|
1
|
Kevat S, Mistry A, Oza N, Majmudar M, Patel N, Shah R, Ramachandran AV, Chauhan R, Haque S, Parashar NC, Tuli HS, Parashar G. Cancer Stem Cell Regulation as a Target of Therapeutic Intervention: Insights into Breast, Cervical and Lung Cancer. Cell Biochem Biophys 2025; 83:1521-1535. [PMID: 39843681 DOI: 10.1007/s12013-025-01666-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2025] [Indexed: 01/24/2025]
Abstract
Cancer Stem Cells (CSCs) play an important role in the development, resistance, and recurrence of many malignancies. These subpopulations of tumor cells have the potential to self-renew, differentiate, and resist conventional therapy, highlighting their importance in cancer etiology. This review explores the regulatory mechanisms of CSCs in breast, cervical, and lung cancers, highlighting their plasticity, self-renewal, and differentiation capabilities. CD44+/CD24- cells are a known marker for breast CSCs. Markers like as CD133 and ALDH have been discovered in cervical cancer CSCs. Similarly, in lung cancer, CSCs identified by CD44, CD133, and ALDH are linked to aggressive tumor behavior and poor therapy results. The commonalities between these tumors highlight the general necessity of targeting CSCs in treatment efforts. However, the intricacies of CSC activity, such as their interaction with the tumor microenvironment and particular signaling pathways differ between cancer types, demanding specialized methods. Wnt/β-catenin, Notch, and Hedgehog pathways are one of the essential signaling pathways, targeting them, may show ameliorative effects on breast, lung and cervical carcinomas and their respective CSCs. Pre-clinical data suggests targeting specific signaling pathways can eliminate CSCs, but ongoing clinical trials are on utilizing signaling pathway inhibitors in patients. In recent studies it has been reported that CAR T based targeting of specific markers may be used as combination therapy. Ongoing research related to nanobiotechnology can also play a significant role in diagnosis and treatment purpose targeting CSCs, as nanomaterials can be used for precise targeting and identification of CSCs. Further research into the targeting of signaling pathways and its precursors could prove to be right step into directing therapies towards CSCs for cancer therapy.
Collapse
Affiliation(s)
- Sakshi Kevat
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Archie Mistry
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Naman Oza
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Mohit Majmudar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Netra Patel
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Rushabh Shah
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - A V Ramachandran
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Ritu Chauhan
- Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia
- School Of Medicine, Universidad Espiritu Santo, Samborondon, Ecuador
| | | | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to be University), Ambala, Haryana, India
| | - Gaurav Parashar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India.
| |
Collapse
|
|
2
|
Henry M, Ngwegya T, Lekena N, Barth S. In vitro anti-tumour activities of a novel recombinant immunotoxin targeting differentially overexpressed Leucine-rich repeat-containing G-protein-coupled receptor 5 in cervical cancer. Immunopharmacol Immunotoxicol 2025:1-18. [PMID: 40376858 DOI: 10.1080/08923973.2025.2504904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
Cervical cancer is the fourth most common cancer among women worldwide and is associated with infection by high-risk human papillomaviruses (HPV). In 2022, an estimated 660,000 new cases and around 350,000 deaths were recorded. The burden of this disease remains disproportionately high in low- and middle-income countries, highlighting significant disparities in access to national HPV vaccination, screening, treatment, and social and economic determinants. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a receptor that is differentially overexpressed in various cancers, including cervical cancer and is associated with tumour progression, metastasis, and poor prognosis. Targeting LGR5 with a novel recombinant immunotoxin offers a promising therapeutic approach.ObjectiveThe study aims to develop a novel recombinant anti-LGR5 immunotoxin candidate based on a truncated form of Pseudomonas exotoxin A (ETA).MethodsTo develop this LGR5-specific recombinant immunotoxin, a corresponding single chain antibody fragment (αLGR5(scFv)) fused to ETA, was expressed under osmotic stress in the presence of compatible solutes in Escherichia coli BL21 DE3 cells. Expression was monitored by Western blot analysis facilitated by an N-terminal 10x-His tag. Purification was done using immobilized metal affinity chromatography (IMAC) and size exclusion chromatography (SEC). The recombinant immunotoxin (rIT) was assessed for cell surface binding on cervical cancer cell lines using confocal microscopy and flow cytometry. The rIT was then used in an XTT cell viability assay to assess targeted cell killing.Results and discussionUpon confirmation of full-length protein by Western blot, purified protein was used to confirm binding on LGR5-positive cervical cancer cell lines via confocal microscopy and flow cytometry using anti-His PE antibody as a secondary antibody. Selective cell-killing of this novel recombinant immunotoxin was illustrated by the dose-dependent reduction in cell viability at IC50 values in nanomolar concentrations on antigen-positive but not antigen-negative cell lines.ConclusionsIn conclusion, the rIT described is a promising candidate to treat cervical cancer, which however, would finally need to be confirmed by preclinical in vivo studies.
Collapse
Affiliation(s)
- Marc Henry
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Takunda Ngwegya
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Nkhasi Lekena
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Stefan Barth
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| |
Collapse
|
|
3
|
Djamgoz MBA. Stemness of Cancer: A Study of Triple-negative Breast Cancer From a Neuroscience Perspective. Stem Cell Rev Rep 2025; 21:337-350. [PMID: 39531198 PMCID: PMC11872763 DOI: 10.1007/s12015-024-10809-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Stemness, giving cancer cells massive plasticity enabling them to survive in dynamic (e.g. hypoxic) environments and become resistant to treatment, especially chemotherapy, is an important property of aggressive tumours. Here, we review some essentials of cancer stemness focusing on triple-negative breast cancer (TNBC), the most aggressive form of all breast cancers. TNBC cells express a range of genes and mechanisms associated with stemness, including the fundamental four "Yamanaka factors". Most of the evidence concerns the transcription factor / oncogene c-Myc and an interesting case is the expression of the neonatal splice variant of voltage-gated sodium channel subtype Nav1.5. On the whole, measures that reduce the stemness make cancer cells less aggressive, reducing their invasive/metastatic potential and increasing/restoring their chemosensitivity. Such measures include gene silencing techniques, epigenetic therapies as well as novel approaches like optogenetics aiming to modulate the plasma membrane voltage. Indeed, simply hyperpolarizing their membrane potential can make stem cells differentiate. Finally, we give an overview of the clinical aspects and exploitation of cancer/TNBC stemness, including diagnostics and therapeutics. In particular, personalised mRNA-based therapies and mechanistically meaningful combinations are promising and the emerging discipline of 'cancer neuroscience' is providing novel insights to both fundamental issues and clinical applications.
Collapse
Affiliation(s)
- Mustafa B A Djamgoz
- Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
| |
Collapse
|
|
4
|
Limones-Gonzalez JE, Aguilar Esquivel P, Vazquez-Santillan K, Castro-Oropeza R, Lizarraga F, Maldonado V, Melendez-Zajgla J, Piña-Sanchez P, Mendoza-Almanza G. Changes in the molecular nodes of the Notch and NRF2 pathways in cervical cancer tissues from the precursor stages to invasive carcinoma. Oncol Lett 2024; 28:522. [PMID: 39268158 PMCID: PMC11391250 DOI: 10.3892/ol.2024.14655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/24/2024] [Indexed: 09/15/2024] Open
Abstract
Cancer is a multifactorial disease characterized by the loss of control in the expression of genes known as cancer driver genes. Cancer driver genes trigger uncontrolled cell replication, which leads to the development of malignant tumors. A cluster of signal transduction pathways that contain cancer driver genes involved in cellular processes, such as cell proliferation, differentiation, apoptosis and dysregulated organ growth, are associated with cancer initiation and progression. In the present study, three signal transduction pathways involved in cervical cancer (CC) development were analyzed: The Hippo pathway (FAT atypical cadherin, yes-associated protein 1, SMAD4 and TEA domain family member 2), the Notch pathway [cellular-MYC, cAMP response element-binding binding protein (CREBBP), E1A-associated cellular p300 transcriptional co-activator protein and F-Box and WD repeat domain containing 7] and the nuclear factor erythroid 2-related factor 2 (NRF2) pathway [NRF2, kelch-like ECH-associated protein 1 (KEAP1), AKT and PIK3-catalytic subunit α]. Tumor samples from patients diagnosed with various stages of CC, including cervical intraepithelial neoplasia (CIN) 1, CIN 2, CIN 3, in situ CC and invasive CC, were analyzed. The mRNA expression levels were analyzed using reverse transcription-quantitative PCR assays, whereas protein expression levels were assessed through immunohistochemical tissue microarrays. High mRNA expression levels of c-MYC and AKT and low expression levels of NRF2 and KEAP1 were associated with a decreased survival time of patients with CC. Additionally, increased expression levels of c-MYC were detected in the invasive CC stage. At the protein level, increased NRF2 expression levels were observed in all five stages of CC samples compared with those in the cancer-free control samples. AKT1 was found to be dysregulated in the CIN 1 and CIN 2 stages, PI3K in the in situ and invasive stages, and CREBBP in the CIN 3 and in situ stages. In summary, the present study demonstrated significant changes in proteins of the Notch and NRF2 pathways in CC. NRF2 was overexpressed in all cervical cancer stages (cervical intraepithelial neoplasia, in situ CC and invasive CC). The present study makes an important contribution to the possible biomarker proteins to be analyzed for the presence of premalignant and malignant lesions in the cervix.
Collapse
Affiliation(s)
| | - Perla Aguilar Esquivel
- Department of Pathology, Zacatecas General Hospital Luz González Cosío, Zacatecas 98160, Mexico
| | - Karla Vazquez-Santillan
- Innovation in Precision Medicine Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Rosario Castro-Oropeza
- Molecular Oncology Laboratory, Oncology Research Unit, XXI Century National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Floria Lizarraga
- Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Vilma Maldonado
- Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Jorge Melendez-Zajgla
- Functional Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Patricia Piña-Sanchez
- Molecular Oncology Laboratory, Oncology Research Unit, XXI Century National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Gretel Mendoza-Almanza
- Epigenetics Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| |
Collapse
|
|
5
|
Liu W, Wang Y, Xia L, Li J. Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer. Nutrients 2024; 16:797. [PMID: 38542707 PMCID: PMC10975298 DOI: 10.3390/nu16060797] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 01/04/2025] Open
Abstract
As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.
Collapse
Affiliation(s)
| | | | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
| |
Collapse
|
|
6
|
Jafari A, Farahani M, Abdollahpour-Alitappeh M, Manzari-Tavakoli A, Yazdani M, Rezaei-Tavirani M. Unveiling diagnostic and therapeutic strategies for cervical cancer: biomarker discovery through proteomics approaches and exploring the role of cervical cancer stem cells. Front Oncol 2024; 13:1277772. [PMID: 38328436 PMCID: PMC10847843 DOI: 10.3389/fonc.2023.1277772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 12/27/2023] [Indexed: 02/09/2024] Open
Abstract
Cervical cancer (CC) is a major global health problem and leading cause of cancer deaths among women worldwide. Early detection through screening programs has reduced mortality; however, screening compliance remains low. Identifying non-invasive biomarkers through proteomics for diagnosis and monitoring response to treatment could improve patient outcomes. Here we review recent proteomics studies which have uncovered biomarkers and potential drug targets for CC. Additionally, we explore into the role of cervical cancer stem cells and their potential implications in driving CC progression and therapy resistance. Although challenges remain, proteomics has the potential to revolutionize the field of cervical cancer research and improve patient outcomes.
Collapse
Affiliation(s)
- Ameneh Jafari
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Farahani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Asma Manzari-Tavakoli
- Department of Biology, Faculty of Science, Rayan Center for Neuroscience and Behavior, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mohsen Yazdani
- Laboratory of Bioinformatics and Drug Design, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | | |
Collapse
|
|
7
|
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
|
|
8
|
Faghihkhorasani A, Dalvand A, Derafsh E, Tavakoli F, Younis NK, Yasamineh S, Gholizadeh O, Shokri P. The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells. Cancer Cell Int 2023; 23:250. [PMID: 37880659 PMCID: PMC10599042 DOI: 10.1186/s12935-023-03099-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/13/2023] [Indexed: 10/27/2023] Open
Abstract
Cancer Stem Cells (CSCs) are the main "seeds" for the initiation, growth, metastasis, and recurrence of tumors. According to many studies, several viral infections, including the human papillomaviruses, hepatitis B virus, Epstein-Barr virus, and hepatitis C virus, promote the aggressiveness of cancer by encouraging the development of CSC features. Therefore, a better method for the targeted elimination of CSCs and knowledge of their regulatory mechanisms in human carcinogenesis may lead to the development of a future tool for the management and treatment of cancer. Oncolytic viruses (OVs), which include the herpes virus, adenovirus, vaccinia, and reovirus, are also a new class of cancer therapeutics that have favorable properties such as selective replication in tumor cells, delivery of numerous eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumor immunity, as well as a tolerable safety profile that essentially differs from that of other cancer therapeutics. The effects of viral infection on the development of CSCs and the suppression of CSCs by OV therapy were examined in this paper. The purpose of this review is to investigate the dual role of viruses in CSCs (oncolytic virotherapy and viral oncogenes).
Collapse
Affiliation(s)
| | - Alaleh Dalvand
- Tehran Medical Branch, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Ehsan Derafsh
- Department of Basic Medical Science, Windsor University School of Medicine, Brighton's Estate, Cayton, St. Kitts And Nevis
| | - Farnaz Tavakoli
- Nephrology and Transplantation Ward, Shariati Hospital Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | | | - Pooria Shokri
- Department of Medical Science, Faculty of Medical Science, Arak University of Medical Sciences, Arak, Iran.
| |
Collapse
|
|
9
|
Naumova LA, Starodumova VA. Modern concepts in cervical carcinogenesis. BULLETIN OF SIBERIAN MEDICINE 2023; 22:145-155. [DOI: 10.20538/1682-0363-2023-2-145-155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The article discusses modern ideas about cervical carcinogenesis as a multi-stage process of multifactorial genesis. Currently, ideas about the pathogenesis of cervical cancer (CC) are based not only on understanding the role of high-risk oncogenic human papillomavirus (HPV) in this process and accumulation of genetic changes caused by it, but also on formation of a complex HPV interactome, or a network of intermolecular interactions of HPV oncoproteins with host cell proteins. Carcinogenesis also involves a wide range of epigenetic events and, above all, impairment of the regulatory function of miRNAs. An important role in cervical carcinogenesis is attributed to the concept of cancer stem cells (CSCs) formulated in recent years, which is closely related to the explanation of disease recurrence and treatment resistance, as well as to new approaches to treatment. The cervicovaginal microbiome and cervical microenvironment, which are responsible for natural clearance of HPV, regression of epithelial lesions, and modeling of the immune response, are becoming promising objects for research.The aim of the review was to present up-to-date information on the most important mechanisms of cervical carcinogenesis, as well as on new approaches to the treatment of CC, based, in particular, on the use of knowledge about regulatory miRNAs, CSC markers, and the state of the cervicovaginal microbiota.
Collapse
|
|
10
|
Desai N, Hasan U, K J, Mani R, Chauhan M, Basu SM, Giri J. Biomaterial-based platforms for modulating immune components against cancer and cancer stem cells. Acta Biomater 2023; 161:1-36. [PMID: 36907233 DOI: 10.1016/j.actbio.2023.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/02/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023]
Abstract
Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells.
Collapse
Affiliation(s)
- Nimeet Desai
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Uzma Hasan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Jeyashree K
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Rajesh Mani
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Meenakshi Chauhan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Suparna Mercy Basu
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Jyotsnendu Giri
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
| |
Collapse
|
|
11
|
Maldonado-Rodríguez E, Hernández-Barrales M, Reyes-López A, Godina-González S, Gallegos-Flores PI, Esparza-Ibarra EL, González-Curiel IE, Aguayo-Rojas J, López-Saucedo A, Mendoza-Almanza G, Ayala-Luján JL. Presence of Human Papillomavirus DNA in Malignant Neoplasia and Non-Malignant Breast Disease. Curr Issues Mol Biol 2022; 44:3648-3665. [PMID: 36005146 PMCID: PMC9406622 DOI: 10.3390/cimb44080250] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Breast cancer is the leading cause of cancer death among women worldwide. Multiple extrinsic and intrinsic factors are associated with this disease’s development. Various research groups worldwide have reported the presence of human papillomavirus (HPV) DNA in samples of malignant breast tumors. Although its role in mammary carcinogenesis is not fully understood, it is known that the HPV genome, once inserted into host cells, has oncogenic capabilities. The present study aimed to detect the presence of HPV DNA in 116 breast tissue biopsies and classify them according to their histology. It was found that 50.9% of the breast biopsies analyzed were malignant neoplasms, of which 74.6% were histologically classified as infiltrating ductal carcinoma. In biopsies with non-malignant breast disease, fibroadenoma was the most common benign neoplasm (39.1%). Detection of HPV DNA was performed through nested PCR using the external primer MY09/11 and the internal primer GP5+/6+. A hybridization assay genotyped HPV. HPV DNA was identified in 20.3% (12/59) of malignant neoplasms and 35% non-malignant breast disease (16/46). It was also detected in 27.3% (3/11) of breast tissue biopsies without alteration. However, there are no statistically significant differences between these groups and the existence of HPV DNA (p = 0.2521). Its presence was more frequent in non-malignant alterations than in malignant neoplasias. The most frequent genotypes in the HPV-positive samples were low-risk (LR) HPV-42 followed by high-risk (HR) HPV-31.
Collapse
Affiliation(s)
- Erika Maldonado-Rodríguez
- Master in Science and Chemical Technology, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | | | - Adrián Reyes-López
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Susana Godina-González
- Master in Science and Chemical Technology, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Perla I. Gallegos-Flores
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98068, Mexico
| | - Edgar L. Esparza-Ibarra
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98068, Mexico
| | - Irma E. González-Curiel
- Master in Science and Chemical Technology, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Jesús Aguayo-Rojas
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Adrián López-Saucedo
- Health Sciences Area, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
| | - Gretel Mendoza-Almanza
- National Council of Science and Technology, Autonomous University of Zacatecas, Zacatecas 98000, Mexico
- Correspondence: (G.M.-A.); (J.L.A.-L.)
| | - Jorge L. Ayala-Luján
- Master in Science and Chemical Technology, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico
- Correspondence: (G.M.-A.); (J.L.A.-L.)
| |
Collapse
|
|
12
|
Satriyo PB, Suma AAT, Waskitha SSW, Wahyuningsih TD, Sholikhah EN. A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells. Drug Des Devel Ther 2022; 16:2325-2339. [PMID: 35899233 PMCID: PMC9309293 DOI: 10.2147/dddt.s350913] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/20/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Pamungkas Bagus Satriyo
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Artania Adnin Tri Suma
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Stephanus Satria Wira Waskitha
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Tutik Dwi Wahyuningsih
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Eti Nurwening Sholikhah
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| |
Collapse
|
|
13
|
Di Fiore R, Suleiman S, Drago-Ferrante R, Subbannayya Y, Pentimalli F, Giordano A, Calleja-Agius J. Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review. Int J Mol Sci 2022; 23:ijms23095167. [PMID: 35563557 PMCID: PMC9106065 DOI: 10.3390/ijms23095167] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/01/2022] [Accepted: 05/04/2022] [Indexed: 12/24/2022] Open
Abstract
Cervical cancer (CC) is the fourth most common type of gynecological malignancy affecting females worldwide. Most CC cases are linked to infection with high-risk human papillomaviruses (HPV). There has been a significant decrease in the incidence and death rate of CC due to effective cervical Pap smear screening and administration of vaccines. However, this is not equally available throughout different societies. The prognosis of patients with advanced or recurrent CC is particularly poor, with a one-year relative survival rate of a maximum of 20%. Increasing evidence suggests that cancer stem cells (CSCs) may play an important role in CC tumorigenesis, metastasis, relapse, and chemo/radio-resistance, thus representing potential targets for a better therapeutic outcome. CSCs are a small subpopulation of tumor cells with self-renewing ability, which can differentiate into heterogeneous tumor cell types, thus creating a progeny of cells constituting the bulk of tumors. Since cervical CSCs (CCSC) are difficult to identify, this has led to the search for different markers (e.g., ABCG2, ITGA6 (CD49f), PROM1 (CD133), KRT17 (CK17), MSI1, POU5F1 (OCT4), and SOX2). Promising therapeutic strategies targeting CSC-signaling pathways and the CSC niche are currently under development. Here, we provide an overview of CC and CCSCs, describing the phenotypes of CCSCs and the potential of targeting CCSCs in the management of CC.
Collapse
Affiliation(s)
- Riccardo Di Fiore
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
- Correspondence: (R.D.F.); (J.C.-A.)
| | - Sherif Suleiman
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
| | | | - Yashwanth Subbannayya
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway;
| | - Francesca Pentimalli
- Department of Medicine and Surgery, LUM University “Giuseppe DeGennaro”, 70010 Casamassima, Italy;
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
- Correspondence: (R.D.F.); (J.C.-A.)
| |
Collapse
|
|
14
|
In Vitro Antineoplastic and Antiviral Activity and In Vivo Toxicity of Geum urbanum L. Extracts. Molecules 2021; 27:molecules27010245. [PMID: 35011479 PMCID: PMC8747043 DOI: 10.3390/molecules27010245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/26/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
This study evaluated the in vitro antineoplastic and antiviral potential and in vivo toxicity of twelve extracts with different polarity obtained from the herbaceous perennial plant Geum urbanum L. (Rosaceae). In vitro cytotoxicity was determined by ISO 10993-5/2009 on bladder cancer, (T-24 and BC-3C), liver carcinoma (HEP-G2) and normal embryonic kidney (HEK-293) cell lines. The antineoplastic activity was elucidated through assays of cell clonogenicity, apoptosis induction, nuclear factor kappa B p65 (NFκB p65) activation and total glutathione levels. Neutral red uptake study was applied for antiviral activity. The most promising G. urbanum extract was analyzed by UHPLC–HRMS. The acute in vivo toxicity analysis was carried out following OEDC 423. The ethyl acetate extract of aerial parts (EtOAc-AP) exhibited the strongest antineoplastic activity on bladder cancer cell lines (IC50 = 21.33–25.28 µg/mL) by inducing apoptosis and inhibiting NFκB p65 and cell clonogenicity. EtOAc and n-butanol extracts showed moderate antiviral activity against human adenovirus type 5 and human simplex virus type I. Seventy four secondary metabolites (gallic and ellagic acid derivatives, phenolic acids, flavonoids, etc.) were identified in EtOAc-AP by UHPLC–HRMS. This extract induced no signs of acute toxicity in liver and kidney specimens of H-albino mice in doses up to 210 mg/kg. In conclusion, our study contributes substantially to the detailed pharmacological characterization of G. urbanum, thus helping the development of health-promoting phytopreparations.
Collapse
|
|
15
|
Yang H, Hou H, Zhao H, Yu T, Hu Y, Hu Y, Guo J. HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells. Front Oncol 2021; 11:794015. [PMID: 34858863 PMCID: PMC8631922 DOI: 10.3389/fonc.2021.794015] [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: 10/13/2021] [Accepted: 10/25/2021] [Indexed: 01/10/2023] Open
Abstract
The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including SOX2 and OCT4) and drug resistance-related gene MDR1. The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene HK2, providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.
Collapse
Affiliation(s)
- Hao Yang
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Hui Hou
- Department of Pediatric Hematology and Oncology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Haiping Zhao
- Department of Abdominal Tumor Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Tianwei Yu
- Department of Transfusion Medicine, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Yuchong Hu
- Department of Gynaecology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Yue Hu
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Junmei Guo
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| |
Collapse
|
|
16
|
Cervical Carcinoma: Oncobiology and Biomarkers. Int J Mol Sci 2021; 22:ijms222212571. [PMID: 34830452 PMCID: PMC8624663 DOI: 10.3390/ijms222212571] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/01/2021] [Accepted: 11/16/2021] [Indexed: 12/23/2022] Open
Abstract
Cervical cancer is one of the most common types of carcinomas causing morbidity and mortality in women in all countries of the world. At the moment, the oncology, oncobiology, and oncomorphology of cervical cancer are characterized by the accumulation of new information; various molecular biological, genetic, and immunohistochemical methods of investigation of the mechanisms of cervical carcinogenesis are tested and applied; targeted antitumour drugs and diagnostic, prognostic, and predictive biomarkers are being searched for. Many issues of the etiopathogenesis of cervical cancer have not been sufficiently studied, and the role of many biomarkers characterizing various stages of cervical carcinogenesis remains unclear. Therefore, the target of this review is to systematize and understand several problems in the pathogenesis of cervical cancer and to evaluate the significance and role of biomarkers in cervical carcinogenesis.
Collapse
|
|
17
|
HOTAIR Contributes to Stemness Acquisition of Cervical Cancer through Regulating miR-203 Interaction with ZEB1 on Epithelial-Mesenchymal Transition. JOURNAL OF ONCOLOGY 2021; 2021:4190764. [PMID: 34539782 PMCID: PMC8448614 DOI: 10.1155/2021/4190764] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/10/2021] [Indexed: 01/04/2023]
Abstract
Cervical cancer stem cells contribute respond to considerable recurrence and metastasis of patients with cervical cancer. The stemness properties were partly regulated by the interaction of lncRNAs and miRNAs. HOTAIR functions as an oncogenic lncRNA. Previous research studies revealed its role in regulating stemness properties in various cancers. However, the role of HOTAIR in cervical cancer stem cells is still unknown. Here, cisplatin-resistant and serum-free cultured cells exhibited stem cells properties. Cervical cancer stem cells exhibited greater invasion and migration compared with their parental cells, which was similar to cells overexpressing HOTAIR. HOTAIR was significantly overexpressed in cervical cancer stem cells, and knockdown of HOTAIR generated statistical downregulation of stemness markers. Additionally, HOTAIR expression was negatively correlated with the level of miR-203, which was found to be an inhibitory miRNA in regulating the expressions of stemness markers. Also, miR-203 expression was negatively correlated with ZEB1. These findings suggested that HOTAIR should be a positive contributor in stemness acquisition of cervical cancer cells, and this effect should correlate with the interaction with miR-203, which can be suppressed by ZEB1.
Collapse
|
|
18
|
Li L, Xiao Y, Xu Z, Wang S. Zileuton inhibits arachidonate-5-lipoxygenase to exert antitumor effects in preclinical cervical cancer models. Cancer Chemother Pharmacol 2021; 88:953-960. [PMID: 34477945 DOI: 10.1007/s00280-021-04343-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/17/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study evaluated the efficacy of zileuton in cervical cancer, determined the molecular mechanism of action, and assessed ALOX5 expression in cervical cancer patients. METHODS The effects of zileuton were evaluated using cervical cancer cell lines and xenograft mouse models. Loss-of-function analysis of ALOX5 was performed using siRNA. The levels of ALOX5 and 5-HETE were determined using immunohistochemistry and ELISA. RESULTS Zileuton resulted in cell proliferation inhibition and apoptosis induction in a dose-dependent manner, regardless of cellular origin or HPV infection. In two independent cervical cancer xenograft mouse models, zileuton at nontoxic doses significantly prevented tumor formation and decreased tumor growth. Zileuton acts on cervical cancer cells by inhibiting the ALOX5-5-HETE axis. Of note, ALOX5-5-HETE was significantly upregulated in cervical cancer compared with normal tissue. Inhibition of ALOX5 via the siRNA approach mimics the inhibitory effects of zileuton and confirms the roles of ALOX5 in cervical cancer. CONCLUSIONS Our work demonstrates that the ALOX5-5-HETE axis is activated in cervical cancer, with important roles in growth and survival, and this can be therapeutically targeted by zileuton. Our findings also provide preclinical evidence to assess the efficacy of zileuton in cervical cancer in clinical settings.
Collapse
Affiliation(s)
- Liling Li
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Yifang Xiao
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Zhengzheng Xu
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Shaoshuai Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Rd 1095, Qiaokou District, Wuhan, 430030, China.
| |
Collapse
|
|
19
|
The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer. Int J Mol Sci 2021; 22:ijms22168812. [PMID: 34445518 PMCID: PMC8396230 DOI: 10.3390/ijms22168812] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
From all types of cancer, cervical cancer manages to be in top four most frequent types, with a 6.5% rate of occurrence. The infectious vector that induces the disease, the high-risk Human papillomavirus (HPV), which is a sexually transmitted virus, is capable of transforming the host cell by modulating some of the principal signaling pathways responsible for cell cycle arrest, proliferation, and survival. Fortunately, like other cancer types, cervical cancer can be treated by chirurgical interventions or chemoradiotherapy, but these methods are not exactly the lucky clover of modern medicine because of the adverse effects they have. That is the reason why in the last years the emphasis has been on alternative medicine, more specifically on phytochemicals, as a substantial number of studies showed that diet contributes to cancer prevention and treatment. All these studies are trying to find new chemopreventive agents with less toxicity but high effectiveness both in vitro and in vivo. The aim of this review is to evaluate the literature in order to underline the advantages and disadvantages of polyphenols, a class of dietary compounds, as chemopreventive and chemotherapeutic agents. This review also aims to present polyphenols from different perspectives, starting with mechanisms of action and ending with their toxicity. The bigger picture illustrates that polyphenols have great potential in cervical cancer prevention, with strong effects on gene modulation.
Collapse
|
|
20
|
Kaushik V, Kulkarni Y, Felix K, Azad N, Iyer AKV, Yakisich JS. Alternative models of cancer stem cells: The stemness phenotype model, 10 years later. World J Stem Cells 2021; 13:934-943. [PMID: 34367485 PMCID: PMC8316871 DOI: 10.4252/wjsc.v13.i7.934] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/05/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
The classical cancer stem cell (CSCs) theory proposed the existence of a rare but constant subpopulation of CSCs. In this model cancer cells are organized hierarchically and are responsible for tumor resistance and tumor relapse. Thus, eliminating CSCs will eventually lead to cure of cancer. This simplistic model has been challenged by experimental data. In 2010 we proposed a novel and controversial alternative model of CSC biology (the Stemness Phenotype Model, SPM). The SPM proposed a non-hierarchical model of cancer biology in which there is no specific subpopulation of CSCs in tumors. Instead, cancer cells are highly plastic in term of stemness and CSCs and non-CSCs can interconvert into each other depending on the microenvironment. This model predicts the existence of cancer cells ranging from a pure CSC phenotype to pure non-CSC phenotype and that survival of a single cell can originate a new tumor. During the past 10 years, a plethora of experimental evidence in a variety of cancer types has shown that cancer cells are indeed extremely plastic and able to interconvert into cells with different stemness phenotype. In this review we will (1) briefly describe the cumulative evidence from our laboratory and others supporting the SPM; (2) the implications of the SPM in translational oncology; and (3) discuss potential strategies to develop more effective therapeutic regimens for cancer treatment.
Collapse
Affiliation(s)
- Vivek Kaushik
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States
| | - Yogesh Kulkarni
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States
| | - Kumar Felix
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States
| | - Neelam Azad
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States
| | - Anand Krishnan V Iyer
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States
| | - Juan Sebastian Yakisich
- School of Pharmacy, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668, United States.
| |
Collapse
|
|
21
|
Martínez-Rodríguez F, Limones-González JE, Mendoza-Almanza B, Esparza-Ibarra EL, Gallegos-Flores PI, Ayala-Luján JL, Godina-González S, Salinas E, Mendoza-Almanza G. Understanding Cervical Cancer through Proteomics. Cells 2021; 10:1854. [PMID: 34440623 PMCID: PMC8391734 DOI: 10.3390/cells10081854] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/05/2021] [Accepted: 07/20/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer is one of the leading public health issues worldwide, and the number of cancer patients increases every day. Particularly, cervical cancer (CC) is still the second leading cause of cancer death in women from developing countries. Thus, it is essential to deepen our knowledge about the molecular pathogenesis of CC and propose new therapeutic targets and new methods to diagnose this disease in its early stages. Differential expression analysis using high-throughput techniques applied to biological samples allows determining the physiological state of normal cells and the changes produced by cancer development. The cluster of differential molecular profiles in the genome, the transcriptome, or the proteome is analyzed in the disease, and it is called the molecular signature of cancer. Proteomic analysis of biological samples of patients with different grades of cervical intraepithelial neoplasia (CIN) and CC has served to elucidate the pathways involved in the development and progression of cancer and identify cervical proteins associated with CC. However, several cervical carcinogenesis mechanisms are still unclear. Detecting pathologies in their earliest stages can significantly improve a patient's survival rate, prognosis, and recurrence. The present review is an update on the proteomic study of CC.
Collapse
Affiliation(s)
- Fátima Martínez-Rodríguez
- Microbiology Department, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes 20100, Mexico;
| | | | - Brenda Mendoza-Almanza
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98068, Mexico; (B.M.-A.); (E.L.E.-I.); (P.I.G.-F.)
| | - Edgar L. Esparza-Ibarra
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98068, Mexico; (B.M.-A.); (E.L.E.-I.); (P.I.G.-F.)
| | - Perla I. Gallegos-Flores
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98068, Mexico; (B.M.-A.); (E.L.E.-I.); (P.I.G.-F.)
| | - Jorge L. Ayala-Luján
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico; (J.L.A.-L.); (S.G.-G.)
| | - Susana Godina-González
- Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico; (J.L.A.-L.); (S.G.-G.)
| | - Eva Salinas
- Microbiology Department, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes 20100, Mexico;
| | - Gretel Mendoza-Almanza
- Master in Biomedical Sciences, Autonomous University of Zacatecas, Zacatecas 98160, Mexico;
- National Council of Science and Technology, Autonomous University of Zacatecas, Zacatecas 98000, Mexico
| |
Collapse
|
|
22
|
Expression of the E5 Oncoprotein of HPV16 Impacts on the Molecular Profiles of EMT-Related and Differentiation Genes in Ectocervical Low-Grade Lesions. Int J Mol Sci 2021; 22:ijms22126534. [PMID: 34207106 PMCID: PMC8235634 DOI: 10.3390/ijms22126534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Infection with human papillomavirus type 16 (HPV16) is one of the major risk factors for the development of cervical cancer. Our previous studies have demonstrated the involvement of the early oncoprotein E5 of HPV16 (16E5) in the altered isoform switch of fibroblast growth factor receptor 2 (FGFR2) and the consequent expression in human keratinocytes of the mesenchymal FGFR2c isoform, whose aberrant signaling leads to EMT, invasiveness, and dysregulated differentiation. Here, we aimed to establish the possible direct link between these pathological features or the appearance of FGFR2c and the expression of 16E5 in low-grade squamous intraepithelial lesions (LSILs). Molecular analysis showed that the FGFR2c expression displayed a statistically significant positive correlation with that of the viral oncoprotein, whereas the expression values of the epithelial FGR2b variant, as well as those of the differentiation markers keratin 10 (K10), loricrin (LOR) and involucrin (INV), were inversely linked to the 16E5 expression. In contrast, the expression of EMT-related transcription factors Snail1 and ZEB1 overlapped with that of 16E5, becoming a statistically significant positive correlation in the case of Snail2. Parallel analysis performed in human cervical LSIL-derived W12 cells, containing episomal HPV16, revealed that the depletion of 16E5 by siRNA was able to counteract these molecular events, proving to represent an effective strategy to identify the specific role of this viral oncoprotein in determining LSIL oncogenic and more aggressive profiles. Overall, coupling in vitro approaches to the molecular transcript analysis in ectocervical early lesions could significantly contribute to the characterization of specific gene expression profiles prognostic for those LSILs with a greater probability of direct neoplastic progression.
Collapse
|
|
23
|
Li C, Guo L, Li S, Hua K. Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and transcriptional activities of ECs in CC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 24:682-694. [PMID: 33996252 PMCID: PMC8099483 DOI: 10.1016/j.omtn.2021.03.017] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 03/28/2021] [Indexed: 11/17/2022]
Abstract
Cervical cancer (CC) is the fourth leading cause of deaths in gynecological malignancies. Although the etiology of CC has been extensively investigated, the exact pathogenesis of CC remains incomplete. Recently, single-cell technologies demonstrated advantages in exploring intra-tumoral diversification among various tumor cells. However, single-cell transcriptome analysis (single-cell RNA sequencing [scRNA-seq]) of CC cells and microenvironment has not been conducted. In this study, a total of 20,938 cells from CC and adjacent normal tissues were examined by scRNA-seq. We identified four tumor cell subpopulations in tumor cells, which had specific signature genes with different biological functions and presented different prognoses. Among them, we identified a subset of cancer stem cells (CSCs) that was related to the developmental hierarchy of tumor progression. Then, we compared the expressive differences between tumor-derived endothelial cells (TECs) and normal ECs (NECs) and revealed higher expression of several metabolism-related genes in TECs. Then, we explored the potential biological function of ECs in vascularization and found several marker genes, which played a prior role in connections between cancer cells and ECs. Our findings provide valuable resources for deciphering the intra-tumoral heterogeneity of CC and uncover the developmental procedure of ECs, which paves the way for CC therapy.
Collapse
Affiliation(s)
- Chunbo Li
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Luopei Guo
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Shengli Li
- Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Keqin Hua
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| |
Collapse
|
|
24
|
Zuccherato LW, Machado CMT, Magalhães WCS, Martins PR, Campos LS, Braga LC, Teixeira-Carvalho A, Martins-Filho OA, Franco TMRF, Paula SOC, da Silva IT, Drummond R, Gollob KJ, Salles PGO. Cervical Cancer Stem-Like Cell Transcriptome Profiles Predict Response to Chemoradiotherapy. Front Oncol 2021; 11:639339. [PMID: 34026616 PMCID: PMC8138064 DOI: 10.3389/fonc.2021.639339] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer (CC) represents a major global health issue, particularly impacting women from resource constrained regions worldwide. Treatment refractoriness to standard chemoradiotheraphy has identified cancer stem cells as critical coordinators behind the biological mechanisms of resistance, contributing to CC recurrence. In this work, we evaluated differential gene expression in cervical cancer stem-like cells (CCSC) as biomarkers related to intrinsic chemoradioresistance in CC. A total of 31 patients with locally advanced CC and referred to Mário Penna Institute (Belo Horizonte, Brazil) from August 2017 to May 2018 were recruited for the study. Fluorescence-activated cell sorting was used to enrich CD34+/CD45- CCSC from tumor biopsies. Transcriptome was performed using ultra-low input RNA sequencing and differentially expressed genes (DEGs) using Log2 fold differences and adjusted p-value < 0.05 were determined. The analysis returned 1050 DEGs when comparing the Non-Responder (NR) (n=10) and Responder (R) (n=21) groups to chemoradiotherapy. These included a wide-ranging pattern of underexpressed coding genes in the NR vs. R patients and a panel of lncRNAs and miRNAs with implications for CC tumorigenesis. A panel of biomarkers was selected using the rank-based AUC (Area Under the ROC Curve) and pAUC (partial AUC) measurements for diagnostic sensitivity and specificity. Genes overlapping between the 21 highest AUC and pAUC loci revealed seven genes with a strong capacity for identifying NR vs. R patients (ILF2, RBM22P2, ACO16722.1, AL360175.1 and AC092354.1), of which four also returned significant survival Hazard Ratios. This study identifies DEG signatures that provide potential biomarkers in CC prognosis and treatment outcome, as well as identifies potential alternative targets for cancer therapy.
Collapse
Affiliation(s)
| | | | | | | | - Larissa S. Campos
- Núcleo de Ensino e Pesquisa - Instituto Mário Penna, Belo Horizonte, Brazil
| | - Letícia C. Braga
- Núcleo de Ensino e Pesquisa - Instituto Mário Penna, Belo Horizonte, Brazil
| | | | | | | | | | | | - Rodrigo Drummond
- International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Kenneth J. Gollob
- Núcleo de Ensino e Pesquisa - Instituto Mário Penna, Belo Horizonte, Brazil
- Translational Immuno-Oncology Laboratory, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil
| | | |
Collapse
|
|
25
|
The Role of microRNAs in the Cisplatin- and Radio-Resistance of Cervical Cancer. Cancers (Basel) 2021; 13:cancers13051168. [PMID: 33803151 PMCID: PMC7963155 DOI: 10.3390/cancers13051168] [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: 01/11/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/30/2022] Open
Abstract
Cervical cancer is the fourth leading cause of cancer-related death among women worldwide. The chemotherapeutical agent cisplatin, a small platinum-based compound, is considered as the standard therapy for locally advanced cervical cancer or recurrent cancers, sometimes in combination with radiotherapy or other drugs. However, drug resistance and radio-resistance phenomena could reduce the life expectancy of cervical cancer patients. Resistance mechanisms are complex and often involve multiple cellular pathways in which microRNAs (miRNAs) play a fundamental role. miRNAs are a class of endogenous non-coding small RNAs responsible for post-transcriptional gene regulation. Convincing evidence demonstrates that several deregulated miRNAs are important regulators in the onset of drug and radioresistance in cervical cancer, thus underlying their potential applications in a clinical setting. In this review, we summarized the mechanisms by which miRNAs affect both cisplatin and radioresistance in cervical cancer. We also described the regulatory loops between miRNAs and lncRNAs promoting drug resistance. Besides, we reported evidence for the role of miRNAs in sensitizing cancer cells to cisplatin-based chemotherapy, and provided some suggestions for the development of new combined therapies for cervical cancer.
Collapse
|
|
26
|
Radiation Response of Cervical Cancer Stem Cells Is Associated with Pretreatment Proportion of These Cells and Physical Status of HPV DNA. Int J Mol Sci 2021; 22:ijms22031445. [PMID: 33535561 PMCID: PMC7867083 DOI: 10.3390/ijms22031445] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/24/2021] [Accepted: 01/28/2021] [Indexed: 12/17/2022] Open
Abstract
Radio- and chemoresistance of cancer stem cells (CSCs) is considered as one of the possible causes of adverse results of chemoradiotherapy for various malignancies, including cervical cancer. However, little is known about quantitative changes in the CSC subpopulation in the course of treatment and mechanisms for individual response of CSCs to therapy. The purpose of the study was to evaluate the association of radiation response of cervical CSCs with clinical and morphological parameters of disease and features of human papillomavirus (HPV) infection. The proportion of CD44+CD24low CSCs was determined by flow cytometry in cervical scrapings from 55 patients with squamous cell carcinoma of uterine cervix before treatment and after fractionated irradiation at a total dose of 10 Gy. Real-time PCR assay was used to evaluate molecular parameters of HPV DNA. Post-radiation increase in the CSC proportion was found in 47.3% of patients. Clinical and morphological parameters (stage, status of lymph node involvement, and histological type) were not significantly correlated with radiation changes in the CSC proportion. Single- and multifactor analyses revealed two independent indicators affecting the radiation response of CSCs: initial proportion of CSCs and physical status of HPV DNA (R = 0.86, p = 0.001 for the multiple regression model in the whole).
Collapse
|
|
27
|
Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
Collapse
Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
| |
Collapse
|
|
28
|
Budhwani M, Lukowski SW, Porceddu SV, Frazer IH, Chandra J. Dysregulation of Stemness Pathways in HPV Mediated Cervical Malignant Transformation Identifies Potential Oncotherapy Targets. Front Cell Infect Microbiol 2020; 10:307. [PMID: 32670895 PMCID: PMC7330094 DOI: 10.3389/fcimb.2020.00307] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomically diverse regions, and the majority of cervical intraepithelial neoplasia and cancers arise within the cervical squamo-columnar junction where undifferentiated basal progenitor cells with stem cell properties are found. The cancer stem cell theory particularly associates tumorigenesis, invasion, dissemination, and metastasis with cancer cells exhibiting stem cell properties. In this perspective, we discuss evidence of a cervical cancer stem cell niche and explore the association of stemness related genes with 5-year survival using a publicly available transcriptomic dataset of a cervical cancer cohort. We report that poor prognosis in this cohort correlates with overexpression of a subset of stemness pathway genes, a majority of which regulate the central Focal Adhesion pathway, and are also found to be enriched in the HPV infection pathway. These observations support therapeutic targeting of stemness genes overexpressed by mucosal cells infected with high-risk HPVs.
Collapse
Affiliation(s)
- Megha Budhwani
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Samuel W Lukowski
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Sandro V Porceddu
- Cancer Services, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Ian H Frazer
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Janin Chandra
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
| |
Collapse
|
|
29
|
Wen X, Liu S, Sheng J, Cui M. Recent advances in the contribution of noncoding RNAs to cisplatin resistance in cervical cancer. PeerJ 2020; 8:e9234. [PMID: 32523813 PMCID: PMC7263300 DOI: 10.7717/peerj.9234] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/04/2020] [Indexed: 12/11/2022] Open
Abstract
Cervical cancer (CC) remains a major disease burden on the female population worldwide. Chemotherapy with cisplatin (cis-diamminedichloroplatinum (II); CDDP) and related drugs are the main treatment option for CC; however, their efficacy is limited by the development of drug resistance. Noncoding RNAs (ncRNAs) have been found to play critical roles in numerous physiological and pathological cellular processes, including drug resistance of cancer cells. In this review, we describe some of the ncRNAs, including miRNAs, lncRNAs and circRNAs, that are involved in the sensitivity/resistance of CC to CDDP-based chemotherapy and discuss their mechanisms of action. We also describe some ncRNAs that could be therapeutic targets to improve the sensitivity of CC to CDDP-based chemotherapy.
Collapse
Affiliation(s)
- Xin Wen
- The Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Shui Liu
- The Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Jiyao Sheng
- The Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Manhua Cui
- The Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
30
|
Clemente-Periván SI, Gómez-Gómez Y, Leyva-Vázquez MA, Lagunas-Martínez A, Organista-Nava J, Illades-Aguiar B. Role of Oct3/4 in Cervical Cancer Tumorigenesis. Front Oncol 2020; 10:247. [PMID: 32219062 PMCID: PMC7079573 DOI: 10.3389/fonc.2020.00247] [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: 08/01/2019] [Accepted: 02/13/2020] [Indexed: 12/16/2022] Open
Abstract
Cervical cancer (CC) is the fourth most common type of cancer that affects women. Compared to other types of cancer, CC has a high mortality rate in women worldwide. Several factors contribute to the development of CC, but persistent high-risk human papillomavirus infection is the main etiologic agent associated with the development of CC. Moreover, several studies reported that alterations in the expression of transcription factors present in a small subpopulation of cells within tumors called cancer stem cells (CSCs), which contribute to the development of CC by promoting tumorigenicity and metastasis. These transcription factors affect self-renewal and maintenance of pluripotency and differentiation in stem cells. OCT3/4 belongs to the family of transcription factors with the POU domain. It consists of five exons and can be edited by alternative splicing into three main transcripts: OCT3/4A, OCT3/4B, and OCT3/4B1. The OCT3/4 expression in CSCs promotes carcinogenesis and the development of malignant tumors, and the loss of expression leads to the loss of self-renewal and proliferation and favors apoptosis. This review describes the main roles of OCT3/4 in CC and its importance in several biological processes that contribute to the development of CC and may serve as molecular targets to improve prognosis of CC.
Collapse
Affiliation(s)
- Sayuri Itzel Clemente-Periván
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Mexico
| | - Yazmín Gómez-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Mexico
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Mexico
| | - Alfredo Lagunas-Martínez
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Mexico
| | - Jorge Organista-Nava
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Mexico
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Mexico
| |
Collapse
|
|
31
|
Wang Q, Liu F, Wang L, Xie C, Wu P, Du S, Zhou S, Sun Z, Liu Q, Yu L, Liu B, Li R. Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells. Int J Nanomedicine 2020; 15:1283-1295. [PMID: 32161458 PMCID: PMC7049776 DOI: 10.2147/ijn.s234679] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/26/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit. METHODS Sal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial-mesenchymal transition (epithelial interstitial transformation) signal-related molecules. RESULTS Sal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial-mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal. CONCLUSION To the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.
Collapse
Affiliation(s)
- Qin Wang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Fangcen Liu
- The Comprehensive Cancer Centre, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Lifeng Wang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Chen Xie
- Key Laboratory for Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, Nanjing210023, People’s Republic of China
| | - Puyuan Wu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Shiyao Du
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Shujuan Zhou
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Zhichen Sun
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Qin Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Lixia Yu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| | - Rutian Li
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing210008, People’s Republic of China
| |
Collapse
|