|
1
|
Tan J, Zheng B, Zhou S. Deciphering the "Rosetta Stone" of ovarian cancer stem cells: Opportunities and challenges. Biochim Biophys Acta Rev Cancer 2025:189346. [PMID: 40339667 DOI: 10.1016/j.bbcan.2025.189346] [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: 11/26/2024] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Ovarian cancer stem cells (OCSCs) play a pivotal role in the initiation, maintenance, and progression of ovarian cancer, functioning through complex molecular mechanisms that are closely linked to metastasis and drug resistance. The complexity of these underlying mechanisms contributes to cancer hallmarks such as the high plasticity of OCSCs, leading to chemotherapy resistance; activation of invasion and metastasis, epigenetic reprogramming, and cell death resistance; and deregulation of cellular metabolism. OCSCs are characterized by the expression of markers including ALDH, CD133, CD44, and CD24. They preserve their stemness through intricate molecular mechanisms that involve interactions with the tumor microenvironment and various signaling pathways. To investigate these molecular mechanisms, both in vitro and in vivo models of OCSC have been established. The results of these studies can be applied in clinical practice, facilitating the development of various new therapies. This review aims to provide a deeper understanding of the mechanisms through which OCSCs function, highlighting significant opportunities for future research aimed at improving ovarian cancer treatment.
Collapse
Affiliation(s)
- Jixue Tan
- Department of Obstetrics and Gynecology, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, PR China
| | - Bohao Zheng
- Department of Obstetrics and Gynecology, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, PR China; Wuxi School of Medicine, Jiangnan University, Wuxi, PR China
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, PR China.
| |
Collapse
|
|
2
|
Acharya SK, Shai S, Choon YF, Gunardi I, Hartanto FK, Kadir K, Roychoudhury A, Amtha R, Vincent-Chong VK. Cancer Stem Cells in Oral Squamous Cell Carcinoma: A Narrative Review on Experimental Characteristics and Methodological Challenges. Biomedicines 2024; 12:2111. [PMID: 39335624 PMCID: PMC11429394 DOI: 10.3390/biomedicines12092111] [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: 07/14/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation of cancer cells that are believed to initiate and drive cancer progression. In animal models, xenotransplanted CSCs have demonstrated the ability to produce tumors. Since their initial isolation in blood cancers, CSCs have been identified in various solid human cancers, including oral squamous cell carcinoma (OSCC). In addition to their tumorigenic properties, dysregulated stem-cell-related signaling pathways-Wnt family member (Wnt), neurogenic locus notch homolog protein (Notch), and hedgehog-have been shown to endow CSCs with characteristics like self-renewal, phenotypic plasticity, and chemoresistance, contributing to recurrence and treatment failure. Consequently, CSCs have become targets for new therapeutic agents, with some currently in different phases of clinical trials. Notably, small molecule inhibitors of the hedgehog signaling pathway, such as vismodegib and glasdegib, have been approved for the treatment of basal cell carcinoma and acute myeloid leukemia, respectively. Other strategies for eradicating CSCs include natural compounds, nano-drug delivery systems, targeting mitochondria and the CSC microenvironment, autophagy, hyperthermia, and immunotherapy. Despite the extensive documentation of CSCs in OSCC since its first demonstration in head and neck (HN) SCC in 2007, none of these novel pharmacological approaches have yet entered clinical trials for OSCC patients. This narrative review summarizes the in vivo and in vitro evidence of CSCs and CSC-related signaling pathways in OSCC, highlighting their role in promoting chemoresistance and immunotherapy resistance. Additionally, it addresses methodological challenges and discusses future research directions to improve experimental systems and advance CSC studies.
Collapse
Affiliation(s)
- Surendra Kumar Acharya
- Department of Oral Medicine, Radiology and Surgery, Faculty of Dentistry, Lincoln University College, Petaling Jaya 47301, Selangor, Malaysia
| | - Saptarsi Shai
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA;
| | - Yee Fan Choon
- Department of Oral and Maxillofacial Surgical Sciences, Faculty of Dentistry, MAHSA University, Jenjarom 42610, Selangor, Malaysia;
| | - Indrayadi Gunardi
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Firstine Kelsi Hartanto
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Kathreena Kadir
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Ajoy Roychoudhury
- Department of Oral and Maxillofacial Surgery, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Rahmi Amtha
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Vui King Vincent-Chong
- Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| |
Collapse
|
|
3
|
Chen B, Liu J. Advances in ovarian tumor stem cells and therapy. Cell Biochem Biophys 2024; 82:1871-1892. [PMID: 38955927 DOI: 10.1007/s12013-024-01385-8] [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: 06/21/2024] [Indexed: 07/04/2024]
Abstract
Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70-80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer's recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells' sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.
Collapse
Affiliation(s)
- Biqing Chen
- Harbin Medical University, Harbin, Heilongjiang, China.
| | - Jiaqi Liu
- Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
4
|
Obaid Saleh R, Shbeer AM, Jetti R, Ahmed Robadi I, Hjazi A, Hussein Kareem A, Noori Shakir M, Qasim Alasheqi M, Alawadi A, Haslany A. Association between lncRNAs with stem cells in cancer; a particular focus on lncRNA-CSCs axis in cancer immunopathogenesis. Int Immunopharmacol 2024; 136:112306. [PMID: 38833843 DOI: 10.1016/j.intimp.2024.112306] [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: 04/02/2024] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
A unique population of cells known as cancer stem cells (CSCs) is essential to developing and spreading cancer. Cancer initiation, maintenance, and progression are all believed to be significantly impacted by the distinct characteristics these cells exhibit regarding self-renewal, proliferation, and differentiation. Transcriptional, post-transcriptional, and translational processes are the only steps of gene expression that lncRNAs can affect. As a result, these proteins participate in numerous biological processes, including the repair of DNA damage, inflammatory reactions, metabolic control, the survival of cells, intercellular communication, and the development and specialization of cells. Studies have indicated that lncRNAs are important for controlling the increase in the subset of CSCs contributing to cancer development. The knowledge that is currently available about lncRNAs and their critical role in maintaining the biological properties of CSCs is highlighted in this study.
Collapse
Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Abdullah M Shbeer
- Department of Surgery, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia.
| | - Raghu Jetti
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ibrahim Ahmed Robadi
- Department of Pathology, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Haslany
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| |
Collapse
|
|
5
|
Chen H, Lee LJ, Vincent KM, Xu Z, Liu J, Zhang G, Nakevska Z, Smith D, Lee CH, Postovit LM, Fu Y. Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer. Oncogene 2024; 43:1688-1700. [PMID: 38594503 DOI: 10.1038/s41388-024-03026-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 03/27/2024] [Accepted: 04/02/2024] [Indexed: 04/11/2024]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America. Current therapeutic regimens are ineffective against advanced EOC. A better understanding of the molecular mechanisms that regulate the biology of EOC will be a critical step toward developing more efficacious therapies against EOC. Herein, we demonstrate that elevated expression of transcription factor ZIC2 was associated with lower survival of EOC patients. Knockout of endogenous ZIC2 in EOC cells attenuated the tumorigenic phenotypes associated with both bulk and cancer stem cells in vitro and in vivo, indicating a pro-tumorigenic role of ZIC2 in EOC. On the other hand, however, overexpression of ZIC2 in EOC cells that do not express endogenous ZIC2 promoted cell migration and sphere formation, but inhibited cell growth and colony formation in vitro and tumor growth in vivo, indicating that the role for ZIC2 in EOC is context dependent. Our transcriptomic analysis showed that ZIC2-regulated genes were involved in multiple biological processes and signaling pathways associated with tumor progression. In conclusion, our findings reveal a context-dependent role for ZIC2 in regulating tumorigenic phenotypes in EOC, providing evidence that ZIC2 can be a potential therapeutic target for EOCs that express a high level of ZIC2.
Collapse
Affiliation(s)
- Huachen Chen
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Laura Jiyoung Lee
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Krista M Vincent
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Zhihua Xu
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Jiahui Liu
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Guihua Zhang
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Zorica Nakevska
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - DuPreez Smith
- Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Cheng-Han Lee
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Lynne-Marie Postovit
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
- Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
| | - YangXin Fu
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
- Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
| |
Collapse
|
|
6
|
Al-Alem L, Prendergast JM, Clark J, Zarrella B, Zarrella DT, Hill SJ, Growdon WB, Pooladanda V, Spriggs DR, Cramer D, Elias KM, Nazer RI, Skates SJ, Behrens J, Dransfield DT, Rueda BR. Sialyl-Tn serves as a potential therapeutic target for ovarian cancer. J Ovarian Res 2024; 17:71. [PMID: 38566237 PMCID: PMC10985924 DOI: 10.1186/s13048-024-01397-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer. METHODS We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples. RESULTS Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis. CONCLUSIONS Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.
Collapse
Affiliation(s)
- Linah Al-Alem
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
| | | | - Justin Clark
- Siamab Therapeutics, Inc, Newton, MA, 02458, USA
| | - Bianca Zarrella
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Dominique T Zarrella
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Sarah J Hill
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Whitfield B Growdon
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Venkatesh Pooladanda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - David R Spriggs
- Division of Hematology-Oncology, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Daniel Cramer
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Kevin M Elias
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | | | - Steven J Skates
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Jeff Behrens
- Siamab Therapeutics, Inc, Newton, MA, 02458, USA
| | | | - Bo R Rueda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA.
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
| |
Collapse
|
|
7
|
Ruszkowska-Ciastek B, Kwiatkowska K, Marques-da-Silva D, Lagoa R. Cancer Stem Cells from Definition to Detection and Targeted Drugs. Int J Mol Sci 2024; 25:3903. [PMID: 38612718 PMCID: PMC11011379 DOI: 10.3390/ijms25073903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs' involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.
Collapse
Affiliation(s)
- Barbara Ruszkowska-Ciastek
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland
| | - Katarzyna Kwiatkowska
- Department of Laboratory Diagnostics, Jan Biziel University Hospital No. 2, 85-168 Bydgoszcz, Poland;
| | - Dorinda Marques-da-Silva
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Ricardo Lagoa
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| |
Collapse
|
|
8
|
Soundararajan L, Warrier S, Dharmarajan A, Bhaskaran N. Predominant factors influencing reactive oxygen species in cancer stem cells. J Cell Biochem 2024; 125:3-21. [PMID: 37997702 DOI: 10.1002/jcb.30506] [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: 08/19/2023] [Revised: 10/17/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self-renewal and tumorigenic potential and are resistant to conventional chemo- and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus-faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS-mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.
Collapse
Affiliation(s)
- Loshini Soundararajan
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Sudha Warrier
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research, Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
- Stem Cell and Cancer Biology laboratory, Curtin University, Perth, Western Australia, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Natarajan Bhaskaran
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| |
Collapse
|
|
9
|
Gisina A, Kim Y, Yarygin K, Lupatov A. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons. Int J Mol Sci 2023; 24:17398. [PMID: 38139228 PMCID: PMC10744290 DOI: 10.3390/ijms242417398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
Collapse
Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| | | | | | | |
Collapse
|
|
10
|
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
|
|
11
|
Yu F, Zhang Z, Chang X, Ye X, Cheng H, Li Y, Cui H. Immunization with Embryonic Stem Cells/Induced Pluripotent Stem Cells Induces Effective Immunity against Ovarian Tumor-Initiating Cells in Mice. Stem Cells Int 2023; 2023:8188324. [PMID: 38058983 PMCID: PMC10696476 DOI: 10.1155/2023/8188324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/07/2023] [Accepted: 10/10/2023] [Indexed: 12/08/2023] Open
Abstract
Cancer stem cells (CSCs) express pluripotent markers and share many features with normal pluripotent stem cells. It is possible that immunity induced by embryonic stem cells (ESCs) and induced pluripotent stem cells- (IPSCs-) based vaccines may selectively target CSCs. In our study, cells expressing the pluripotent marker CD133 in the murine ovarian cancer cell-line ID8 were isolated and identified as CSCs. We investigated the preventive efficacy of ESCs and IPSCs-based vaccines against the development of ovarian cancer in vivo and evaluated the humoral and cellular immunities targeting CSCs in vitro. Our study showed that preimmunization with both mouse-derived embryonic stem cells (mESCs) and mouse-induced pluripotent stem cells (mIPSCs) lysates, combined with an immunostimulatory adjuvant CpG, elicited strong humoral and cellular responses. These responses effectively suppressed the development of CSC-derived tumors. Immune sera collected from mESCs and mIPSCs-vaccinated mice contained antibodies that were capable of selectively targeting CSCs, resulting in the lysis of CSCs in the presence of complement. Cytotoxic T-lymphocytes generated from splenocytes of mESCs and mIPSCs-vaccinated hosts could secrete interferon- (IFN-) γ in response to CSCs and kill CSCs in vitro. These findings indicate that vaccines based on mESCs and mIPSCs can elicit effective antitumor immunities. These immunities are related to the conferring of humoral and cellular responses that directly target CSCs.
Collapse
Affiliation(s)
- Fengsheng Yu
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Zujuan Zhang
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Xiaohong Chang
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Xue Ye
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Hongyan Cheng
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Yi Li
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Heng Cui
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| |
Collapse
|
|
12
|
McGonigal S, Wu R, Grimley E, Turk EG, Zhai Y, Cho KR, Buckanovich RJ. A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors. Gynecol Oncol 2023; 176:139-146. [PMID: 37535994 PMCID: PMC10653209 DOI: 10.1016/j.ygyno.2023.07.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 08/05/2023]
Abstract
Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.
Collapse
Affiliation(s)
- Stacy McGonigal
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rong Wu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ed Grimley
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ekrem G Turk
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yali Zhai
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kathleen R Cho
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ronald J Buckanovich
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
| |
Collapse
|
|
13
|
Englisz A, Smycz-Kubańska M, Mielczarek-Palacz A. Evaluation of the Potential Diagnostic Utility of the Determination of Selected Immunological and Molecular Parameters in Patients with Ovarian Cancer. Diagnostics (Basel) 2023; 13:diagnostics13101714. [PMID: 37238197 DOI: 10.3390/diagnostics13101714] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/28/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Ovarian cancer is one of the most serious challenges in modern gynaecological oncology. Due to its non-specific symptoms and the lack of an effective screening procedure to detect the disease at an early stage, ovarian cancer is still marked by a high mortality rate among women. For this reason, a great deal of research is being carried out to find new markers that can be used in the detection of ovarian cancer to improve early diagnosis and survival rates of women with ovarian cancer. Our study focuses on presenting the currently used diagnostic markers and the latest selected immunological and molecular parameters being currently investigated for their potential use in the development of new diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Aleksandra Englisz
- The Doctoral School, Medical University of Silesia, 40-055 Katowice, Poland
| | - Marta Smycz-Kubańska
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Aleksandra Mielczarek-Palacz
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| |
Collapse
|
|
14
|
Li Y, Hu Y, Yang L, Liu J, Cui C, Yang M, Zou D, Zhou L, Zhou Q, Ge W, Lang T. Luteolin directly binds to KDM4C and attenuates ovarian cancer stemness via epigenetic suppression of PPP2CA/YAP axis. Biomed Pharmacother 2023; 160:114350. [PMID: 36804120 DOI: 10.1016/j.biopha.2023.114350] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/18/2023] Open
Abstract
Long-term use of low-toxic natural products holds the promise for eradicating cancer stem cells. In this study, we report that luteolin, a natural flavonoid, attenuates the stemness of ovarian cancer stem cells (OCSCs) by directly binding to KDM4C and epigenetic suppression of PPP2CA/YAP axis. Ovarian cancer stem like cells (OCSLCs) isolated by suspension culture and CD133 + ALDH+ cell sorting was employed as OCSCs model. The maximal non-toxic dose of luteolin suppressed stemness properties, including sphere-forming capacity, the expression of OCSCs markers, sphere-initiating and tumor-initiating capacities, as well as the percentage of CD133 + ALDH+ cells of OCSLCs. Mechanistic study showed that luteolin directly binds to KDM4C, blocks KDM4C-induced histone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephosphorylation, thereby attenuating YAP activity and the stemness of OCSLCs. Furthermore, luteolin sensitized OCSLCs to traditional chemotherapeutic drugs in vitro and in vivo. In summary, our work revealed the direct target of luteolin and the underlying mechanism of the inhibitory effect of luteolin on the stemness of OCSCs. This finding thus suggests a novel therapeutic strategy for eradicating human OCSCs driven by KDM4C.
Collapse
Affiliation(s)
- Yunzhe Li
- College of Bioengineering, Chongqing University, Chongqing 400044, People's Republic of China
| | - Yunran Hu
- Department of Pharmacy, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, People's Republic of China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, People's Republic of China
| | - Lingling Yang
- School of Medicine, Chongqing University, Chongqing 400044, People's Republic of China
| | - Jingshu Liu
- Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Chenxi Cui
- School of Medicine, Chongqing University, Chongqing 400044, People's Republic of China
| | - Muyao Yang
- College of Bioengineering, Chongqing University, Chongqing 400044, People's Republic of China
| | - Dongling Zou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing 400030, People's Republic of China
| | - Lei Zhou
- School of Optometry; Department of Applied Biology and Chemical Technology; Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hong Kong; Centre for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong
| | - Qi Zhou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing 400030, People's Republic of China.
| | - Weihong Ge
- Department of Pharmacy, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, People's Republic of China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, People's Republic of China.
| | - Tingyuan Lang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing 400030, People's Republic of China; Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, People's Republic of China.
| |
Collapse
|
|
15
|
Rodriguez Torres S, Gresseau L, Benhamida M, Fernandez-Marrero Y, Annabi B. Epigallocatechin-3-Gallate Prevents the Acquisition of a Cancer Stem Cell Phenotype in Ovarian Cancer Tumorspheres through the Inhibition of Src/JAK/STAT3 Signaling. Biomedicines 2023; 11:1000. [PMID: 37189618 PMCID: PMC10135615 DOI: 10.3390/biomedicines11041000] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 05/17/2023] Open
Abstract
Three-dimensional tumorsphere cultures recapitulate the expression of several cancer stem cell (CSC) biomarkers and represent an effective in vitro platform to screen the anti-CSC properties of drugs. Whereas ovarian carcinoma is among the leading causes of death for women, ovarian CSC (OvCSC), a highly malignant subpopulation of ovarian cancer cells, is thought to be responsible for therapy resistance, metastasis, and tumor relapse. Epigallocatechin-3-gallate (EGCG), a diet-derived active polyphenol found in green tea leaves, can suppress ovarian cancer cell proliferation and induce apoptosis. However, its capacity to prevent the acquisition of cancer stemness traits in ovarian malignancies remains unclear. Here, we exploited the in vitro three-dimensional tumorsphere culture model to explore the capacity of EGCG to alter CSC biomarkers expression, signal transducing events and cell chemotaxis. Total RNA and protein lysates were isolated from human ES-2 ovarian cancer cell tumorspheres for gene assessment by RT-qPCR and protein expression by immunoblot. Real-time cell chemotaxis was assessed with xCELLigence. Compared with their parental adherent cells, tumorspheres expressed increased levels of the CSC markers NANOG, SOX2, PROM1, and Fibronectin. EGCG treatment reduced dose-dependently tumorspheres size and inhibited the transcriptional regulation of those genes. Src and JAK/STAT3 signaling pathways appeared to be relevant for CSC phenotype and chemotactic response. In conclusion, these data highlight and support the chemopreventive benefits of the diet-derived EGCG and its capacity to target intracellular transducing events that regulate the acquisition of an invasive CSC phenotype.
Collapse
Affiliation(s)
- Sahily Rodriguez Torres
- Laboratoire d’Oncologie Moléculaire, Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3J7, Canada
| | - Loraine Gresseau
- Laboratoire d’Oncologie Moléculaire, Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3J7, Canada
| | - Meriem Benhamida
- Laboratoire d’Oncologie Moléculaire, Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3J7, Canada
| | | | - Borhane Annabi
- Laboratoire d’Oncologie Moléculaire, Département de Chimie, and CERMO-FC, Université du Québec à Montréal, Montreal, QC H3C 3J7, Canada
| |
Collapse
|
|
16
|
Short peptide domains of the Wnt inhibitor sFRP4 target ovarian cancer stem cells by neutralizing the Wnt β-catenin pathway, disrupting the interaction between β-catenin and CD24 and suppressing autophagy. Life Sci 2023; 316:121384. [PMID: 36646377 DOI: 10.1016/j.lfs.2023.121384] [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: 09/29/2022] [Revised: 01/02/2023] [Accepted: 01/07/2023] [Indexed: 01/15/2023]
Abstract
AIMS One of the hallmarks of cancer stem cells (CSC) is hyperactive Wnt β-catenin signaling due to the decreased presence of Wnt antagonists such as secreted frizzled related protein 4 (SFRP4). Cysteine-rich domain (CRD) and netrin-like domain (NLD) are the two functional domains of SFRP4 having anti-tumor properties. In this study, we have explored the effectiveness of short micropeptides SC-301 (from CRD) and SC-401 (from NLD) on CSC properties, EMT, apoptosis and autophagy in ovarian CSCs enriched from PA-1 and SKOV-3 cell lines. MAIN METHODS Gene expression analysis, Western blot and immunocytochemistry were performed on ovarian CSCs to evaluate the inhibitory potential of micropeptides to various CSC associated oncogenic properties. Co-immunoprecipitation was performed to detect the binding of CD24 to β-catenin protein complex. CYTO-ID Autophagy Detection Kit 2.0 was used to monitor autophagic flux in peptide treated CSCs. KEY FINDINGS It is clearly seen that the micropeptides derived from both the domains inhibit Wnt pathway, initiate apoptosis, inhibit migration and chemosensitize CSCs. Specifically, CD24, a defining marker of ovarian CSC was suppressed by peptide treatment. Notably, interaction between CD24 and β-catenin was disrupted upon peptide treatment. SFRP4 peptide treatment also suppressed the autophagic process which is crucial for CSC survival. SIGNIFICANCE The study demonstrated that although both peptides have inhibitory effects, SC-401 was emphatically more effective in targeting CSC properties and down regulating the Wnt β-catenin machinery.
Collapse
|
|
17
|
Varier L, Sundaram SM, Gamit N, Warrier S. An Overview of Ovarian Cancer: The Role of Cancer Stem Cells in Chemoresistance and a Precision Medicine Approach Targeting the Wnt Pathway with the Antagonist sFRP4. Cancers (Basel) 2023; 15:cancers15041275. [PMID: 36831617 PMCID: PMC9954718 DOI: 10.3390/cancers15041275] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 02/11/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
Ovarian cancer is one of the most prevalent gynecological cancers, having a relatively high fatality rate with a low five-year chance of survival when detected in late stages. The early detection, treatment and prevention of metastasis is pertinent and a pressing research priority as many patients are diagnosed only in stage three of ovarian cancer. Despite surgical interventions, targeted immunotherapy and adjuvant chemotherapy, relapses are significantly higher than other cancers, suggesting the dire need to identify the root cause of metastasis and relapse and present more precise therapeutic options. In this review, we first describe types of ovarian cancers, the existing markers and treatment modalities. As ovarian cancer is driven and sustained by an elusive and highly chemoresistant population of cancer stem cells (CSCs), their role and the associated signature markers are exhaustively discussed. Non-invasive diagnostic markers, which can be identified early in the disease using circulating tumor cells (CTCs), are also described. The mechanism of the self-renewal, chemoresistance and metastasis of ovarian CSCs is regulated by the Wnt signaling pathway. Thus, its role in ovarian cancer in promoting stemness and metastasis is delineated. Based on our findings, we propose a novel strategy of Wnt inhibition using a well-known Wnt antagonist, secreted frizzled related protein 4 (sFRP4), wherein short micropeptides derived from the whole protein can be used as powerful inhibitors. The latest approaches to early diagnosis and novel treatment strategies emphasized in this review will help design precision medicine approaches for an effective capture and destruction of highly aggressive ovarian cancer.
Collapse
Affiliation(s)
- Lavanya Varier
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
| | - S. Mohana Sundaram
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
| | - Naisarg Gamit
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
| | - Sudha Warrier
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
- Correspondence:
| |
Collapse
|
|
18
|
Ma H, Tian T, Cui Z. Targeting ovarian cancer stem cells: a new way out. Stem Cell Res Ther 2023; 14:28. [PMID: 36788591 PMCID: PMC9926632 DOI: 10.1186/s13287-023-03244-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 01/18/2023] [Indexed: 02/16/2023] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy due to tumor heterogeneity, the lack of reliable early diagnosis methods and the high incidence of chemoresistant recurrent disease. Although there are developments in chemotherapies and surgical techniques to improve the overall survival of OC patients, the 5-year survival of advanced OC patients is still low. To improve the prognosis of OC patients, it is important to search for novel therapeutic approaches. Cancer stem cells (CSCs) are a subpopulation of tumor cells that participate in tumor growth, metastasis and chemoresistance. It is important to study the role of CSCs in a highly heterogeneous disease such as OC, which may be significant to a better understanding of the oncogenetic and metastatic pathways of the disease and to develop novel strategies against its progression and platinum resistance. Here, we summarized the current findings about targeting methods against ovarian cancer stem cells, including related signaling pathways, markers and drugs, to better manage OC patients using CSC-based therapeutic strategies.
Collapse
Affiliation(s)
- Huiying Ma
- grid.412521.10000 0004 1769 1119Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Tian Tian
- grid.412521.10000 0004 1769 1119Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Zhumei Cui
- Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.
| |
Collapse
|
|
19
|
Chang MR, Rusanov DA, Arakelyan J, Alshehri M, Asaturova AV, Kireeva GS, Babak MV, Ang WH. Targeting emerging cancer hallmarks by transition metal complexes: Cancer stem cells and tumor microbiome. Part I. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
|
|
20
|
Suicide gene strategies applied in ovarian cancer studies. Cancer Gene Ther 2023:10.1038/s41417-023-00590-6. [PMID: 36717737 DOI: 10.1038/s41417-023-00590-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/06/2023] [Accepted: 01/17/2023] [Indexed: 02/01/2023]
Abstract
Ovarian cancer represents the most lethal gynecological malignancy among women in developed countries. Despite the recent innovations, the improvements in the 5-year survival rate have been insufficient and the management of this disease still remains a challenge. The fact that the majority of patients experience recurrent or resistant disease have substantiated the necessity of an innovative treatment. Among various strategies investigated, the recent strides made in gene delivery techniques have made gene therapy, including suicide gene strategies, a potential alternative for treating ovarian cancer. Various suicide gene candidates, which are capable of promoting cancer cell apoptosis directly after its entry or indirectly by prodrug administration, can be separated into three systems using enzyme-coding, toxin or pro-apoptotic genes. With this review, we aim to provide an overview of different suicide genes depending on therapeutic strategies, the vectors used to deliver these transgenes specifically to malignant cells, and the combined treatments of these genes with various therapeutic regimens.
Collapse
|
|
21
|
Izycka N, Rucinski M, Andrzejewska M, Szubert S, Nowak-Markwitz E, Sterzynska K. The Prognostic Value of Cancer Stem Cell Markers (CSCs) Expression-ALDH1A1, CD133, CD44-For Survival and Long-Term Follow-Up of Ovarian Cancer Patients. Int J Mol Sci 2023; 24:ijms24032400. [PMID: 36768723 PMCID: PMC9916537 DOI: 10.3390/ijms24032400] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/18/2023] [Accepted: 01/21/2023] [Indexed: 01/27/2023] Open
Abstract
Recurrent disease and treatment-associated chemoresistance are the two main factors accounting for poor clinical outcomes of ovarian cancer (OC) patients. Both can be associated with cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence. Hence, this study investigated whether the expression of known CSC-associated markers ALDH1A, CD44, and CD133 may predict OC patient prognosis. We analyzed their expression in primary epithelial ovarian cancer (EOC) patients using immunohistochemistry and related them to clinicopathological data, including overall survival (OS) and progression-free survival (PFS). Expression of ALDH1A1 was detected in 32%, CD133 in 28%, and CD44 in 33% of cases. While Kaplan-Meier analysis revealed no association of the expression of CD133 and CD44 with PFS and OS, ALDH1A1-positive patients were characterized with both significantly shorter OS (p = 0.00022) and PFS (p = 0.027). Multivariate analysis demonstrated that the expression of ALDH1A1, FIGO stage III-IV, and residual disease after suboptimal debulking or neoadjuvant chemotherapy correlated with shorter OS. The results of this study identify ALDH1A1 as a potential independent prognostic factor of shorter OS and PFS in EOC patients. Therefore, targeting ALDH1A1-positive cancer cells may be a promising therapeutic strategy to influence the disease course and treatment response.
Collapse
Affiliation(s)
- Natalia Izycka
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznań, Poland
| | - Marcin Rucinski
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland
| | - Malgorzata Andrzejewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland
| | - Sebastian Szubert
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznań, Poland
| | - Ewa Nowak-Markwitz
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznań, Poland
| | - Karolina Sterzynska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland
- Correspondence: ; Tel.: +48-61-8546455
| |
Collapse
|
|
22
|
Predicting Prognosis and Platinum Resistance in Ovarian Cancer: Role of Immunohistochemistry Biomarkers. Int J Mol Sci 2023; 24:ijms24031973. [PMID: 36768291 PMCID: PMC9916805 DOI: 10.3390/ijms24031973] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 01/20/2023] Open
Abstract
Ovarian cancer is a lethal reproductive tumour affecting women worldwide. The advancement in presentation and occurrence of chemoresistance are the key factors for poor survival among ovarian cancer women. Surgical debulking was the mainstay of systemic treatment for ovarian cancer, which was followed by a successful start to platinum-based chemotherapy. However, most women develop platinum resistance and relapse within six months of receiving first-line treatment. Thus, there is a great need to identify biomarkers to predict platinum resistance before enrolment into chemotherapy, which would facilitate individualized targeted therapy for these subgroups of patients to ensure better survival and an improved quality of life and overall outcome. Harnessing the immune response through immunotherapy approaches has changed the treatment way for patients with cancer. The immune outline has emerged as a beneficial tool for recognizing predictive and prognostic biomarkers clinically. Studying the tumour microenvironment (TME) of ovarian cancer tissue may provide awareness of actionable targets for enhancing chemotherapy outcomes and quality of life. This review analyses the relevance of immunohistochemistry biomarkers as prognostic biomarkers in predicting chemotherapy resistance and improving the quality of life in ovarian cancer.
Collapse
|
|
23
|
The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance. Int J Mol Sci 2022; 23:ijms232113577. [PMID: 36362359 PMCID: PMC9656305 DOI: 10.3390/ijms232113577] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure.
Collapse
|
|
24
|
Chen YA, Lu CY, Cheng WF, Kuo KT, Yu CW, Ho HN, Chen HF, Pan SH. An experimental model for ovarian cancer: propagation of ovarian cancer initiating cells and generation of ovarian cancer organoids. BMC Cancer 2022; 22:967. [PMID: 36085021 PMCID: PMC9463800 DOI: 10.1186/s12885-022-10042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 08/23/2022] [Indexed: 11/10/2022] Open
Abstract
Background Ovarian cancer (OC) is the most lethal gynecological cancer due to the recurrence of drug-resistance. Cancer initiating cells (CICs) are proposed to be responsible for the aggressiveness of OC. The rarity and difficulty of in vitro long-term cultivation of CICs challenge the development of CIC-targeting therapeutics. Reprogramming cancer cells into induced cancer initiating cell (iCICs) could be an approach to solve these. Several inducible CICs have been acquired by activating the expression of stemness genes in different cancer cells. However, few reports have demonstrated the feasibility in OC. Methods Patients with primary OC receiving surgery were enrolled. Tumor tissue were collected, and OCT4, SOX2, and NANOG expressions were assessed by immunohistochemistry (IHC) staining to investigate the association of stemness markers with overall survival (OS). An high-grade serous ovarian cancer (HGSOC) cell line, OVCAR-3 was reprogrammed by transducing Yamanaka four factors OCT4, SOX2, KLF4 and MYC (OSKM) to establish an iOCIC model, iOVCAR-3-OSKM. CIC characteristics of iOVCAR-3-OSKM were evaluated by RT-PCR, sphere formation assay and animal experiments. Drug-resistance and migration ability were accessed by dye-efflux activity assay, MTT assay and migration assay. Gene profile was presented through RNA-sequencing. Lineage differentiation ability and organoid culture were determined by in vitro differentiation assays. Results In OC patients, the co-expression of multiple stem-related transcription factors (OCT4, SOX2, and NANOG) was associated with worse OS. iOVCAR-3-OSKM cells generated by reprogramming successfully exhibited stemness characteristics with strong sphere-forming and tumorigenesis ability. iOVCAR-3-OSKM cells also showed malignant potential with higher drug resistance to chemodrug, Paclitaxel (PTX) and migration ability. iOVCAR-3-OSKM was maintainable and expandable on feeder-dependent culture condition, it also preserved ovarian lineage differentiation abilities, which could well differentiate into OC cells with CK-7 and CA125 expressions and develop into an organoid mimic poor prognostic OC histological feature. Conclusions The establishment of iOVCAR-3-OSKM not only allows us to fill the gap in the information on induced CICs in OC but also provides a potential strategy to develop personalized CICs and organoid models for treating OC in the near future. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10042-3.
Collapse
|
|
25
|
Cho JG, Kim SW, Lee A, Jeong HN, Yun E, Choi J, Jeong SJ, Chang W, Oh S, Yoo KH, Lee JB, Yoon S, Lee MS, Park JH, Jung MH, Kim SW, Kim KH, Suh DS, Choi KU, Choi J, Kim J, Kwon BS. MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:803-822. [PMID: 36159587 PMCID: PMC9463562 DOI: 10.1016/j.omtn.2022.08.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 08/17/2022] [Indexed: 01/22/2023]
|
|
26
|
Yin J, Wen Y, Zeng J, Zhang Y, Chen J, Zhang Y, Han T, Li X, Huang H, Cai Y, Jin Y, Li Y, Guo W, Pan L. CDC50A might be a novel biomarker of epithelial ovarian cancer-initiating cells. BMC Cancer 2022; 22:903. [PMID: 35982417 PMCID: PMC9389740 DOI: 10.1186/s12885-022-09953-y] [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: 04/06/2022] [Accepted: 07/28/2022] [Indexed: 11/23/2022] Open
Abstract
Background The aim of this work was to screen and validate biomarkers of ovarian cancer-initiating cells to detect the mechanisms of recurrence of epithelial ovarian cancer (EOC). Methods Stably labelled the amino acid in side population (SP) cells of epithelial ovarian cancer which were rich in cancer-initiating cells and non-SP cells with isotope in culture and differentially expressed cellular membrane proteins in SP cells were identified through proteomics technology. The new candidate biomarker was screened and validated through RT-PCR and western blot. Both in cell lines and primary EOC, cancer-initiating biofunctions of CDC50A positive cells were validated. Moreover, the characteristics of mesenchymal transition (EMT) was also detected and the correlation between the biomarker and clinical prognosis was observed. Results Through proteomics technology, candidate protein CDC50A was screened, and its significantly differential expression in SP cells was validated. CDC50A-positive cells from cell lines and primary ovarian cancer tissues were validated to show characteristics of cancer-initiating cells both in vitro and in vivo, including sphere-forming, self-renewal, differentiation, tumor metastasis and tumorigenicity in mice. The relationship between CDC50A-positive cells from primary tissues and tumour metastasis was confirmed based on their mesenchymal transition characteristics. Among 16 high-grade ovarian serous cancer patients, a high ratio of CDC50A-positive cells in primary tumours was correlated with a shorter platinum-free interval (p = 0.031, HR 0.260, 95% CI 0.77 ~ 0.885). Conclusion CDC50A could be used to screen ovarian cancer-initiating cells and might be a new target to resolve tumour development in EOC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09953-y.
Collapse
Affiliation(s)
- Jie Yin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Yiping Wen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China.,Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Zeng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Yanyan Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Jiayu Chen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Yanmei Zhang
- Department of Basic Medicine, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China
| | - Tiantian Han
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Xiaoying Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Hong Huang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Yan Cai
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Ying Jin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Yan Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China
| | - Wei Guo
- Department of Basic Medicine, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China.
| | - Lingya Pan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuai Fu Yuan, Dongcheng district, Beijing, 100730, China.
| |
Collapse
|
|
27
|
Pompili S, Vetuschi A, Sferra R, Cappariello A. Extracellular Vesicles and Resistance to Anticancer Drugs: A Tumor Skeleton Key for Unhinging Chemotherapies. Front Oncol 2022; 12:933675. [PMID: 35814444 PMCID: PMC9259994 DOI: 10.3389/fonc.2022.933675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/20/2022] [Indexed: 11/13/2022] Open
Abstract
Although surgical procedures and clinical care allow reaching high success in fighting most tumors, cancer is still a formidable foe. Recurrence and metastatization dampen the patients’ overall survival after the first diagnosis; nevertheless, the large knowledge of the molecular bases drives these aspects. Chemoresistance is tightly linked to these features and is mainly responsible for the failure of cancer eradication, leaving patients without a crucial medical strategy. Many pathways have been elucidated to trigger insensitiveness to drugs, generally associated with the promotion of tumor growth, aggressiveness, and metastatisation. The main mechanisms reported are the expression of transporter proteins, the induction or mutations of oncogenes and transcription factors, the alteration in genomic or mitochondrial DNA, the triggering of autophagy or epithelial-to-mesenchymal transition, the acquisition of a stem phenotype, and the activation of tumor microenvironment cells. Extracellular vesicles (EVs) can directly transfer or epigenetically induce to a target cell the molecular machinery responsible for the acquisition of resistance to drugs. In this review, we resume the main body of knowledge supporting the crucial role of EVs in the context of chemoresistance, with a particular emphasis on the mechanisms related to some of the main drugs used to fight cancer.
Collapse
|
|
28
|
Zhang Y, Wang Y, Zhao G, Tanner EJ, Adli M, Matei D. FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway. J Clin Invest 2022; 132:e151591. [PMID: 35349489 PMCID: PMC9106354 DOI: 10.1172/jci151591] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 03/23/2022] [Indexed: 11/17/2022] Open
Abstract
Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1α (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs.
Collapse
Affiliation(s)
- Yaqi Zhang
- Department of Obstetrics and Gynecology
- Driskill Graduate Training Program in Life Sciences, and
| | - Yinu Wang
- Department of Obstetrics and Gynecology
| | - Guangyuan Zhao
- Department of Obstetrics and Gynecology
- Driskill Graduate Training Program in Life Sciences, and
| | - Edward J. Tanner
- Department of Obstetrics and Gynecology
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Mazhar Adli
- Department of Obstetrics and Gynecology
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Daniela Matei
- Department of Obstetrics and Gynecology
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
| |
Collapse
|
|
29
|
Otaegi-Ugartemendia M, Matheu A, Carrasco-Garcia E. Impact of Cancer Stem Cells on Therapy Resistance in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14061457. [PMID: 35326607 PMCID: PMC8946717 DOI: 10.3390/cancers14061457] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 12/04/2022] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance.
Collapse
Affiliation(s)
| | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (M.O.-U.); (A.M.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Estefania Carrasco-Garcia
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (M.O.-U.); (A.M.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-943-006296
| |
Collapse
|
|
30
|
Wilczyński JR, Wilczyński M, Paradowska E. Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies. Int J Mol Sci 2022; 23:ijms23052496. [PMID: 35269636 PMCID: PMC8910575 DOI: 10.3390/ijms23052496] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.
Collapse
Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
- Correspondence:
| | - Miłosz Wilczyński
- Department of Gynecological, Endoscopic and Oncological Surgery, Polish Mother’s Health Center—Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland;
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland;
| |
Collapse
|
|
31
|
Proskurina AS, Kupina VV, Efremov YR, Dolgova EV, Ruzanova VS, Ritter GS, Potter EA, Kirikovich SS, Levites EV, Ostanin AA, Chernykh ER, Babaeva OG, Sidorov SV, Bogachev SS. Karanahan: A Potential New Treatment Option for Human Breast Cancer and Its Validation in a Clinical Setting. BREAST CANCER: BASIC AND CLINICAL RESEARCH 2022; 16:11782234211059931. [PMID: 35185333 PMCID: PMC8851498 DOI: 10.1177/11782234211059931] [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: 08/26/2020] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction: Karanahan, a cancer treatment technology aimed at eradicating tumor-initiating stem cells, has already proven effective in 7 tumor models. Karanahan comprises the following procedures: (1) collecting surgical specimens, (2) determining the duration of the DNA repair process in tumor cells exposed to a cross-linking cytostatic agent, and (3) determining the time point, when cells, including tumor-initiating stem cells, are synchronized in the certain phase of the cell cycle after triple exposure to the cytostatic, becoming vulnerable for the terminal treatment, which is supposed to completely eliminate the rest of survived tumor-initiating stem cells. Determining these basic tumor properties allows to design the schedule for the administration of a cross-linking cytostatic and a complex composite DNA preparation. Being conducted in accordance with the schedule designed, Karanahan results in the large-scale apoptosis of tumor cells with elimination of tumor-initiating stem cells. Methods: Breast tumor specimens were obtained from patients, and basic tumor properties essential for conducting Karanahan therapy were determined. Results: We report the first use of Karanahan in patients diagnosed with breast cancer. Technical details of handling surgical specimens for determining the essential Karanahan parameters (tumor volume, cell number, cell proliferation status, etc) have been worked out. The terminally ill patient, who was undergoing palliative treatment and whose tumor specimen matched the required criteria, received a complete course of Karanahan. Conclusions: The results of the treatment conducted indicate that Karanahan technology has a therapeutic potency and can be used as a breast cancer treatment option.
Collapse
Affiliation(s)
- Anastasia S Proskurina
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | | | - Yaroslav R Efremov
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.,Novosibirsk National Research State University, Novosibirsk, Russia
| | - Evgenia V Dolgova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Vera S Ruzanova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.,Novosibirsk National Research State University, Novosibirsk, Russia
| | - Genrikh S Ritter
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Ekaterina A Potter
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Svetlana S Kirikovich
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Evgeniy V Levites
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Alexandr A Ostanin
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Elena R Chernykh
- Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Oksana G Babaeva
- Oncology Department, Municipal Hospital No 1, Novosibirsk, Russia
| | - Sergey V Sidorov
- Novosibirsk National Research State University, Novosibirsk, Russia.,Oncology Department, Municipal Hospital No 1, Novosibirsk, Russia
| | - Sergey S Bogachev
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| |
Collapse
|
|
32
|
Terada M, Ide S, Naito T, Kimura N, Matsusaki M, Kaji N. Label-Free Cancer Stem-like Cell Assay Conducted at a Single Cell Level Using Microfluidic Mechanotyping Devices. Anal Chem 2021; 93:14409-14416. [PMID: 34628861 DOI: 10.1021/acs.analchem.1c02316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The mechanical phenotype of cells is an intrinsic property of individual cells. In fact, this property could serve as a label-free, non-destructive, diagnostic marker of the state of cells owing to its remarkable translational potential. A microfluidic device is a strong candidate for meeting the demand of this translational research as it can be used to diagnose a large population of cells at a single cell level in a high-throughput manner, without the need for off-line pretreatment operations. In this study, we investigated the mechanical phenotype of the human colon adenocarcinoma cell, HT29, which is known to be a heterogeneous cell line with both multipotency and self-renewal abilities. This type of cancer stem-like cell (CSC) is believed to be the unique originators of all tumor cells and may serve as the leading cause of cancer metastasis and drug resistance. By combining consecutive constrictions and microchannels with an ionic current sensing system, we found a high heterogeneity of cell deformability in the population of HT29 cells. Moreover, based on the level of aldehyde dehydrogenase (ALDH) activity and the expression level of CD44s, which are biochemical markers that suggest the multipotency of cells, the high heterogeneity of cell deformability was concluded to be a potential mechanical marker of CSCs. The development of label-free and non-destructive identification and collection techniques for CSCs has remarkable potential not only for cancer diagnosis and prognosis but also for the discovery of a new treatment for cancer.
Collapse
Affiliation(s)
- Miyu Terada
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Sachiko Ide
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Toyohiro Naito
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Niko Kimura
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Michiya Matsusaki
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Noritada Kaji
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.,Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya 464-8603, Japan
| |
Collapse
|
|
33
|
Gorczyca G, Wartalski K, Wiater J, Samiec M, Tabarowski Z, Duda M. Anabolic Steroids-Driven Regulation of Porcine Ovarian Putative Stem Cells Favors the Onset of Their Neoplastic Transformation. Int J Mol Sci 2021; 22:ijms222111800. [PMID: 34769230 PMCID: PMC8583785 DOI: 10.3390/ijms222111800] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Nandrolone (Ndn) and boldenone (Bdn), the synthetic testosterone analogues with strong anabolic effects, despite being recognized as potentially carcinogenic compounds, are commonly abused by athletes and bodybuilders, which includes women, worldwide. This study tested the hypothesis that different doses of Ndn and Bdn can initiate neoplastic transformation of porcine ovarian putative stem cells (poPSCs). Immunomagnetically isolated poPSCs were expanded ex vivo in the presence of Ndn or Bdn, for 7 and 14 days. Results show that pharmacological doses of both Ndn and Bdn, already after 7 days of poPSCs culture, caused a significant increase of selected, stemness-related markers of cancer cells: CD44 and CD133. Notably, Ndn also negatively affected poPSCs growth not only by suppressing their proliferation and mitochondrial respiration but also by inducing apoptosis. This observation shows, for the first time, that chronic exposure to Ndn or Bdn represents a precondition that might enhance risk of poPSCs neoplastic transformation. These studies carried out to accomplish detailed molecular characterization of the ex vivo expanded poPSCs and their potentially cancerous derivatives (PCDs) might be helpful to determine their suitability as nuclear donor cells (NDCs) for further investigations focused on cloning by somatic cell nuclear transfer (SCNT). Such investigations might also be indispensable to estimate the capabilities of nuclear genomes inherited from poPSCs and their PCDs to be epigenetically reprogrammed (dedifferentiated) in cloned pig embryos generated by SCNT. This might open up new possibilities for biomedical research aimed at more comprehensively recognizing genetic and epigenetic mechanisms underlying not only tumorigenesis but also reversal/retardation of pro-tumorigenic intracellular events.
Collapse
Affiliation(s)
- Gabriela Gorczyca
- Department of Endocrinology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
| | - Kamil Wartalski
- Department of Histology, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7 Street, 31-034 Krakow, Poland; (K.W.); (J.W.)
| | - Jerzy Wiater
- Department of Histology, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7 Street, 31-034 Krakow, Poland; (K.W.); (J.W.)
| | - Marcin Samiec
- Department of Reproductive Biotechnology and Cryoconservation, National Research Institute of Animal Production, Krakowska 1 Street, 32-083 Balice near Kraków, Poland
- Correspondence: (M.S.); (M.D.)
| | - Zbigniew Tabarowski
- Department of Experimental Hematology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
| | - Małgorzata Duda
- Department of Endocrinology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
- Correspondence: (M.S.); (M.D.)
| |
Collapse
|
|
34
|
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
|
|
35
|
Nowicki A, Kulus M, Wieczorkiewicz M, Pieńkowski W, Stefańska K, Skupin-Mrugalska P, Bryl R, Mozdziak P, Kempisty B, Piotrowska-Kempisty H. Ovarian Cancer and Cancer Stem Cells-Cellular and Molecular Characteristics, Signaling Pathways, and Usefulness as a Diagnostic Tool in Medicine and Oncology. Cancers (Basel) 2021; 13:cancers13164178. [PMID: 34439332 PMCID: PMC8394875 DOI: 10.3390/cancers13164178] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/04/2021] [Accepted: 08/13/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Ovarian cancer is still a high-risk, metastatic disease, often diagnosed at a late stage. Difficulties in its treatment are associated with high resistance to chemotherapy and recurrence. Responsible for the malignant features of cancer are considered to be cancer stem cells (CSCs), which generate new cells by modifying various signaling pathways. Signaling pathways are crucial for the regulation of epithelial-mesenchymal transition, metastasis, and self-renewal of CSCs. New therapies based on the use of inhibitors that block CSC growth and proliferation signals are being investigated. The current histological classification of ovarian tumors, their epidemiology, and the recent knowledge of ovarian CSCs, with particular emphasis on their molecular basis, are important considerations. Abstract Despite the increasing development of medicine, ovarian cancer is still a high-risk, metastatic disease that is often diagnosed at a late stage. In addition, difficulties in its treatment are associated with high resistance to chemotherapy and frequent relapse. Cancer stem cells (CSCs), recently attracting significant scientific interest, are considered to be responsible for the malignant features of tumors. CSCs, as the driving force behind tumor development, generate new cells by modifying different signaling pathways. Moreover, investigations on different types of tumors have shown that signaling pathways are key to epithelial-mesenchymal transition (EMT) regulation, metastasis, and self-renewal of CSCs. Based on these established issues, new therapies are being investigated based on the use of inhibitors to block CSC growth and proliferation signals. Many reports indicate that CSC markers play a key role in cancer metastasis, with hopes placed in their targeting to block this process and eliminate relapses. Current histological classification of ovarian tumors, their epidemiology, and the most recent knowledge of ovarian CSCs, with particular emphasis on their molecular background, are important aspects for consideration. Furthermore, the importance of signaling pathways involved in tumor growth, development, and metastasis, is also presented.
Collapse
Affiliation(s)
- Andrzej Nowicki
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland;
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (B.K.)
| | - Maria Wieczorkiewicz
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
| | - Wojciech Pieńkowski
- Division of Perinatology and Women’s Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland;
| | - Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Paulina Skupin-Mrugalska
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 60-780 Poznan, Poland;
| | - Rut Bryl
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Paul Mozdziak
- Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (B.K.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland;
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
- Correspondence:
| |
Collapse
|
|
36
|
Wu CC, Hsu YT, Chang CL. Hyperthermic intraperitoneal chemotherapy enhances antitumor effects on ovarian cancer through immune-mediated cancer stem cell targeting. Int J Hyperthermia 2021; 38:1013-1022. [PMID: 34192990 DOI: 10.1080/02656736.2021.1945688] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
PURPOSE We aimed to determine the effects and possible mechanisms of hyperthermic intraperitoneal chemotherapy (HIPEC) in targeting ovarian cancer stem-like cells (CSCs). METHODS Murine ovarian cancer cell lines presenting CSC surface markers were grown intraperitoneally in both immunocompetent and immunodeficient mice, which were then treated by intraperitoneal hyperthermia with the chemotherapeutic agents: paclitaxel and cisplatin. Tumor growth was measured by non-invasive luminescent imaging. Intraperitoneal immune cells, such as CD4+, CD8+ T cells, macrophages, and dendritic cells, were evaluated through flow cytometry analysis. RESULTS Combined hyperthermia and chemotherapy exhibited an efficient therapeutic effect in the immunocompetent mice. However, a similar effect was not observed in the immunodeficient mice. Intraperitoneal hyperthermia increased the number of Intraperitoneal macrophages and dendritic cells that were lost due to chemotherapy. Compared with ovarian cancer bulk cells, CSCs were more susceptible to phagocytosis by macrophages. CONCLUSION We demonstrated that the superior therapeutic efficacy and reduced proportion of CSCs associated with intraperitoneal hyperthermic chemotherapy were immune-related. Hyperthermia recruits the phagocytes that target surviving CSCs after chemotherapy. These results provide a novel mechanism for the efficacy of HIPEC in treating ovarian cancer.
Collapse
Affiliation(s)
- Chao-Chih Wu
- Departmental of Medical Research, MacKay Memorial Hospital, Taipei City, Taiwan.,MacKay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan
| | - Yun-Ting Hsu
- Departmental of Medical Research, MacKay Memorial Hospital, Taipei City, Taiwan.,MacKay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan
| | - Chih-Long Chang
- Departmental of Medical Research, MacKay Memorial Hospital, Taipei City, Taiwan.,Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei City, Taiwan.,Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| |
Collapse
|
|
37
|
Erkisa M, Sariman M, Geyik OG, Geyik CG, Stanojkovic T, Ulukay E. Natural Products as a Promising Therapeutic Strategy to Target Cancer Stem Cells. Curr Med Chem 2021; 29:741-783. [PMID: 34182899 DOI: 10.2174/0929867328666210628131409] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 11/22/2022]
Abstract
Cancer is still a deadly disease, and its treatment desperately needs to be managed in a very sophisticated way through fast-developing novel strategies. Most of the cancer cases eventually develop into recurrencies, for which cancer stem cells (CSCs) are thought to be responsible. They are considered as a subpopulation of all cancer cells of tumor tissue with aberrant regulation of self-renewal, unbalanced proliferation, and cell death properties. Moreover, CSCs show a serious degree of resistance to chemotherapy or radiotherapy and immune surveillance as well. Therefore, new classes of drugs are rushing into the market each year, which makes the cost of therapy increase dramatically. Natural products are also becoming a new research area as a diverse chemical library to suppress CSCs. Some of the products even show promise in this regard. So, the near future could witness the introduction of natural products as a source of new chemotherapy modalities, which may result in the development of novel anticancer drugs. They could also be a reasonably-priced alternative to highly expensive current treatments. Nowadays, considering the effects of natural compounds on targeting surface markers, signaling pathways, apoptosis, and escape from immunosurveillance have been a highly intriguing area in preclinical and clinical research. In this review, we present scientific advances regarding their potential use in the inhibition of CSCs and the mechanisms by which they kill the CSCs.
Collapse
Affiliation(s)
- Merve Erkisa
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Melda Sariman
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Oyku Gonul Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Caner Geyik Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Tatjana Stanojkovic
- Experimental Oncology Deparment, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Pasterova 14. Serbia
| | - Engin Ulukay
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| |
Collapse
|
|
38
|
Cermeño EA, O'Melia MJ, Han WM, Veith A, Barber G, Huang EH, Thomas SN, García AJ. Hydrodynamic shear-based purification of cancer cells with enhanced tumorigenic potential. Integr Biol (Camb) 2021; 12:1-11. [PMID: 31965190 DOI: 10.1093/intbio/zyz038] [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: 05/01/2019] [Revised: 11/01/2019] [Accepted: 11/05/2019] [Indexed: 11/13/2022]
Abstract
Tumor-initiating cells (TICs), a subpopulation of cancerous cells with high tumorigenic potential and stem-cell-like properties, drive tumor progression and are resistant to conventional therapies. Identification and isolation of TICs are limited by their low frequency and lack of robust markers. Here, we characterize the heterogeneous adhesive properties of a panel of human and murine cancer cells and demonstrate differences in adhesion strength among cells, which exhibit TIC properties and those that do not. These differences in adhesion strength were exploited to rapidly (~10 min) and efficiently isolate cancerous cells with increased tumorigenic potential in a label-free manner by use of a microfluidic technology. Isolated murine and human cancer cells gave rise to larger tumors with increased growth rate and higher frequency in both immunocompetent and immunocompromised mice, respectively. This rapid and label-free TIC isolation technology has the potential to be a valuable tool for facilitating research into TIC biology and the development of more efficient diagnostics and cancer therapies.
Collapse
Affiliation(s)
- Efraín A Cermeño
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Meghan J O'Melia
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.,Coulter Department of Biomedical Engineering, Georgia Tech/Emory, Atlanta, GA, USA
| | - Woojin M Han
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Austin Veith
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Graham Barber
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Emina H Huang
- Lerner Research Institute, Department of Cancer Biology, Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Susan N Thomas
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| |
Collapse
|
|
39
|
Motohara T, Yoshida GJ, Katabuchi H. The hallmarks of ovarian cancer stem cells and niches: Exploring their harmonious interplay in therapy resistance. Semin Cancer Biol 2021; 77:182-193. [PMID: 33812986 DOI: 10.1016/j.semcancer.2021.03.038] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 03/20/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022]
Abstract
The concept of a "cancer stem cell" has evolved over the past decades, and research on cancer stem cell biology has entered into a stage of remarkable progress. Cancer stem cells are a major determining factor contributing to the establishment of phenotypic and functional intratumoral heterogeneity in synchronization with their surrounding "cancer stem cell niches." They serve as the driving force for cancer initiation, metastasis, and therapeutic resistance in various types of malignancies. In verity, reciprocal interplay between ovarian cancer stem cells and their niches involves a complex but ingeniously orchestrated tumor microenvironment within the intraperitoneal milieu and especially contribute to chemotherapy resistance in patients with advanced ovarian cancer. Herein, we review the principles of our current understanding of the biological features of ovarian cancer stem cells, focusing mainly on the precise mechanisms underlying acquired chemotherapy resistance. Furthermore, we highlight the specific roles of various cancer-associated stromal and immune cells in creating possible cancer stem cell niches that regulate ovarian cancer stemness.
Collapse
Affiliation(s)
- Takeshi Motohara
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City, Kumamoto, 860-8556, Japan.
| | - Go J Yoshida
- Department of Immunological Diagnosis, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hidetaka Katabuchi
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City, Kumamoto, 860-8556, Japan
| |
Collapse
|
|
40
|
Chesnokov MS, Khan I, Park Y, Ezell J, Mehta G, Yousif A, Hong LJ, Buckanovich RJ, Takahashi A, Chefetz I. The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma. Cancers (Basel) 2021; 13:1369. [PMID: 33803586 PMCID: PMC8003094 DOI: 10.3390/cancers13061369] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 02/02/2023] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.
Collapse
Affiliation(s)
- Mikhail S. Chesnokov
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; (M.S.C.); (I.K.); (A.Y.); (A.T.)
| | - Imran Khan
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; (M.S.C.); (I.K.); (A.Y.); (A.T.)
| | - Yeonjung Park
- Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (Y.P.); (J.E.); (R.J.B.)
| | - Jessica Ezell
- Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (Y.P.); (J.E.); (R.J.B.)
| | - Geeta Mehta
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Abdelrahman Yousif
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; (M.S.C.); (I.K.); (A.Y.); (A.T.)
| | - Linda J. Hong
- Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Ronald J. Buckanovich
- Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (Y.P.); (J.E.); (R.J.B.)
- Division of Hematology Oncology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Akimasa Takahashi
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; (M.S.C.); (I.K.); (A.Y.); (A.T.)
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, Shiga 5202152, Japan
| | - Ilana Chefetz
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; (M.S.C.); (I.K.); (A.Y.); (A.T.)
- Masonic Cancer Center, Minneapolis, MN 55455, USA
- Stem Cell Institute, Minneapolis, MN 55455, USA
| |
Collapse
|
|
41
|
Werbowetski-Ogilvie TE. From sorting to sequencing in the molecular era: the evolution of the cancer stem cell model in medulloblastoma. FEBS J 2021; 289:1765-1778. [PMID: 33714236 DOI: 10.1111/febs.15817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/01/2021] [Accepted: 03/10/2021] [Indexed: 12/11/2022]
Abstract
The cancer stem cell (CSC) model posits that tumors contain subpopulations that display defining features of normal stem cells including self-renewal capacity and differentiation. Tumor cells exhibiting these features are now considered to be responsible for tumor propagation and drug resistance in a wide variety of cancers. Therefore, the identification of robust CSC markers and characterization of CSC-specific molecular signatures may lead to the identification of novel therapeutics that selectively abolish this clinically relevant cell population while preserving normal tissue. Brain tumor researchers have been at the forefront of the CSC field. From initial in vitro cell sorting experiments to the sophisticated bioinformatic technologies that now exquisitely resolve primary brain tumors at a single-cell level, recent glioma and medulloblastoma (MB) studies have integrated developmental state with genomic and transcriptome data to identify the spectrum of cell types that may drive tumor progression. This review will examine the last two decades of CSC studies in the field. Seminal discoveries, emerging controversies, and outstanding questions will be covered with a particular focus on MB, the most common malignant primary brain tumor in children.
Collapse
Affiliation(s)
- Tamra E Werbowetski-Ogilvie
- Department of Biochemistry and Medical Genetics and Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada
| |
Collapse
|
|
42
|
Gao J, Yang T, Wang X, Zhang Y, Wang J, Zhang B, Tang D, Liu Y, Gao T, Lin Q, Tang J, Cai J. Identification and characterization of a subpopulation of CD133 + cancer stem-like cells derived from SK-UT-1 cells. Cancer Cell Int 2021; 21:157. [PMID: 33685462 PMCID: PMC7938532 DOI: 10.1186/s12935-021-01817-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/12/2020] [Accepted: 02/06/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Uterine leiomyosarcoma (ULMS) is a malignant tumor found in the smooth muscle lining the walls of the uterus. Cancer stem cells (CSCs) are responsible for metastasis, drug resistance, and relapse of cancer, resulting in treatment failure. However, little is known about CSCs and their associated-markers in ULMS. We aimed to characterize and identify a subpopulation of CD133+ cancer stem-like cells derived from SK-UT-1 cell line. METHODS SK-UT-1 cells were sphere-forming cultured in vitro. We also sorted the CD133+ cells derived from SK-UT-1 cell line by immunomagnetic beads. CD133+ subpopulation and apoptotic cells were detected by flow cytometry. Self-renewal and anchorage-independent growth capabilities were examined using sphere and colony formation assays. The tumorigenicity of the fourth-passage spheres and parental SK-UT-1 cells was used by mouse xenograft model in vivo. Cell proliferation ability and sensitivity to doxorubicin (DXR) were assessed by CCK-8 assay. Cell migration and invasion were tested by wound healing assay or Transwell migration and invasion assays. Expressions of CSC-related marker were analyzed by Western blotting. RESULTS The fourth-passage spheres were defined as a CD133+ cell population, which was accompanied by increase of sphere and colony forming rate, migration and invasion abilities, as well as drug-resistant properties in vitro. Moreover, the fourth-passage spheres showed a stronger tumorigenic potential in vivo. CD133+ cell population sorted from SK-UT-1 line showed an increased ability in sphere and colony formation, proliferation, migration, invasion, resistance to apoptosis after treatment with doxorubicin (DXR) compared with CD133- cell population. The expression levels of CSCs-related markers (e.g., CD44, ALDH1,BMI1, and Nanog), were significantly elevated in CD133+ cells compared with those in CD133- cells. CONCLUSIONS Collectively, our findings indicated that CD133 may be a significant marker for cancer stem-like cells, and it may be a potential therapeutic target for human ULMS.
Collapse
Affiliation(s)
- Jiuping Gao
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Ting Yang
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Xu Wang
- Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha, China
| | - Yi Zhang
- Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha, China
| | - Jing Wang
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Beilei Zhang
- Department of Gynecology and obstetrics, The second people's Hospital of Hunan Province, Changsha, China
| | - Dihong Tang
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Yanqiong Liu
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Ting Gao
- Department of Gynecology and obstetrics, Central Hospital of Yiyang City, Yiyang, Hunan Province, China
| | - Qiuhui Lin
- Department of Gynecology and Obstetrics, The First People's Hospital of Shaoguang, Shaoguan, Guangdong Province, China
| | - Jun Tang
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Jingting Cai
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China.
| |
Collapse
|
|
43
|
Distinct Side Population Cell Subtypes Have Different Stemness Levels in Human Ovarian Cancer Cells. Curr Med Sci 2021; 41:127-132. [PMID: 33582916 DOI: 10.1007/s11596-021-2327-0] [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: 12/29/2019] [Accepted: 09/30/2020] [Indexed: 10/22/2022]
Abstract
The stemness of different side population (SP) cell subtypes in ovarian cancer cells was studied, and the heterogeneity of ovarian cancer stem cells was analyzed. The cisplatin-resistant human serous ovarian cancer cell line C13 was stained with the bisbenzimide Hoechst 33342. A flow cytometry-based fluorescence-activated sorting method was used to obtain lower-SP (LSP) cells, upper-SP (USP) cells, and non-SP cells (NSP) based on their sensitivity to the staining time and Hoechst dye concentration. The sphere-forming capability, expression levels of stem cell markers, resistance to high concentrations of cisplatin, and subcutaneous tumorigenicity in NOD/SCID mice of the different cell subtypes were evaluated. The C13 cells contained SP cells with stemness characteristics, and the LSP cell subtype expressed higher levels of stem cell markers, had higher in vitro sphere-forming capability, higher cisplatin resistance and higher in vivo subcutaneous tumorigenesis than USP cells (P<0.05). NSP cells had no stemness. In conclusion, different subtypes of ovarian cancer SP cells have different stemness levels, and ovarian cancer stem cells may be heterogeneous.
Collapse
|
|
44
|
Tang Z, Tang N, Jiang S, Bai Y, Guan C, Zhang W, Fan S, Huang Y, Lin H, Ying Y. The Chemosensitizing Role of Metformin in Anti-Cancer Therapy. Anticancer Agents Med Chem 2021; 21:949-962. [PMID: 32951587 DOI: 10.2174/1871520620666200918102642] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/23/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anti-cancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anti-cancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of Cancer Stem Cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse Epithelial to Mesenchymal Transition (EMT), and Multidrug Resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1 α, and Mitogen- Activated Protein Kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and Pyruvate Kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.>.
Collapse
Affiliation(s)
- Zhimin Tang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Nan Tang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shanxi Provincial People's Hospital, Xian 710000, China
| | - Yangjinming Bai
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Chenxi Guan
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wansi Zhang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Shipan Fan
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China
| | - Yonghong Huang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| |
Collapse
|
|
45
|
Zhang L, Ma R, Gao M, Zhao Y, Lv X, Zhu W, Han L, Su P, Fan Y, Yan Y, Zhao L, Ma H, Wei M, He M. SNORA72 Activates the Notch1/c-Myc Pathway to Promote Stemness Transformation of Ovarian Cancer Cells. Front Cell Dev Biol 2020; 8:583087. [PMID: 33224949 PMCID: PMC7669759 DOI: 10.3389/fcell.2020.583087] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are responsible for the migration and recurrence of cancer progression. Small nucleolar RNAs (snoRNAs) play important roles in tumor development. However, how snoRNAs contribute to the regulation of the stemness of ovarian CSCs (OCSCs) remains unclear. In the present study, we found that SNORA72 was significantly upregulated in OVCAR-3 spheroids (OS) and CAOV-3 spheroids (CS) with the OCSC characteristics attained by serum-free culture in a suspension of OVCAR-3 (OV) and CAOV-3 (CA) cells. The overexpression of SNORA72 increased self-renewal abilities and migration abilities in OV and CA cells and upregulated the expressions of the stemness markers Nanog, Oct4, and CD133. In addition, the ectopic expression of SNORA72 can elevate the messenger RNA (mRNA) and protein expression levels of Notch1 and c-Myc in parental cells. The opposite results were observed in SNORA72-silenced OCSCs. Moreover, we found that Notch1 knockdown inversed the migration abilities and self-renewal abilities raised by overexpressing SNORA72. In summary, stemness transformation of ovarian cancer cells can be activated by SNORA72 through the Notch1/c-Myc pathway. This study introduces a novel therapeutic strategy for improving the treatment efficiency of ovarian cancer.
Collapse
Affiliation(s)
- Liwen Zhang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Rong Ma
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Mengcong Gao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Yanyun Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Xuemei Lv
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Wenjing Zhu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Li Han
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Panpan Su
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Yue Fan
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Yuanyuan Yan
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Heyao Ma
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Miao He
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| |
Collapse
|
|
46
|
Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma. Int J Mol Sci 2020; 21:ijms21186467. [PMID: 32899775 PMCID: PMC7554888 DOI: 10.3390/ijms21186467] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/28/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC.
Collapse
|
|
47
|
Chang CL, Wu CC, Hsu YT, Hsu YC. Immune vulnerability of ovarian cancer stem-like cells due to low CD47 expression is protected by surrounding bulk tumor cells. Oncoimmunology 2020; 9:1803530. [PMID: 32923164 PMCID: PMC7458642 DOI: 10.1080/2162402x.2020.1803530] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recurrence of advanced epithelial ovarian cancer is common despite optimal surgical debulking and initial favorable responses to chemotherapy. Evidences suggest that cancer stem cells (CSCs) have inherent resistance to conventional therapies such as chemotherapy and play a decisive role in cancer recurrence. Cancer stem cells are also believed to be able to evade immunological attack. However, this study showed a different scenario in which cancer stem-like cells are more vulnerable to immunosurveillance. Our study demonstrated that isolated murine cancer stem-like cells, stem cell antigen (SCA)-1+ ID8 and CD133+ HM-1 cells, were susceptible to phagocytosis by macrophages and consequent CD8+ T cell immunity. The increased phagocytosis of these stem cell-like cells is attributed to low CD47 protein expression. SCA-1+ ID8 cells were able to grow in syngeneic mice but were soon rejected. Restoring CD47 expression delayed this immune-mediated rejection. SCA-1+ ID8 cells showed rapid growth by mixing with bulk ID8 cells. These results suggest that stem-like cells could be protected by surrounding non-stem cancer cells from immune attack. Similarly, both isolated human CD24−/low SKOV3 stem-like cells and spheroid OVCAR3 cells expressed lower CD47 levels. Our study provided novel insights into the immune characteristics of CSCs within a tumor microenvironment. The results might lead to the design of more effective treatment strategies for ovarian cancer.
Collapse
Affiliation(s)
- Chih-Long Chang
- Departmental of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan.,Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei City, Taiwan.,Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chao-Chih Wu
- Departmental of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan.,Department of Nursing, Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan
| | - Yun-Ting Hsu
- Departmental of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
| |
Collapse
|
|
48
|
Zong X, Wang W, Ozes A, Fang F, Sandusky GE, Nephew KP. EZH2-Mediated Downregulation of the Tumor Suppressor DAB2IP Maintains Ovarian Cancer Stem Cells. Cancer Res 2020; 80:4371-4385. [PMID: 32816909 DOI: 10.1158/0008-5472.can-20-0458] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 07/14/2020] [Accepted: 08/14/2020] [Indexed: 01/06/2023]
Abstract
The majority of women diagnosed with epithelial ovarian cancer eventually develop recurrence, which rapidly evolves into chemoresistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy may be responsible for emergence of resistant tumors. In this study, we demonstrate that in OCSC, the tumor suppressor disabled homolog 2-interacting protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in epithelial ovarian cancer cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in ovarian cancer significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse phase protein array further demonstrated activation of noncanonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Coadministration of EZH2 inhibitor GSK126 and RAC1 inhibitor NSC23766 suppressed OCSC survival in vitro and inhibited tumor growth and increased platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent ovarian cancer recurrence and has potential for clinical translation. SIGNIFICANCE: These findings show that combining an epigenetic therapy with a noncanonical WNT signaling pathway inhibitor has the potential to eradicate ovarian cancer stem cells and to prevent ovarian cancer recurrence.
Collapse
Affiliation(s)
- Xingyue Zong
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Weini Wang
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Ali Ozes
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Fang Fang
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - George E Sandusky
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kenneth P Nephew
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana. .,Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| |
Collapse
|
|
49
|
Ghahremani H, Nabati S, Tahmori H, Peirouvi T, Sirati-Sabet M, Salami S. Long-Term Glucose Restriction with or without β-Hydroxybutyrate Enrichment Distinctively Alters Epithelial-Mesenchymal Transition-Related Signalings in Ovarian Cancer Cells. Nutr Cancer 2020; 73:1708-1726. [PMID: 32799692 DOI: 10.1080/01635581.2020.1804947] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The beneficial impacts of the ketogenic diet and metabolic reprograming were recently reported for ovarian cancer patients. In this study, the effects of glucose restriction with or without beta-hydroxybutyrate (bHB) enrichment were studied in drug-resistant CD133high A2780CP and CD133low SK-OV-3 ovarian cancer cells to scrutinize the impact of experimental ketosis on ATP production, epithelial to mesenchymal transition (EMT), and related signaling pathways including Wnt, Hippo, and Hedgehog. Cells were adapted and maintained for a month with restricted levels of glucose (250 mg/l) with or without the therapeutic concentration of bHB (5 mM). Quantitative PCR, Western blot analysis, flow cytometry, chemiluminescence, and wound healing assay were used in this study. Glucose restriction and bHB enrichment reduced the stemness marker and diminished In Vitro migration in both cell lines. Glucose restriction significantly reduced ATP levels in both cells, but bHB enrichment was partially compensated for the ATP levels solely in SK-OV-3 cells. Glucose restriction mainly inhibited the Wnt pathway in the CD133high A2780CP cells, but the Hedgehog pathway was the main target in CD133low SK-OV-3 cells. In Conclusion, Prior targeted evaluations of key genes' expression would help to predict the distinctive impacts of metabolic fuels and to optimize the efficacy of ketogenic diets.
Collapse
Affiliation(s)
- Hossein Ghahremani
- Cell Death and Differentiation Signaling Research Lab, Clinical Biochemistry Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeedeh Nabati
- Cell Death and Differentiation Signaling Research Lab, Clinical Biochemistry Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hanieh Tahmori
- Cell Death and Differentiation Signaling Research Lab, Clinical Biochemistry Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahmineh Peirouvi
- Departments of Histology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Majid Sirati-Sabet
- Cell Death and Differentiation Signaling Research Lab, Clinical Biochemistry Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siamak Salami
- Cell Death and Differentiation Signaling Research Lab, Clinical Biochemistry Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
50
|
Raghavan S, Snyder CS, Wang A, McLean K, Zamarin D, Buckanovich RJ, Mehta G. Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling. Cancers (Basel) 2020; 12:cancers12082063. [PMID: 32726910 PMCID: PMC7464970 DOI: 10.3390/cancers12082063] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 12/11/2022] Open
Abstract
Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.
Collapse
Affiliation(s)
- Shreya Raghavan
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (C.S.S.)
| | - Catherine S. Snyder
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (C.S.S.)
| | - Anni Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Karen McLean
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA;
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Dmitriy Zamarin
- Department of Gynecologic Medical Oncology and Immunotherapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Ronald J. Buckanovich
- Director of Ovarian Cancer Research, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA;
| | - Geeta Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (C.S.S.)
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Macromolecular Sciences and Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Precision Health, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence: ; Tel.: +1-734-763-3957; Fax: +1-734-763-4788
| |
Collapse
|