determine the degree of cellular injury and often the severity of redox-mediated chemoresistance. The study group comprised 27 patients with serous OC of which 18% were classified as Federation of Gynecology and Obstetrics (FIGO) stages I/II, while the rest were diagnosed grades III/IV. The control group comprised of 15 ovarian tissue samples. The results were compared with genetic data from The Cancer Genome Atlas. Nitro-oxidative stress, inflammation and apoptosis biomarkers were measured colorimetrically/fluorometrically or via real-time PCR in the primary ovarian tumor and healthy tissue. Stratification of patients according to FIGO stages revealed that high-grade carcinoma exhibited substantial alterations in redox balance, including the accumulation of protein glycoxidation and lipid peroxidation products. TCGA data demonstrated only limited prognostic usefulness of the studied genes. In conclusion, high-grade serous OC is associated with enhanced tissue oxidative/nitrosative stress and macromolecule damage that could not be overridden by the simultaneously augmented measures of antioxidant defense. Therefore, it can be assumed that tumor cells acquire adaptive mechanisms that enable them to withstand the potential toxic effects of elevated reactive oxygen species.
Collapse
Affiliation(s)
- Elżbieta Supruniuk
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Marta Baczewska
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland; (M.B.); (P.K.)
| | - Ewa Żebrowska
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland;
| | - Kamil Klaudiusz Lauko
- Students’ Scientific Club ‘Biochemistry of Civilization Diseases’ at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland;
| | - Patrycja Dajnowicz-Brzezik
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Patrycja Milewska
- Biobank, Medical University of Bialystok, Waszyngtona 13 Street, 15-269 Bialystok, Poland;
| | - Paweł Knapp
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland; (M.B.); (P.K.)
- University Oncology Center, University Clinical Hospital in Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland
| | - Anna Zalewska
- Independent Laboratory of Experimental Dentistry, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland;
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| |
Collapse
|
5
|
Hasanzadeh A, Ebadati A, Dastanpour L, Aref AR, Sahandi Zangabad P, Kalbasi A, Dai X, Mehta G, Ghasemi A, Fatahi Y, Joshi S, Hamblin MR, Karimi M. Applications of Innovation Technologies for Personalized Cancer Medicine: Stem Cells and Gene-Editing Tools. ACS Pharmacol Transl Sci 2023; 6:1758-1779. [PMID: 38093832 PMCID: PMC10714436 DOI: 10.1021/acsptsci.3c00102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 02/16/2024]
Abstract
Personalized medicine is a new approach toward safer and even cheaper treatments with minimal side effects and toxicity. Planning a therapy based on individual properties causes an effective result in a patient's treatment, especially in a complex disease such as cancer. The benefits of personalized medicine include not only early diagnosis with high accuracy but also a more appropriate and effective therapeutic approach based on the unique clinical, genetic, and epigenetic features and biomarker profiles of a specific patient's disease. In order to achieve personalized cancer therapy, understanding cancer biology plays an important role. One of the crucial applications of personalized medicine that has gained consideration more recently due to its capability in developing disease therapy is related to the field of stem cells. We review various applications of pluripotent, somatic, and cancer stem cells in personalized medicine, including targeted cancer therapy, cancer modeling, diagnostics, and drug screening. CRISPR-Cas gene-editing technology is then discussed as a state-of-the-art biotechnological advance with substantial impacts on medical and therapeutic applications. As part of this section, the role of CRISPR-Cas genome editing in recent cancer studies is reviewed as a further example of personalized medicine application.
Collapse
Affiliation(s)
- Akbar Hasanzadeh
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Arefeh Ebadati
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Lida Dastanpour
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Amir R. Aref
- Department
of Medical Oncology and Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States
| | - Parham Sahandi Zangabad
- Monash
Institute of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical
Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
| | - Alireza Kalbasi
- Department
of Medical Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts 02115, United States
| | - Xiaofeng Dai
- School of
Biotechnology, Jiangnan University, Wuxi 214122, China
- National
Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
- Jiangsu Provincial
Research Center for Bioactive Product Processing Technology, Jiangnan University, Wuxi 214122, China
| | - Geeta Mehta
- Department
of Biomedical Engineering, University of
Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Materials Science and Engineering, University
of Michigan, Ann Arbor, Michigan 48109, United States
- Macromolecular
Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel Cancer
Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Precision
Health, University of Michigan, Ann Arbor, Michigan 48105, United States
| | - Amir Ghasemi
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Department
of Materials Science and Engineering, Sharif
University of Technology, Tehran 14588, Iran
| | - Yousef Fatahi
- Nanotechnology
Research Centre, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran 14166, Iran
- Department
of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14166, Iran
- Universal
Scientific Education and Research Network (USERN), Tehran 14166, Iran
| | - Suhasini Joshi
- Chemical
Biology Program, Memorial Sloan Kettering
Cancer Center, New York, New York 10065, United States
| | - Michael R. Hamblin
- Laser Research
Centre, Faculty of Health Science, University
of Johannesburg, Doornfontein 2028, South Africa
- Radiation
Biology Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
| | - Mahdi Karimi
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Oncopathology
Research Center, Iran University of Medical
Sciences, Tehran 14535, Iran
- Research
Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran 14166, Iran
- Applied
Biotechnology Research Centre, Tehran Medical Science, Islamic Azad University, Tehran 14166, Iran
| |
Collapse
|
6
|
Ibarra AMC, Aguiar EMG, Ferreira CBR, Siqueira JM, Corrêa L, Nunes FD, Franco ALDS, Cecatto RB, Hamblin MR, Rodrigues MFSD. Photodynamic therapy in cancer stem cells - state of the art. Lasers Med Sci 2023; 38:251. [PMID: 37919479 DOI: 10.1007/s10103-023-03911-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/14/2023] [Indexed: 11/04/2023]
Abstract
Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies.
Collapse
Affiliation(s)
- Ana Melissa C Ibarra
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Cássia B R Ferreira
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Luciana Corrêa
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | - Fabio D Nunes
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | | | - Rebeca B Cecatto
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Johannesburg, South Africa
| | - Maria Fernanda S D Rodrigues
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil.
| |
Collapse
|
7
|
Wang C, Zhang Y. Current Application of Nanoparticle Drug Delivery Systems to the Treatment of Anaplastic Thyroid Carcinomas. Int J Nanomedicine 2023; 18:6037-6058. [PMID: 37904863 PMCID: PMC10613415 DOI: 10.2147/ijn.s429629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/18/2023] [Indexed: 11/01/2023] Open
Abstract
Anaplastic thyroid carcinomas (ATCs) are a rare subtype of thyroid cancers with a low incidence but extremely high invasiveness and fatality. The treatment of ATCs is very challenging, and currently, a comprehensive individualized therapeutic strategy involving surgery, radiotherapy (RT), chemotherapy, BRAF/MEK inhibitors (BRAFi/MEKi) and immunotherapy is preferred. For ATC patients in stage IVA/IVB, a surgery-based comprehensive strategy may provide survival benefits. Unfortunately, ATC patients in IVC stage barely get benefits from the current treatment. Recently, nanoparticle delivery of siRNAs, targeted drugs, cytotoxic drugs, photosensitizers and other agents is considered as a promising anti-cancer treatment. Nanoparticle drug delivery systems have been mainly explored in the treatment of differentiated thyroid cancer (DTC). With the rapid development of drug delivery techniques and nanomaterials, using hybrid nanoparticles as the drug carrier to deliver siRNAs, targeted drugs, immune drugs, chemotherapy drugs and phototherapy drugs to ATC patients have become a hot research field. This review aims to describe latest findings of nanoparticle drug delivery systems in the treatment of ATCs, thus providing references for the further analyses.
Collapse
Affiliation(s)
- Chonggao Wang
- Department of Thyroid Surgery, Nanjing Hospital of Chinese Medicine, Nanjing, 210001, People’s Republic of China
- School of Medicine, Southeast University, Nanjing, 210001, People’s Republic of China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of China
| |
Collapse
|
8
|
Taylor MA, Kandyba E, Halliwill K, Delrosario R, Koroshkin M, Goodarzi H, Quigley D, Li YR, Wu D, Bollam S, Mirzoeva O, Akhurst RJ, Balmain A. Gene networks reveal stem-cell state convergence during preneoplasia and progression to malignancy in multistage skin carcinogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.08.539863. [PMID: 37215032 PMCID: PMC10197547 DOI: 10.1101/2023.05.08.539863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Adult mammalian stem cells play critical roles in normal tissue homeostasis, as well as in tumor development, by contributing to cell heterogeneity, plasticity, and development of drug resistance. The relationship between different types of normal and cancer stem cells is highly controversial and poorly understood. Here, we carried out gene expression network analysis of normal and tumor samples from genetically heterogeneous mice to create network metagenes for visualization of stem-cell networks, rather than individual stem-cell markers, at the single-cell level during multistage carcinogenesis. We combined this approach with lineage tracing and single-cell RNASeq of stem cells and their progeny, identifying a previously unrecognized hierarchy in which Lgr6+ stem cells from tumors generate progeny that express a range of other stem-cell markers including Sox2, Pitx1, Foxa1, Klf5, and Cd44. Our data identify a convergence of multiple stem-cell and tumor-suppressor pathways in benign tumor cells expressing markers of lineage plasticity and oxidative stress. This same single-cell population expresses network metagenes corresponding to markers of cancer drug resistance in human tumors of the skin, lung and prostate. Treatment of mouse squamous carcinomas in vivo with the chemotherapeutic cis-platin resulted in elevated expression of the genes that mark this cell population. Our data have allowed us to create a simplified model of multistage carcinogenesis that identifies distinct stem-cell states at different stages of tumor progression, thereby identifying networks involved in lineage plasticity, drug resistance, and immune surveillance, providing a rich source of potential targets for cancer therapy.
Collapse
Affiliation(s)
- Mark A. Taylor
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Eve Kandyba
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Kyle Halliwill
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Reyno Delrosario
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Matvei Koroshkin
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Hani Goodarzi
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - David Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Yun Rose Li
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Di Wu
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Saumya Bollam
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Olga Mirzoeva
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Rosemary J. Akhurst
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| |
Collapse
|
9
|
Varsha VK, Savita JK, Girish HC, Shyamala K. Role of hypoxia and epithelial-mesenchymal transition in the formation and maintenance of oral cancer stem cells in oral squamous cell carcinomas and metastatic lymph node: An immunohistochemical analysis. J Oral Maxillofac Pathol 2023; 27:307-314. [PMID: 37854934 PMCID: PMC10581292 DOI: 10.4103/jomfp.jomfp_368_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/14/2022] [Accepted: 12/06/2022] [Indexed: 10/20/2023] Open
Abstract
Background Inspite of having advanced treatment modalities the overall survival rate in oral squamous cell carcinoma (OSCC) remains poor. This is considered to be mainly due to local recurrence and distant metastasis. Various studies have concentrated on the role of oral cancer stem cells (OCSCs) in the progression and metastasis of OSCC. However, the role of tumor microenvironment components has been less delved into. Hence clarity on cell biology and metastatic potential OCSCs is essential for the development of more effective anti-cancer treatment. Aim To establish the role of OCSCs in different grades of OSCC and metastatic lymph nodes through the expression of cluster of differentiation 44 (CD44). To demonstrate and correlate the role of hypoxia and Epithelial mesenchymal transition (EMT) in the various grades and metastatic lymph nodes in the formation and maintenance of OCSCs by employing Hypoxia-inducible factor-1 Alpha (HIF 1α) and Snail respectively. Method and Material A total of 36 cases of OSCC, 12 from each grade and 12 normal oral mucosal tissues were included in the study. Immunohistochemical staining was performed for the demonstration of CD44, HIF1α, and Snail. Statistics Descriptive analysis, Chi-square, and Spearman's rank correlation were used to analyze frequency and proportion, to compare expression and correlate between lesion proper and lymph node in each group respectively. Results Significant expression of CD44, HIF1 α, and Snail among advancing grades of OSCC and their metastatic lymph node were observed. A positive correlation was seen between them. Conclusions The prognosis of OSCC can be improved by better understanding and targeting the molecules involved in the formation and maintenance of OCSCs.
Collapse
Affiliation(s)
- VK Varsha
- Department of Oral and Maxillofacial Pathology, Rajarajeswari Dental College and Hospital, #14, Ramohalli Cross, Mysore Road, Kumbalgodu, Bengaluru, Karnataka, India
| | - JK Savita
- Department of Oral and Maxillofacial Pathology, Rajarajeswari Dental College and Hospital, #14, Ramohalli Cross, Mysore Road, Kumbalgodu, Bengaluru, Karnataka, India
| | - HC Girish
- Department of Oral and Maxillofacial Pathology, Rajarajeswari Dental College and Hospital, #14, Ramohalli Cross, Mysore Road, Kumbalgodu, Bengaluru, Karnataka, India
| | - K Shyamala
- Department of Oral and Maxillofacial Pathology, Rajarajeswari Dental College and Hospital, #14, Ramohalli Cross, Mysore Road, Kumbalgodu, Bengaluru, Karnataka, India
| |
Collapse
|
10
|
Hoque S, Dhar R, Kar R, Mukherjee S, Mukherjee D, Mukerjee N, Nag S, Tomar N, Mallik S. Cancer stem cells (CSCs): key player of radiotherapy resistance and its clinical significance. Biomarkers 2023; 28:139-151. [PMID: 36503350 DOI: 10.1080/1354750x.2022.2157875] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are self-renewing and slow-multiplying micro subpopulations in tumour microenvironments. CSCs contribute to cancer's resistance to radiation (including radiation) and other treatments. CSCs control the heterogeneity of the tumour. It alters the tumour's microenvironment cellular singling and promotes epithelial-to-mesenchymal transition (EMT). Current research decodes the role of extracellular vesicles (EVs) and CSCs interlink in radiation resistance. Exosome is a subpopulation of EVs and originated from plasma membrane. It is secreted by several active cells. It involed in cellular communication and messenger of healthly and multiple pathological complications. Exosomal biological active cargos (DNA, RNA, protein, lipid and glycan), are capable to transform recipient cells' nature. The molecular signatures of CSCs and CSC-derived exosomes are potential source of cancer theranostics development. This review discusse cancer stem cells, radiation-mediated CSCs development, EMT associated with CSCs, the role of exosomes in radioresistance development, the current state of radiation therapy and the use of CSCs and CSCs-derived exosomes biomolecules as a clinical screening biomarker for cancer. This review gives new researchers a reason to keep an eye on the next phase of scientific research into cancer theranostics that will help mankind.
Collapse
Affiliation(s)
- Saminur Hoque
- Department of Radiology, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Rajib Dhar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Rishav Kar
- Department of Medical Biotechnology, Ramakrishna Mission Vivekananda Educational and Research Institute
| | - Sayantanee Mukherjee
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | | | - Nobendu Mukerjee
- Department of Microbiology, West Bengal State University, Kolkata, West Bengal, India.,Department of Health Sciences, Novel Global Community Educational Foundation, Australia
| | - Sagnik Nag
- Department of Biotechnology, School of Biosciences & Technology, Vellore Institute of Technology (VIT), Tamil Nadu, India
| | - Namrata Tomar
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Saurav Mallik
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, MA, USA
| |
Collapse
|
11
|
Koh EY, Kim KS, Park HB, Kim JS, Kim PH. Active Targeting of Versatile Nanocomplex Using the Novel Biomarker of Breast Cancer Stem Cells. Int J Mol Sci 2022; 24:ijms24010685. [PMID: 36614128 PMCID: PMC9821020 DOI: 10.3390/ijms24010685] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Breast cancer in women is one of the most common life-threatening malignancies. Despite of the development for the improved treatment, there are still many limitations to overcome. Among them, cancer stem cells (CSCs) are well known for tumor formation, development, cellular heterogeneity, and cancer recurrence. Therefore, to completely cure breast cancer, treatment of both cancer and CSC is required. To selectively target CSCs, we generated a liposome-based smart nano complex using CEACAM 6 (CD66c) antibody (Ab), a novel cell-surface biomarker of breast-derived CSCs (BCSCs) discovered in our previous research. Selective and increased cellular uptake was observed in BCSCs treated with CD66c Ab-conjugated rhodamine-labeled liposomes (CDRHOL) depending on the expression level of CD66c. CD66c Ab-conjugated doxorubicin (DOX)-loaded liposomes (CDDOXL) selectively showed increased cell killing effects in BCSCs with high CD66c expression levels. In an in vivo animal study, CDRHOL showed enhanced accumulation in xenografted BCSC tumors with low delivery into non-target organs. Moreover, mice treated with CDDOXL have assessed the decreased induction ability of immune response by low expression levels of pro-inflammatory cytokines and reduced liver toxicity by histopathological analysis. Finally, the improved antitumor effect of CDDOXL was evaluated in a metastatic BCSC mouse model via systemic administration. Collectively, our study is the first to demonstrate that a multi-functional nano complex using a novel surface biomarker of BCSC may be a more effective therapeutic agent for the treatment of cancer and CSCs.
Collapse
Affiliation(s)
- Eun-Young Koh
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea
| | - Keun-Sik Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea
| | - Hee-Bin Park
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Pyung-Hwan Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea
- Correspondence: ; Tel.: +82-42-600-8436; Fax: +82-42-600-8408
| |
Collapse
|
12
|
Kim SI, Woo SR, Noh JK, Lee MK, Lee YC, Lee JW, Kong M, Ko SG, Eun YG. Association between cancer stem cell gene expression signatures and prognosis in head and neck squamous cell carcinoma. BMC Cancer 2022; 22:1077. [PMID: 36261806 PMCID: PMC9583594 DOI: 10.1186/s12885-022-10184-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022] Open
Abstract
Background Various cancer stem cell (CSC) biomarkers and the genes encoding them in head and neck squamous cell carcinoma (HNSCC) have been identified and evaluated. However, the validity of these factors in the prognosis of HNSCC has been questioned and remains unclear. In this study, we examined the clinical significance of CSC biomarker genes in HNSCC, using five publicly available HNSCC cohorts. Methods To predict the prognosis of patients with HNSCC, we developed and validated the expression signatures of CSC biomarker genes whose mRNA expression levels correlated with at least one of the four CSC genes (CD44, MET, ALDH1A1, and BMI1). Results Patients in The Cancer Genome Atlas (TCGA) HNSCC cohort were classified into CSC gene expression-associated high-risk (CSC-HR; n = 285) and CSC gene expression-associated low-risk (CSC-LR; n = 281) subgroups. The 5-year overall survival and recurrence-free survival rates were significantly lower in the CSC-HR subgroup than in the CSC-LR subgroup (p = 0.04 and 0.02, respectively). The clinical significance of the CSC gene expression signature was validated using four independent cohorts. Analysis using Cox proportional hazards models showed that the CSC gene expression signature was an independent prognostic factor of non-oropharyngeal HNSCC which mostly indicates HPV (–) status. Furthermore, the CSC gene expression signature was associated with the prognosis of HNSCC patients who received radiotherapy. Conclusion The CSC gene expression signature is associated with the prognosis of HNSCC and may help in personalized treatments for patients with HNSCC, especially in cases with HPV (–) status who were classified in more detail. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10184-4.
Collapse
Affiliation(s)
- Su Il Kim
- Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University Medical Center, #1 Hoegi-dong, Dongdaemun-gu, Seoul, 02447, Korea
| | - Seon Rang Woo
- Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University Medical Center, #1 Hoegi-dong, Dongdaemun-gu, Seoul, 02447, Korea
| | - Joo Kyung Noh
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Korea
| | - Min Kyeong Lee
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Korea
| | - Young Chan Lee
- Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University Medical Center, #1 Hoegi-dong, Dongdaemun-gu, Seoul, 02447, Korea
| | - Jung Woo Lee
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul, Korea
| | - Moonkyoo Kong
- Department of Radiation Oncology, Division of Lung & Head and Neck Oncology, Kyung Hee University Medical Center, Seoul, Korea
| | - Seong-Gyu Ko
- Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Korea
| | - Young-Gyu Eun
- Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University Medical Center, #1 Hoegi-dong, Dongdaemun-gu, Seoul, 02447, Korea. .,Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Korea.
| |
Collapse
|
13
|
Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective. Bull Cancer 2022; 109:960-971. [DOI: 10.1016/j.bulcan.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 11/19/2022]
|
14
|
Huang W, Wen F, Gu P, Liu J, Xia Y, Li Y, Zhou J, Song S, Ruan S, Gu S, Chen X, Shu P. The inhibitory effect and mechanism of Yi-qi-hua-yu-jie-du decoction on the drug resistance of gastric cancer stem cells based on ABC transporters. Chin Med 2022; 17:93. [PMID: 35941687 PMCID: PMC9361523 DOI: 10.1186/s13020-022-00647-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/29/2022] [Indexed: 01/12/2023] Open
Abstract
Background The drug resistance of tumor stem cells is an obstacle in gastric cancer (GC) treatment and the high expression of ABC transporters is a classic reason for drug resistance. This study aimed to construct a reliable GC drug-resistant stem cell model and explore the inhibitory effect and mechanism of Yi-qi-hua-yu-jie-du medicated serum (YQHY) on the drug resistance of GC stem cells based on ABC transporters. Methods The tumor stemness biomarker CD44 was primary identification from WGCNA. The magnetic-activated cell sorting (MACS) method was used to separate CD44( +)BGC823/5-Fu (BGC823/5–Fu-CSCs) cells and the stemness characteristics were verified from multiple dimensions. Then, the drug resistance index and expression of ABC transporter genes MDR1 and MRP1 were detected in CD44(−)/CD44(+) cells. The inhibition and apoptosis rates of the cells administrated with YQHY or/and 5-Fu were calculated to confirm that YQHY can suppress the drug resistance of BGC823/5-Fu-CSCs. Afterwards, the effects of YQHY on the expression of MDR1 and MRP1 and the activation of the PI3K/Akt/Nrf2 pathway were observed. Finally, under the administration of IGF-1 (the activator of PI3K/Akt pathway) and Nrf2 siRNA, the mechanism of YQHY on reversing the drug resistance of BGC823/5–Fu-CSCs through inhibiting the expression of MDR1 and MRP1 via PI3K/Akt/Nrf2 was verified. Results CD44 was a reliable GC stemness biomarker and can be applied to construct the drug-resistant GC stem cell model CD44(+)BGC823/5-Fu. The growth rate, cell proliferation index, soft agar colony formation, expression of stemness specific genes and tumorigenesis ability of CD44(+)BGC823/5-Fu cells were significantly higher than those of CD44(−)BGC823/5-Fu cells. BGC823/5–Fu-CSCs exhibited strong drug resistance to 5-Fu and high expression of ABC transporter genes MDR1 and MRP1 compared to CD44(-) cells. YQHY increased the inhibition and apoptosis rates to efficiently inhibit the drug resistance of BGC823/5–Fu-CSCs. Meanwhile, it suppressed the expression of MDR1 and MRP1 and restrained the activation of PI3K/Akt/Nrf2 signaling pathway. Finally, it was found that IGF-1 partially restored the activation of PI3K/Akt/Nrf2 pathway, alleviated the inhibition of MDR1 and MRP1, blocked the proliferation-inhibitory and apoptosis-promotion effects. YQHY and si-Nrf2 synergistically suppressed the MDR1/MRP1 expression and the drug resistance of BGC823/5–Fu-CSCs. Conclusions CD44 was a reliable GC stemness biomarker, and the high expression of ABC transporter genes MDR1 and MRP1 was an important feature of drug-resistant stem cells. YQHY inhibited the MDR1 and MRP1 expression via PI3K/Akt/Nrf2 pathway, thus reversing the drug resistance of BGC823/5–Fu-CSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00647-y.
Collapse
Affiliation(s)
- Wenjie Huang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Fang Wen
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peixing Gu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiatong Liu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yun Xia
- Department of Respiratory, Wujin Hospital of Traditional Chinese Medicine, Changzhou, China
| | - Ye Li
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiayu Zhou
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Siyuan Song
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuai Ruan
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Suping Gu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoxue Chen
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China.,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Shu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210000, Jiangsu, China. .,First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| |
Collapse
|
15
|
Yang Y, Lu Y, Zhang C, Guo Q, Zhang W, Wang T, Xia Z, Liu J, Cheng X, Xi T, Jiang F, Zheng L. Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis. Cell Mol Life Sci 2022; 79:360. [PMID: 35690642 PMCID: PMC11072418 DOI: 10.1007/s00018-022-04384-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 11/03/2022]
Abstract
Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24- subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.
Collapse
Affiliation(s)
- Yue Yang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Yuanyuan Lu
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Chunhua Zhang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Ting Wang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Zhuolu Xia
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Jing Liu
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Xiangyu Cheng
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Feng Jiang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| |
Collapse
|
16
|
Ruiu R, Di Lorenzo A, Cavallo F, Conti L. Are Cancer Stem Cells a Suitable Target for Breast Cancer Immunotherapy? Front Oncol 2022; 12:877384. [PMID: 35530300 PMCID: PMC9069673 DOI: 10.3389/fonc.2022.877384] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
There is substantial evidence to suggest that complete tumor eradication relies on the effective elimination of cancer stem cells (CSCs). CSCs have been widely described as mediators of resistance to conventional therapies, including chemo- and radiotherapy, as well as of tumor metastasization and relapse in different tumor types, including breast cancer. However, the resistant phenotype of CSCs makes their targeting a tough task, and immunotherapy may therefore be an interesting option. Nevertheless, although immunotherapeutic approaches to cancer treatment have generated great enthusiasm due to recent success in clinics, breast cancer treatment mostly relies on standard approaches. In this context, we review the existing literature on the immunological properties of breast CSC and immunotherapeutic approaches to them. We will thus attempt to clarify whether there is room for the immunotargeting of breast CSCs in the current landscape of breast cancer therapies. Finally, we will provide our opinion on the CSC-targeting immunotherapeutic strategies that could prospectively be attempted.
Collapse
Affiliation(s)
| | | | - Federica Cavallo
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | | |
Collapse
|
17
|
Ye H, Wu K, Liu Y, Zhu Y, Luo H, Zou W. Zinc oxide nanoparticle attenuates chemotherapy resistance by inducing cell stemness progression of colorectal cancer via miR-1321/HIF-2α axis. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2022.103938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
18
|
Banz-Jansen C, Helweg LP, Kaltschmidt B. Endometrial Cancer Stem Cells: Where Do We Stand and Where Should We Go? Int J Mol Sci 2022; 23:ijms23063412. [PMID: 35328833 PMCID: PMC8955970 DOI: 10.3390/ijms23063412] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/08/2022] [Accepted: 03/19/2022] [Indexed: 02/04/2023] Open
Abstract
Endometrial cancer is one of the most common malignant diseases in women worldwide, with an incidence of 5.9%. Thus, it is the most frequent cancer of the female genital tract, with more than 34,000 women dying, in Europe and North America alone. Endometrial Cancer Stem Cells (CSC) might be drivers of carcinogenesis as well as metastatic and recurrent disease. Therefore, targeting CSCs is of high interest to improve prognosis of patients suffering of advanced or recurrent endometrial cancer. This review describes the current evidence of molecular mechanisms in endometrial CSCs with special emphasis on MYC and NF-κB signaling as well as mitochondrial metabolism. Furthermore, the current status of immunotherapy targeting PD-1 and PD-L1 in endometrial cancer cells and CSCs is elucidated. The outlined findings encourage novel therapies that target signaling pathways in endometrial CSCs as well as immunotherapy as a promising therapeutic approach in the treatment of endometrial cancer to impede cancer progression and prevent recurrence.
Collapse
Affiliation(s)
- Constanze Banz-Jansen
- Department of Gynecology and Obstetrics, and Perinatal Center, Protestant Hospital of Bethel Foundation, University Medical School OWL at Bielefeld, Bielefeld University, Campus Bielefeld-Bethel, Burgsteig 13, 33617 Bielefeld, Germany;
- Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany;
| | - Laureen P. Helweg
- Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany;
- Department of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, Germany
- Correspondence:
| | - Barbara Kaltschmidt
- Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany;
- Department of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, Germany
- Molecular Neurobiology, Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany
| |
Collapse
|
19
|
Ibrahim AIM, Batlle E, Sneha S, Jiménez R, Pequerul R, Parés X, Rüngeler T, Jha V, Tuccinardi T, Sadiq M, Frame F, Maitland NJ, Farrés J, Pors K. Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer. J Med Chem 2022; 65:3833-3848. [PMID: 35212533 PMCID: PMC9007462 DOI: 10.1021/acs.jmedchem.1c01367] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
![]()
Aldehyde dehydrogenases (ALDHs) are
overexpressed in various tumor
types including prostate cancer and considered a potential target
for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB)
has been extensively reported as a pan-inhibitor of ALDH isoforms,
and here, we report on the synthesis, ALDH isoform selectivity, and
cellular potencies in prostate cancer cells of 40 DEAB analogues;
three analogues (14, 15, and 16) showed potent inhibitory activity against ALDH1A3, and two analogues
(18 and 19) showed potent inhibitory activity
against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity
(IC50 = 10–200 μM) compared with DEAB (>200
μM) against three different prostate cancer cell lines. Analogues 14 and 18 were more potent than DEAB against
patient-derived primary prostate tumor epithelial cells, as single
agents or in combination treatment with docetaxel. In conclusion,
our study supports the use of DEAB as an ALDH inhibitor but also reveals
closely related analogues with increased selectivity and potency.
Collapse
Affiliation(s)
- Ali I M Ibrahim
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K.,Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
| | - Elisabet Batlle
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K.,Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Smarakan Sneha
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K
| | - Rafael Jiménez
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Raquel Pequerul
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Xavier Parés
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Till Rüngeler
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Vibhu Jha
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Tiziano Tuccinardi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Maria Sadiq
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K.,Cancer Research Unit, Department of Biology, University of York, Heslington, Yorkshire YO10 5DD, U.K
| | - Fiona Frame
- Cancer Research Unit, Department of Biology, University of York, Heslington, Yorkshire YO10 5DD, U.K
| | - Norman J Maitland
- Cancer Research Unit, Department of Biology, University of York, Heslington, Yorkshire YO10 5DD, U.K
| | - Jaume Farrés
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona E-08193, Spain
| | - Klaus Pors
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Yorkshire BD7 1DP, U.K
| |
Collapse
|
20
|
Shi J, Zhao H, Lian H, Ke L, Zhao L, Wang C, Han Q. CD276 (B7H3) improve cancer stem cells formation in cervical carcinoma cell lines. Transl Cancer Res 2022; 10:65-72. [PMID: 35116240 PMCID: PMC8798926 DOI: 10.21037/tcr-19-2910] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 11/20/2020] [Indexed: 12/15/2022]
Abstract
Background Cancer stem cells (CSCs) have been considered as a potential therapeutic target for cervical carcinoma. CD 276 is a well-known immune check point molecular, but its relationship with cervical CSCs was still unclear. Methods HeLa cell lines were obtained as cervical carcinoma in vitro model. HeLa cell Sphere formation culture was performed and CD276, OCT4 and SOX2 expression were determined by RT-qPCR. Transiently transfection and siRNA interference were used to modify CD276 expression. HeLa cell colony has been counted and cell proliferation was assessed by MTT assay. The relationship between CD276 and chemotherapy resistance of HeLa cell were evaluated by cisplatin treatment. Additionally, the mice model of xenograft tumor was established and CD276’s function was evaluated in vivo. Results Here, we demonstrate that the expression of CD276 is positively correlated with the amount of sphere-forming cells in HeLa cell lines. Overexpression of CD276 causes the inhibition of HeLa cells’ sphere formation, colony formation and cell viability. Meanwhile, the downregulation of CD276 leads to the other way. We also demonstrate that CD276 contributes to the chemotherapy resistance in the cell line. Furthermore, we verify the CD276’s function on HeLa xenotransplantation mice model. Conclusions These results suggest that CD276 elevates the self-renewal capacity of HeLa CSCs.
Collapse
Affiliation(s)
- Jianfeng Shi
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Haishan Zhao
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Huan Lian
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Linnan Ke
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Lei Zhao
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Chunren Wang
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Qianqian Han
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| |
Collapse
|
21
|
Kobayashi H, Imanaka S, Shigetomi H. Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis. Oncol Lett 2022; 23:80. [PMID: 35111249 PMCID: PMC8771630 DOI: 10.3892/ol.2022.13200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Recent advances in molecular genetics have expanded our understanding of ovarian cancer. High levels of reactive oxygen species (ROS) and upregulation of antioxidant genes are common characteristic features of human cancers. This review reconsiders novel therapeutic strategies for ovarian cancer by focusing on redox homeostasis. A literature search was performed for preclinical and clinical studies published between January 1998 and October 2021 in the PubMed database using a combination of specific terms. ROS serves a central role in tumor suppression and progression by inducing DNA damage and mutations, genomic instability, and aberrant anti- and pro-tumorigenic signaling. Cancer cells increase their antioxidant capacity to neutralize the extra ROS. Additionally, antioxidants, such as CD44 variant isoform 9 (CD44v9) and nuclear factor erythroid 2-related factor 2 (Nrf2), mediate redox homeostasis in ovarian cancer. Furthermore, studies conducted on different cancer types revealed the dual role of antioxidants in tumor progression and inhibition. However, in animal models, genetic loss of antioxidant capacity in the host cannot block cancer initiation and progression. Host-derived antioxidant systems are essential to suppress carcinogenesis, suggesting that antioxidants serve a pivotal role in suppressing cancer development. By contrast, antioxidant activation in cancer cells confers aggressive phenotypes. Antioxidant inhibitors can promote cancer cell death by enhancing ROS levels. Concurrent inhibition of CD44v9 and Nrf2 may trigger apoptosis induction, potentiate chemosensitivity and enhance antitumor activities through the ROS-activated p38/p21 pathway. Antioxidants may have tumor-promoting and -suppressive functions. Therefore, an improved understanding of the role of antioxidants in redox homeostasis and developing antioxidant-specific inhibitors is necessary for treating ovarian cancer.
Collapse
Affiliation(s)
- Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Aska Ladies Clinic, Nara 634-0001, Japan
| |
Collapse
|
22
|
Touil Y, Latreche-Carton C, Bouazzati HE, Nugues AL, Jouy N, Thuru X, Laine W, Lepretre F, Figeac M, Tardivel M, Kluza J, Idziorek T, Quesnel B. p65/RelA NF-κB fragments generated by RIPK3 activity regulate tumorigenicity, cell metabolism, and stemness characteristics. J Cell Biochem 2021; 123:543-556. [PMID: 34927768 PMCID: PMC9299825 DOI: 10.1002/jcb.30198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/17/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022]
Abstract
Receptor‐interacting protein kinase 3 (RIPK3) can induce necroptosis, apoptosis, or cell proliferation and is silenced in several hematological malignancies. We previously reported that RIPK3 activity independent of its kinase domain induces caspase‐mediated p65/RelA cleavage, resulting in N‐terminal 1‐361 and C‐terminal 362‐549 fragments. We show here that a noncleavable p65/RelA D361E mutant expressed in DA1‐3b leukemia cells decreases mouse survival times and that coexpression of p65/RelA fragments increases the tumorigenicity of B16F1 melanoma cells. This aggressiveness in vivo did not correlate with NF‐κB activity measured in vitro. The fragments and p65/RelA D361E mutant induced different expression profiles in DA1‐3b and B16F1 cells. Stemness markers were affected: p65/RelA D361E increased ALDH activity in DA1‐3b cells, and fragment expression increased melanoma sphere formation in B16/F1 cells. p65/RelA fragments and the D361E noncleavable mutant decreased oxidative or glycolytic cell metabolism, with differences observed between models. Thus, p65/RelA cleavage initiated by kinase‐independent RIPK3 activity in cancer cells is not neutral and induces pleiotropic effects in vitro and in vivo that may vary across tumor types.
Collapse
Affiliation(s)
- Yasmine Touil
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Céline Latreche-Carton
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Hassiba El Bouazzati
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Anne-Lucie Nugues
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Nathalie Jouy
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Xavier Thuru
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - William Laine
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | | | - Martin Figeac
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Meryem Tardivel
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Jérôme Kluza
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Thierry Idziorek
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Bruno Quesnel
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France.,Service des Maladies du Sang, CHU Lille, Lille, France
| |
Collapse
|
23
|
Senobari Z, Karimi G, Jamialahmadi K. Ellagitannins, promising pharmacological agents for the treatment of cancer stem cells. Phytother Res 2021; 36:231-242. [PMID: 34697838 DOI: 10.1002/ptr.7307] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 12/19/2022]
Abstract
Human tumors comprise subpopulations of cells called cancer stem cells (CSCs) that possess stemness properties. CSCs can initiate tumors and cause recurrence, metastasis and are also responsible for chemo- and radio-resistance. CSCs may use signaling pathways similar to normal stem cells, including Notch, JAK/STAT, Wnt and Hedgehog pathways. Ellagitannins (ETs) are a broad group of substances with chemopreventive and anticancer activities. The antitumor activity of ETs and their derivatives are mainly related to their antiinflammatory capacity. They are therefore able to modulate secretory growth factors and pro-inflammatory mediators such as IL-6, TGF-β, TNF-α, IL-1β and IFN-γ. Evidence suggests that ETs display their anticancer effect by targeting CSCs and disrupting stem cell signaling. However, there are still few studies in this field. Therefore, high-quality studies are needed to firmly establish the clinical efficacy of the ETs on CSCs. This paper reviews the structures, sources and pharmacokinetics of ETs. It also focuses on the function of ETs and their effects on CSCs-related cytokines and the relationship between ETs and signaling pathways in CSCs.
Collapse
Affiliation(s)
- Zohre Senobari
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
24
|
Gastric cancer stem cells survive in stress environments via their autophagy system. Sci Rep 2021; 11:20664. [PMID: 34667215 PMCID: PMC8526688 DOI: 10.1038/s41598-021-00155-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs) play an important role in the progression of carcinoma and have a high potential for survival in stress environments. However, the mechanisms of survival potential of CSCs have been unclear. The aim of this study was to clarify the significance of autophagy systems of CSCs under stress environments. Four gastric cancer cell line were used. Side population (SP) cells were sorted from the parent cells, as CSC rich cells. The expression of stem cell markers was examined by RT-PCR. The viability of cancer cells under starvation and hypoxia was evaluated. The expression level of the autophagy molecule LC3B-II was examined by western blot. The numbers of autophagosomes and autolysosomes were counted by electron microscope. SP cells of OCUM-12 showed a higher expression of stem cell markers and higher viability in starvation and hypoxia. Western blot and electron microscope examinations indicated that the autophagy was more induced in SP cells than in parent cells. The autophagy inhibitor significantly decreased the viability under the stress environments. These findings suggested that Cancer stem cells of gastric cancer might maintain their viability via the autophagy system. Autophagy inhibitors might be a promising therapeutic agent for gastric cancer.
Collapse
|
25
|
MYH9 is crucial for stem cell-like properties in non-small cell lung cancer by activating mTOR signaling. Cell Death Discov 2021; 7:282. [PMID: 34635641 PMCID: PMC8505404 DOI: 10.1038/s41420-021-00681-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/09/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
The fatality rate of non-small cell lung cancer (NSCLC) has been high due to the existence of cancer stem cells (CSCs). Non-muscle myosin heavy chain 9 (MYH9) can promote the progression of various tumors, but its effect on the stem cell-like characteristics of lung cancer cells (LCCs) has not been clarified. Our research found that the stemness characteristics of LCCs were significantly enhanced by the overexpression of MYH9, and the knockout of MYH9 had the opposite effects. The in vivo with inhibitor blebbistatin further confirmed the effect of MYH9 on the stem cell-like behavior of LCCs. Furthermore, western blotting showed that the expression level of CSCs markers (CD44, SOX2, Nanog, CD133, and OCT4) was also regulated by MYH9. Mechanistic studies have shown that MYH9 regulates stem cell-like features of LCCs by regulating the mTOR signaling pathway, which was supported by sphere formation experiments after LCCs were treated with inhibitors Rapamycin and CHIR-99021. Importantly, high expression of MYH9 in lung cancer is positively correlated with poor clinical prognosis and is an independent risk factor for patients with NSCLC.
Collapse
|
26
|
Horst EN, Bregenzer ME, Mehta P, Snyder CS, Repetto T, Yang-Hartwich Y, Mehta G. Personalized models of heterogeneous 3D epithelial tumor microenvironments: Ovarian cancer as a model. Acta Biomater 2021; 132:401-420. [PMID: 33940195 PMCID: PMC8969826 DOI: 10.1016/j.actbio.2021.04.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
Intractable human diseases such as cancers, are context dependent, unique to both the individual patient and to the specific tumor microenvironment. However, conventional cancer treatments are often nonspecific, targeting global similarities rather than unique drivers. This limits treatment efficacy across heterogeneous patient populations and even at different tumor locations within the same patient. Ultimately, this poor efficacy can lead to adverse clinical outcomes and the development of treatment-resistant relapse. To prevent this and improve outcomes, it is necessary to be selective when choosing a patient's optimal adjuvant treatment. In this review, we posit the use of personalized, tumor-specific models (TSM) as tools to achieve this remarkable feat. First, using ovarian cancer as a model disease, we outline the heterogeneity and complexity of both the cellular and extracellular components in the tumor microenvironment. Then we examine the advantages and disadvantages of contemporary cancer models and the rationale for personalized TSM. We discuss how to generate precision 3D models through careful and detailed analysis of patient biopsies. Finally, we provide clinically relevant applications of these versatile personalized cancer models to highlight their potential impact. These models are ideal for a myriad of fundamental cancer biology and translational studies. Importantly, these approaches can be extended to other carcinomas, facilitating the discovery of new therapeutics that more effectively target the unique aspects of each individual patient's TME. STATEMENT OF SIGNIFICANCE: In this article, we have presented the case for the application of biomaterials in developing personalized models of complex diseases such as cancers. TSM could bring about breakthroughs in the promise of precision medicine. The critical components of the diverse tumor microenvironments, that lead to treatment failures, include cellular- and extracellular matrix- heterogeneity, and biophysical signals to the cells. Therefore, we have described these dynamic components of the tumor microenvironments, and have highlighted how contemporary biomaterials can be utilized to create personalized in vitro models of cancers. We have also described the application of the TSM to predict the dynamic patterns of disease progression, and predict effective therapies that can produce durable responses, limit relapses, and treat any minimal residual disease.
Collapse
Affiliation(s)
- Eric N Horst
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Michael E Bregenzer
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Pooja Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Catherine S Snyder
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Taylor Repetto
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Yang Yang-Hartwich
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT 06510, United States
| | - Geeta Mehta
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Precision Health, University of Michigan, Ann Arbor, MI 48109, United States.
| |
Collapse
|
27
|
Fukushi D, Shibuya-Takahashi R, Mochizuki M, Fujimori H, Kogure T, Sugai T, Iwai W, Wakui Y, Abue M, Murakami K, Nakamura Y, Yasuda J, Yamaguchi K, Sugamura K, Shibata C, Katayose Y, Satoh K, Tamai K. BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma. Cancer Sci 2021; 112:4580-4592. [PMID: 34424582 PMCID: PMC8586677 DOI: 10.1111/cas.15115] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/12/2021] [Accepted: 08/21/2021] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain‐expressed X‐linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67‐negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.
Collapse
Affiliation(s)
- Daisuke Fukushi
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.,Division of Cancer Stem Cell, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Gastroenterology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Rie Shibuya-Takahashi
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Mai Mochizuki
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Haruna Fujimori
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Takahiro Sugai
- Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan
| | - Wataru Iwai
- Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan
| | - Yuta Wakui
- Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan
| | - Makoto Abue
- Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan
| | - Kazuhiro Murakami
- Division of Pathology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Jun Yasuda
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Kazunori Yamaguchi
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Kazuo Sugamura
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan
| | - Chikashi Shibata
- Gastroenterologic and Hepato-Biliary-Pancreatic Surgery, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Yu Katayose
- Gastroenterologic and Hepato-Biliary-Pancreatic Surgery, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Kennichi Satoh
- Division of Gastroenterology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Keiichi Tamai
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.,Division of Cancer Stem Cell, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
28
|
ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes. Cell Death Dis 2021; 12:742. [PMID: 34315857 PMCID: PMC8316333 DOI: 10.1038/s41419-021-04005-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-fluorouracil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-β. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-β treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-β, with the aim of avoiding resistance development and relapse in breast cancer.
Collapse
|
29
|
She X, Qin S, Jing B, Jin X, Sun X, Lan X, An R. Radiotheranostic Targeting Cancer Stem Cells in Human Colorectal Cancer Xenografts. Mol Imaging Biol 2021; 22:1043-1053. [PMID: 32125599 DOI: 10.1007/s11307-019-01467-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE The aim of this study was to perform radiotheranostics with radioiodinated monoclonal antibodies (mAbs) for targeting cancer stem cells (CSCs) in human colorectal cancer xenografts and evaluate the relative advantage of a cocktail containing both [131I]CD133 mAb and [131I]CD44 mAb. PROCEDURES Tumor-bearing mice were randomly divided into eight groups: [131I]CD133mAb, [131I]CD44 mAb, [131I]IgG isotype control, radioiodinated mAb cocktail, CD133 mAb, CD44 mAb, unradioiodinated mAb cocktail, and saline groups. In vivo single photon emission computed tomography (SPECT) imaging was used to monitor dynamically changes in the CSC population after treatment. The radioactivity uptake of tumors was quantified ex vivo. The expression of CD133 and CD44 after treatment was also assessed by immunohistochemistry and western blot. Tumor growth curves and survival curves were generated to assess treatment efficacy. Cell apoptosis and proliferation in xenografts 30 days after treatment were measured by TdT-mediated dUTP-biotin nick end labeling (aka, TUNEL) and Ki67 staining. The expression levels of biomarkers in xenografts 30 days after treatment were measured by flow cytometry. RESULTS The radioimmunoimaging (RII) with in vivo SPECT showed that the CSC-targeting radioimmunotherapy (RIT) groups ([131I]CD133 mAb, [131I]CD44 mAb, and radioiodinated mAb cocktail groups) had intense accumulations of radiolabeled agents in the tumor areas. The ex vivo biodistribution confirmed these findings. In the CSC-targeting RIT groups, immunohistochemistry and western blot indicated significant reduction of specific target expression in the xenografts. The tumor growth curves and survival curves showed that the CSC-targeting RIT significantly inhibited tumor growth and prolonged mean survival, respectively. Significantly increased apoptosis and decreased proliferation in xenografts further confirmed the therapeutic efficacy of CSC-targeting RIT. Flow cytometry showed that the decreases in CSCs correlated with the presence of the corresponding antibodies. CONCLUSIONS Our results suggest that the CSC-targeting RIT can effectively reduce CSCs which consequently inhibits tumor development. The radioiodinated mAb cocktail may generate enhanced CSC-targeting specificity.
Collapse
Affiliation(s)
- Xianliang She
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Saimei Qin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Boping Jing
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xueyan Jin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xun Sun
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Rui An
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| |
Collapse
|
30
|
Li X, Liu D, Fan K, Qian M. Cisplatin and si-Notch 1-Folic Acid-Conjugated Mesoporous Silica Nanoparticles Prevent Hepatocellular Carcinoma. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2689] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is still a severe disorder with a high mortality and new effective therapies are urgently required. Our study aimed to explore the effect of combined cisplatin with conjugated mesoporous silica nanoparticles (MSN) on HCC. We prepared copolymer PCL-b-PPEEA
and PEG-b-PCL-Pt(IV) to load drugs, while Pt(IV) MNP/siRNA nanoparticles were synthesized. The nanoparticles were characterized by transmission electron microscopy and Western blot analysis. Flow cytometry was determined to detect apoptosis of CD133 + SMMC7721 cells. Then cells were treated
with Pt(IV) MNP/siRNA, MNP/siRNA or PBS, where the Notch1 and related gene expression were determined by RT-qPCR with clone formation detected by agarose assay. The synthesized nanoparticles were about 90 nm and absorbed by cancer cells with a high stability. Compared with the cisplatin, Pt(IV)
MNP/siNotch1 nanoparticles exhibited enhanced cytotoxicity and downregu-lated expression of cisplatin-induced Notch1 and cancer stem cells. Moreover, the MNP/siNotch1 nanoparticles significantly suppressed the proliferation and clonal formation of CD133 + SMMC7721 cells. Co-delivery of cisplatin,
si-Notch1 and folic acid conjugated MSN can inhibit the development of HCC, indicating that it might be a novel treatment approach for HCC in the future.
Collapse
Affiliation(s)
- Xiaoping Li
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, 310015, China
| | - Donghong Liu
- Department of Laboratory Medicine, Hangyan Hospital of Wenzhou Medical University, Taizhou First People’s Hospital, Taizhou, Zhejiang, 318020, China
| | - Kai Fan
- College of Automation, Hangzhou Dianzi University, Hangzhou, Zhejiang, 310018, China
| | - Miaomiao Qian
- Affiliated Hospital, Hangzhou Dianzi University, Hangzhou, Zhejiang, 310018, China
| |
Collapse
|
31
|
Ishii H, Afify SM, Hassan G, Salomon DS, Seno M. Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy. Cancers (Basel) 2021; 13:cancers13102491. [PMID: 34065315 PMCID: PMC8160785 DOI: 10.3390/cancers13102491] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cancer immunotherapy is gaining attention as a potential fourth treatment following surgery, chemotherapy, and radiation therapy. Cancer stem cells have recently been recognized and validated as a key target for cancer treatment. Cripto-1, which is a GPI-anchored membrane-bound protein that functions as a co-receptor of Nodal, is a marker of cancer stem cells. Since Nodal is a member of the TGF-β family, which performs an important role in stem cells and cancer stem cells, the inhibition of Cripto-1 could be a strategy by which to block Nodal signaling and thereby suppress cancer stem cells. We propose that Cripto-1 may be a novel target for cancer immunotherapy. Abstract The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, and CTLA4, is an effective treatment method. However, no immunotherapeutic target has been found that retains validity in the face of tumor diversity. The transforming growth factor (TGF)-β cytokine family possesses broad biological activity and is involved in the induction and/or transdifferentiation of helper T cells, which are important in immunotherapy. Nodal is a member of the TGF-β family playing important roles in tissue stem cells and cancer stem cells (CSCs), interacting with the co-receptor Cripto-1, as well as with Activin type IB (Alk4) and Activin typeIIreceptors, and maintaining stemness and Notch and Wnt/β-catenin signaling in CSCs. In recent years, it has been reported that Cripto-1 could be a potential therapeutic target in CSCs. Here, we review the accumulated literature on the molecular mechanisms by which Cripto-1 functions in CSCs and discuss the potential of Cripto-1 as an immunotherapeutic target in CSCs.
Collapse
Affiliation(s)
- Hiroko Ishii
- GSP Enterprise, Inc., 1-4-38 12F Minato-machi, Naniwa-ku, Osaka 556-0017, Japan;
| | - Said M. Afify
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (S.M.A.); (G.H.)
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin ElKoum Menoufia 32511, Egypt
| | - Ghmkin Hassan
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (S.M.A.); (G.H.)
| | - David S. Salomon
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
| | - Masaharu Seno
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (S.M.A.); (G.H.)
- Correspondence: ; Tel.: +81-86-251-8216
| |
Collapse
|
32
|
Ge MH, Zhu XH, Shao YM, Wang C, Huang P, Wang Y, Jiang Y, Maimaitiyiming Y, Chen E, Yang C, Naranmandura H. Synthesis and characterization of CD133 targeted aptamer-drug conjugates for precision therapy of anaplastic thyroid cancer. Biomater Sci 2021; 9:1313-1324. [PMID: 33350399 DOI: 10.1039/d0bm01832e] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anaplastic thyroid cancer (ATC) is an undifferentiated and highly aggressive type of thyroid cancer and is extremely resistant to standard therapies such as surgical resection and radioactive iodine therapy. Although targeted therapeutic agents including small molecule drugs and monoclonal antibodies are rapidly developed in recent years, no ATC targeted drugs are available to date; thereby, novel targeted therapies are needed to improve the outcomes of ATC patients. Aptamers are single-stranded DNA (or RNA) molecules that can selectively bind to cancer specific antigens, and aptamer-based targeted therapy has certain advantages over that based on antibodies due to its high binding affinity and low immunogenicity. Here, we identified that CD133, a cancer stem cell marker, was specifically expressed in ATC tumor tissues and cells, implying that CD133 is a potential drug target for ATC therapy. Additionally, we successfully obtained a CD133 targeted aptamer AP-1 by paired cell-based SELEX, which can precisely recognize CD133 antigen in vitro. Furthermore, the truncated AP-1-M aptamer from its precursor AP-1 has shown higher binding affinity for CD133, and specifically accumulated in anaplastic thyroid cancer FRO cell derived tumor in vivo. Conjugation of truncated AP-1-M with doxorubicin could dramatically inhibit CD133 positive FRO cell proliferation, induce cell apoptosis in vitro, and also suppress tumor growth in FRO cell xenograft mice in vivo. Our results clearly demonstrated that the CD133 targeted aptamer AP-1-M conjugated with anticancer drugs has potential to become a promising therapeutic approach against ATC in the near future.
Collapse
Affiliation(s)
- Ming Hua Ge
- Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Xu Hang Zhu
- Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Yi Ming Shao
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Chao Wang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Ping Huang
- Department of Pharmacy, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Yun Wang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Yu Jiang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Yasen Maimaitiyiming
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China. and Department of Public Health, and Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - En Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chang Yang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China. and Department of Public Health, and Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Hua Naranmandura
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China. and Department of Public Health, and Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China and Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
| |
Collapse
|
33
|
Nawara HM, Afify SM, Hassan G, Zahra MH, Seno A, Seno M. Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy. Biomedicines 2021; 9:biomedicines9050500. [PMID: 34063205 PMCID: PMC8147479 DOI: 10.3390/biomedicines9050500] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/25/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Paclitaxel (PTX) is a chemotherapeutical agent commonly used to treat several kinds of cancer. PTX is known as a microtubule-targeting agent with a primary molecular mechanism that disrupts the dynamics of microtubules and induces mitotic arrest and cell death. Simultaneously, other mechanisms have been evaluated in many studies. Since the anticancer activity of PTX was discovered, it has been used to treat many cancer patients and has become one of the most extensively used anticancer drugs. Regrettably, the resistance of cancer to PTX is considered an extensive obstacle in clinical applications and is one of the major causes of death correlated with treatment failure. Therefore, the combination of PTX with other drugs could lead to efficient therapeutic strategies. Here, we summarize the mechanisms of PTX, and the current studies focusing on PTX and review promising combinations.
Collapse
Affiliation(s)
- Hend M. Nawara
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Said M. Afify
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Menoufia 32511, Egypt
| | - Ghmkin Hassan
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus 10769, Syria
| | - Maram H. Zahra
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Akimasa Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Masaharu Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Correspondence: ; Tel.: +81-86-251-8216
| |
Collapse
|
34
|
Dong Y, Wan Z, Gao X, Yang G, Liu L. Reprogramming Immune Cells for Enhanced Cancer Immunotherapy: Targets and Strategies. Front Immunol 2021; 12:609762. [PMID: 33968014 PMCID: PMC8097044 DOI: 10.3389/fimmu.2021.609762] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the leading causes of death and a major public health problem all over the world. Immunotherapy is becoming a revolutionary clinical management for various cancer types. Restoration of aberrant immune surveillance on cancers has achieved markable progress in the past years by either in vivo or ex vivo engineering of the immune cells. Here, we summarized the central roles of immune cells in tumor progression and regression, and the existing and emerging strategies for different immune cell-based immunotherapies. In addition, the current challenges and the potential solutions in translating the immunotherapies into the clinic are also discussed.
Collapse
Affiliation(s)
- Yan Dong
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhuo Wan
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaotong Gao
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Guodong Yang
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Li Liu
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
35
|
Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
Collapse
Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | | |
Collapse
|
36
|
Lv J, Liu Y, Cheng F, Li J, Zhou Y, Zhang T, Zhou N, Li C, Wang Z, Ma L, Liu M, Zhu Q, Liu X, Tang K, Ma J, Zhang H, Xie J, Fang Y, Zhang H, Wang N, Liu Y, Huang B. Cell softness regulates tumorigenicity and stemness of cancer cells. EMBO J 2021; 40:e106123. [PMID: 33274785 PMCID: PMC7809788 DOI: 10.15252/embj.2020106123] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/07/2020] [Accepted: 10/23/2020] [Indexed: 12/26/2022] Open
Abstract
Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+ , ALDH+ , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
Collapse
Affiliation(s)
- Jiadi Lv
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Yaoping Liu
- Institute of MicroelectronicsPeking UniversityBeijingChina
| | - Feiran Cheng
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Jiping Li
- Beijing Smartchip Microelectronics Technology Company LimitedBeijingChina
| | - Yabo Zhou
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Tianzhen Zhang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Nannan Zhou
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Cong Li
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Zhenfeng Wang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Longfei Ma
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Mengyu Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Qiang Zhu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Xiaohan Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Ke Tang
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Jingwei Ma
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Huafeng Zhang
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Jing Xie
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Yi Fang
- National Cancer Center/Cancer HospitalCAMSBeijingChina
| | - Haizeng Zhang
- National Cancer Center/Cancer HospitalCAMSBeijingChina
| | - Ning Wang
- Deaprtment of Mechanical Science and TechnologyThe Grainger College of EngineeringUniversity of Illinois at Urbana‐ChampaignUrbanaILUSA
| | - Yuying Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
- Clinical Immunology CenterCAMSBeijingChina
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
- Clinical Immunology CenterCAMSBeijingChina
| |
Collapse
|
37
|
Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein. Biochem Biophys Res Commun 2021; 537:132-139. [PMID: 33412384 DOI: 10.1016/j.bbrc.2020.11.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 11/06/2020] [Indexed: 01/06/2023]
Abstract
Cancer stem cells (CSCs) are believed to cause cancer metastasis and recurrence. BEX2 (brain expressed X-linked gene 2) is a CSC-related gene that is expressed in dormant CSCs in cholangiocarcinoma and induces resistance against chemotherapy. The aim of the present study was to identify small compounds that have activity to inhibit BEX2 expression and result in the attenuation of CSC-related phenotypes. We screened 9600 small chemical compounds in high-throughput screening using cholangiocarcinoma cell line HuCCT1 expressing BEX2 protein fused with NanoLuc, and identified a compound, BMPP (1, 3-Benzenediol, [4-(4-methoxyphenyl)-1H-pyrazol-3-yl]). BMPP was found to exert decreasing effects on BEX2 protein expression and G0 phase population of the tumor cells, and increasing effects on ATP levels and chemotherapeutic sensitivity of the cells. These findings indicate that BMPP is a valuable chemical compound for reducing dormant CSC-related phenotypes. Thus, the identification of BMPP as a potential CSC suppressor provides scope for the development of novel therapeutic modalities for the treatment of cancers with BEX2 overexpressing CSCs.
Collapse
|
38
|
Chowdhury S, Ghosh S. Cancer Stem Cells. Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
39
|
Tamai K, Nakamura-Shima M, Shibuya-Takahashi R, Kanno SI, Yasui A, Mochizuki M, Iwai W, Wakui Y, Abue M, Yamamoto K, Miura K, Mizuma M, Unno M, Kawamura S, Sato I, Yasuda J, Yamaguchi K, Sugamura K, Satoh K. BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma. Sci Rep 2020; 10:21592. [PMID: 33299012 PMCID: PMC7725823 DOI: 10.1038/s41598-020-78539-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.
Collapse
Affiliation(s)
- Keiichi Tamai
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi, 981-1293, Japan.
| | - Mao Nakamura-Shima
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Rie Shibuya-Takahashi
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi, 981-1293, Japan
| | - Shin-Ichiro Kanno
- IDAC Fellow Research Group for DNA Repair and Dynamic Proteome Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, 980-8575, Japan
| | - Akira Yasui
- IDAC Fellow Research Group for DNA Repair and Dynamic Proteome Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, 980-8575, Japan
| | - Mai Mochizuki
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi, 981-1293, Japan
| | - Wataru Iwai
- Department of Gastroenterology, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Yuta Wakui
- Department of Gastroenterology, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Makoto Abue
- Department of Gastroenterology, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Kuniharu Yamamoto
- Department of Surgery, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan.,Division of Hepatobiliary and Pancreatic Surgery, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino-ku, Sendai, Miyagi, Japan
| | - Koh Miura
- Department of Surgery, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Sadafumi Kawamura
- Department of Urology, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Ikuro Sato
- Department of Pathology, Miyagi Cancer Center, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Jun Yasuda
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Kazunori Yamaguchi
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Kazuo Sugamura
- Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, 47-1, Medeshima-Shiode, Natori, Miyagi, Japan
| | - Kennichi Satoh
- Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi, 981-1293, Japan.,Division of Gastroenterology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino-ku, Sendai, Miyagi, Japan
| |
Collapse
|
40
|
Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target. Biomedicines 2020; 8:biomedicines8120569. [PMID: 33291762 PMCID: PMC7761903 DOI: 10.3390/biomedicines8120569] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/26/2020] [Accepted: 12/01/2020] [Indexed: 12/31/2022] Open
Abstract
Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.
Collapse
|
41
|
Zhang Q, Han Z, Zhu Y, Chen J, Li W. Role of hypoxia inducible factor-1 in cancer stem cells (Review). Mol Med Rep 2020; 23:17. [PMID: 33179080 PMCID: PMC7673349 DOI: 10.3892/mmr.2020.11655] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) have been found to play a decisive role in cancer recurrence, metastasis, and chemo‑, radio‑ and immuno‑resistance. Understanding the mechanism of CSC self‑renewal and proliferation may help overcome the limitations of clinical treatment. The microenvironment of tumor growth consists of a lack of oxygen, and hypoxia has been confirmed to induce cancer cell invasion, metastasis and epithelial‑mesenchymal transition, and is usually associated with poor prognosis and low survival rates. Hypoxia inducible factor‑1 (HIF‑1) can be stably expressed under hypoxia and act as an important molecule to regulate the development of CSCs, but the specific mechanism remains unclear. The present review attempted to explain the role of HIF‑1 in the generation and maintenance of CSCs from the perspective of epigenetics, metabolic reprogramming, tumor immunity, CSC markers, non‑coding RNA and signaling pathways associated with HIF‑1, in order to provide novel targets with HIF‑1 as the core for clinical treatment, and extend the life of patients.
Collapse
Affiliation(s)
- Qi Zhang
- Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Zhenzhen Han
- Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Yanbo Zhu
- Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Jingcheng Chen
- Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Wei Li
- Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| |
Collapse
|
42
|
Spiegel JL, Jakob M, Kruizenga M, Freytag S, Bertlich M, Canis M, Ihler F, Haubner F, Kitz J, Weiss BG. Cancer stem cell markers in adenocarcinoma of the salivary glands - reliable prognostic markers? Eur Arch Otorhinolaryngol 2020; 278:2517-2528. [PMID: 33009929 PMCID: PMC8165058 DOI: 10.1007/s00405-020-06389-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 09/16/2020] [Indexed: 12/21/2022]
Abstract
Purpose Adenocarcinoma of the salivary glands is of low incidence and a broad range of histopathological subtypes. Cancer stem cell markers (CSC) might serve as novel prognostic parameters. To date, only a few studies examined the expression of CSC in adenocarcinoma of the salivary glands with diverging results. To further investigate the reliability in terms of prognostic value, a histopathological analysis of CSCs on a cohort of patients with adenocarcinomas of the major salivary glands was performed. Methods Tumor samples of 40 consecutive patients with adenocarcinoma of the major salivary gland treated with curative intend at one tertiary center were stained with the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2. Expression of these markers was correlated with clinicopathological parameters and survival estimates. Results Correlation of high expression of ALDH1 with higher grading (p < 0.001) and high expression of CD44 with the localization of the neoplasm (p = 0.05), larger tumor size (p = 0.006), positive pN-category (p = 0.023), and advanced UICC stage (p = 0.002) was found. Furthermore, high expression of SOX2 correlated with a negative perineural invasion (p = 0.02). No significant correlation of any investigated marker with survival estimates was observed. Conclusion In conclusion, our study did not find a significant correlation of the investigated CSCs with survival estimates in adenocarcinoma of the major salivary glands. Recapitulating the results of our study in conjunction with data in the literature, the CSCs ALDH1, BMI-1, CD44, Nanog, and SOX2 do not seem to serve as reliable prognostic parameters in the treatment of adenocarcinoma of the salivary glands.
Electronic supplementary material The online version of this article (10.1007/s00405-020-06389-7) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Jennifer L Spiegel
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
| | - Mark Jakob
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany
| | - Marie Kruizenga
- Department of Otorhinolaryngology, Georg August University, University Hospital Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Saskia Freytag
- Molecular Medicine, Harry Perkins Institute of Medical Research, Perth, WA, 6009, Australia
| | - Mattis Bertlich
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany
| | - Martin Canis
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany
| | - Friedrich Ihler
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.,German Centre for Vertigo and Balance 508 Disorders, LMU Klinikum, Marchioninistr. 15, Ludwig-Maximilians-Universität , 81377, Munich, Germany
| | - Frank Haubner
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany
| | - Julia Kitz
- Institute of Pathology, University Hospital Göttingen, Georg August University, Robert-Koch-Str. 40,, 37075, Göttingen, Germany
| | - Bernhard G Weiss
- Department for Otorhinolaryngology, LMU Klinikum, Marchioninistr, Ludwig-Maximilians-Universität München, 81377, Munich, Germany
| |
Collapse
|
43
|
Wnt/β-Catenin Signaling Pathway as Chemotherapeutic Target in Breast Cancer: An Update on Pros and Cons. Clin Breast Cancer 2020; 20:361-370. [DOI: 10.1016/j.clbc.2020.04.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/14/2022]
|
44
|
Doheny D, Sirkisoon S, Carpenter RL, Aguayo NR, Regua AT, Anguelov M, Manore SG, Arrigo A, Jalboush SA, Wong GL, Yu Y, Wagner CJ, Chan M, Ruiz J, Thomas A, Strowd R, Lin J, Lo HW. Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 2020; 39:6589-6605. [PMID: 32929154 PMCID: PMC7572897 DOI: 10.1038/s41388-020-01454-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 08/19/2020] [Accepted: 09/02/2020] [Indexed: 01/01/2023]
Abstract
Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.
Collapse
Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sherona Sirkisoon
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Richard L Carpenter
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-Bloomington, JH 308 1001 E. 3rd St., Bloomington, IN, 47405, USA
| | - Noah Reeve Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Marlyn Anguelov
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara Abu Jalboush
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Yang Yu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Calvin J Wagner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael Chan
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jimmy Ruiz
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Alexandra Thomas
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Roy Strowd
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
| |
Collapse
|
45
|
Doheny D, Manore SG, Wong GL, Lo HW. Hedgehog Signaling and Truncated GLI1 in Cancer. Cells 2020; 9:cells9092114. [PMID: 32957513 PMCID: PMC7565963 DOI: 10.3390/cells9092114] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022] Open
Abstract
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
Collapse
Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Sara G. Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Grace L. Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Correspondence: ; Tel.: +1-336-716-0695
| |
Collapse
|
46
|
Abdou P, Wang Z, Chen Q, Chan A, Zhou DR, Gunadhi V, Gu Z. Advances in engineering local drug delivery systems for cancer immunotherapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1632. [PMID: 32255276 PMCID: PMC7725287 DOI: 10.1002/wnan.1632] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/13/2022]
Abstract
Cancer immunotherapy aims to leverage the immune system to suppress the growth of tumors and to inhibit metastasis. The recent promising clinical outcomes associated with cancer immunotherapy have prompted research and development efforts towards enhancing the efficacy of immune checkpoint blockade, cancer vaccines, cytokine therapy, and adoptive T cell therapy. Advancements in biomaterials, nanomedicine, and micro-/nano-technology have facilitated the development of enhanced local delivery systems for cancer immunotherapy, which can enhance treatment efficacy while minimizing toxicity. Furthermore, locally administered cancer therapies that combine immunotherapy with chemotherapy, radiotherapy, or phototherapy have the potential to achieve synergistic antitumor effects. Herein, the latest studies on local delivery systems for cancer immunotherapy are surveyed, with an emphasis on the therapeutic benefits associated with the design of biomaterials and nanomedicines. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Collapse
Affiliation(s)
- Peter Abdou
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Zejun Wang
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Qian Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren’ai Road, Suzhou, 215123, Jiangsu, PR China
| | - Amanda Chan
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Daojia R. Zhou
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Vivienne Gunadhi
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
| | - Zhen Gu
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| |
Collapse
|
47
|
Dianhydrogalactitol synergizes with topoisomerase poisons to overcome DNA repair activity in tumor cells. Cell Death Dis 2020; 11:577. [PMID: 32709853 PMCID: PMC7381652 DOI: 10.1038/s41419-020-02780-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 12/27/2022]
Abstract
1,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM). In the present study, we investigated the cytotoxic activity of DAG alone or in combination with common chemotherapy agents in GBM and prostate cancer (PCa) cells, and determined the impact of DNA repair pathways on DAG-induced cytotoxicity. We found that DAG produced replication-dependent DNA lesions decorated with RPA32, RAD51, and γH2AX foci. DAG-induced cytotoxicity was unaffected by MLH1, MSH2, and DNA-PK expression, but was enhanced by knockdown of BRCA1. Acting in S phase, DAG displayed selective synergy with topoisomerase I (camptothecin and irinotecan) and topoisomerase II (etoposide) poisons in GBM, PCa, and lung cancer cells with no synergy observed for docetaxel. Importantly, DAG combined with irinotecan treatment enhanced tumor responses and prolonged survival of tumor-bearing mice. This work provides mechanistic insight into DAG cytotoxicity in GBM and PCa cells and offers a rational for exploring combination regimens with topoisomerase I/II poisons in future clinical trials.
Collapse
|
48
|
Tian Y, Tian Y, Tu Y, Zhang G, Zeng X, Lin J, Ai M, Mao Z, Zheng R, Yuan Y. microRNA-124 inhibits stem-like properties and enhances radiosensitivity in nasopharyngeal carcinoma cells via direct repression of expression of JAMA. J Cell Mol Med 2020; 24:9533-9544. [PMID: 32681617 PMCID: PMC7520313 DOI: 10.1111/jcmm.15177] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 01/15/2020] [Accepted: 03/06/2020] [Indexed: 01/30/2023] Open
Abstract
Cancer stem cells (CSCs) are a source of tumour recurrence in patients with nasopharyngeal carcinoma (NPC); however, the function of microRNA‐124 (miR‐124) in NPC CSCs has not been clearly defined. In this study, we investigated the role of miR‐124 in NPC CSCs. qRT‐PCR was performed to measure miR‐124 expression in NPC tissues and cell lines and the effects of miR‐124 on stem‐like properties and radiosensitivity of NPC cells measured. Luciferase reporter assays and rescue experiments were used to investigate the interaction of miR‐124 with the 3′UTR of junctional adhesion molecule A (JAMA). Finally, we examined the effects of miR‐124 in an animal model and clinical samples. Down‐regulation of miR‐124 was detected in cancer tissues and was inversely associated with tumour stage and lymph node metastasis. Overexpression of miR‐124 inhibited stemness properties and enhanced radiosensitivity of NPC cells in vitro and in vivo via targeting JAMA. Up‐regulation of miR‐124 was correlated with superior overall survival of patients with NPC. Our study demonstrates that miR‐124 can inhibit stem‐like properties and enhance radiosensitivity by directly targeting JAMA in NPC. These findings provide novel insights into the molecular mechanisms underlying therapy failure in NPC.
Collapse
Affiliation(s)
- Yunhong Tian
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Yunming Tian
- Department of Radiation Oncology, Hui Zhou Municipal Central Hospital, Huizhou, China
| | - Yinuo Tu
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Guoqian Zhang
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xing Zeng
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jie Lin
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Meiling Ai
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Zixu Mao
- Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Ronghui Zheng
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Yawei Yuan
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
49
|
Sterneck E, Poria DK, Balamurugan K. Slug and E-Cadherin: Stealth Accomplices? Front Mol Biosci 2020; 7:138. [PMID: 32760736 PMCID: PMC7371942 DOI: 10.3389/fmolb.2020.00138] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/08/2020] [Indexed: 12/15/2022] Open
Abstract
During physiological epithelial-mesenchymal transition (EMT), which is important for embryogenesis and wound healing, epithelial cells activate a program to remodel their structure and achieve a mesenchymal fate. In cancer cells, EMT confers increased invasiveness and tumor-initiating capacity, which contribute to metastasis and resistance to therapeutics. However, cellular plasticity that navigates between epithelial and mesenchymal states and maintenance of a hybrid or partial E/M phenotype appears to be even more important for cancer progression. Besides other core EMT transcription factors, the well-characterized Snail-family proteins Snail (SNAI1) and Slug (SNAI2) play important roles in both physiological and pathological EMT. Often mentioned in unison, they do, however, differ in their functions in many scenarios. Indeed, Slug expression does not always correlate with complete EMT or loss of E-cadherin (CDH1). For example, Slug plays important roles in mammary epithelial cell progenitor cell lineage commitment and differentiation, DNA damage responses, hematopoietic stem cell self-renewal, and in pathologies such as pulmonary fibrosis and atherosclerosis. In this Perspective, we highlight Slug functions in mammary epithelial cells and breast cancer as a “non-EMT factor” in basal epithelial cells and stem cells with focus reports that demonstrate co-expression of Slug and E-cadherin. We speculate that Slug and E-cadherin may cooperate in normal mammary gland and breast cancer/stem cells and advocate for functional assessment of such Slug+/E-cadherinlow/+ (SNAI2+/CDH1low/+) “basal-like epithelial” cells. Thus, Slug may be regarded as less of an EMT factor than driver of the basal epithelial cell phenotype.
Collapse
Affiliation(s)
- Esta Sterneck
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Dipak K Poria
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Kuppusamy Balamurugan
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| |
Collapse
|
50
|
Wang F, Zhang Z, Li Q, Yu T, Ma C. Untargeted LC-MS/MS analysis reveals metabolomics feature of osteosarcoma stem cell response to methotrexate. Cancer Cell Int 2020; 20:269. [PMID: 32587477 PMCID: PMC7313215 DOI: 10.1186/s12935-020-01356-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 06/16/2020] [Indexed: 02/08/2023] Open
Abstract
Background Cancer stem cell (CSC) is identified in osteosarcoma (OS) and considered resistant to chemotherapeutic agents. However, the mechanism of osteosarcoma stem cell (OSC) resistant to chemotherapy remains debatable and vague, and the metabolomics feature of OSC is not clarified. Materials and methods OSC was isolated by using sphere forming assay and identified. Untargeted LC-MS/MS analysis was performed to reveal the metabolomics feature of OSC and underlying mechanisms of OSC resistant to methotrexate (MTX). Results OSC was efficiently isolated and identified from human OS 143B and MG63 cell lines with enhanced chemo-resistance to MTX. The untargeted LC-MS analysis revealed that OSC showed differential metabolites and perturbed signaling pathways, mainly involved in metabolisms of fatty acid, amino acid, carbohydrate metabolism and nucleic acid. After treated with MTX, metabolomics feature of OSC was mainly involved metabolisms of amino acid, fatty acid, energy and nucleic acid. Moreover, compared with their parental OS cells response to MTX, the differential metabolites and perturbed signaling pathways were mainly involved in metabolism of amino acid, fatty acid and nucleic acid. What's more, Rap1 signaling pathway and Ras signaling pathway were involved in OS cells and their SCs response to MTX. Conclusion Sphere-forming assay was able to efficiently isolate OSC from human OS cell lines and the untargeted LC-MS/MS analysis was suggested a sufficient methodology to investigate metabolomics features of OS cells and OSCs. Moreover, the metabolomics features of OSCs response to MTX might reveal a further understanding of chemotherapeutic resistance in OS.
Collapse
Affiliation(s)
- Feng Wang
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Zhiyu Zhang
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Qin Li
- Center for Translational Medicine, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Tao Yu
- Center for Translational Medicine, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Chengbin Ma
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| |
Collapse
|