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1
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Bing J, Zhou B, Chen M, Shen Y, Zhou M, Lin H, Wu W, Shi J. Nanomedicine-enabled concurrent regulations of ROS generation and copper metabolism for sonodynamic-amplified tumor therapy. Biomaterials 2025; 318:123137. [PMID: 39884132 DOI: 10.1016/j.biomaterials.2025.123137] [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: 09/26/2024] [Revised: 01/09/2025] [Accepted: 01/23/2025] [Indexed: 02/01/2025]
Abstract
Sonodynamic therapy (SDT) shows substantial potentials in cancer treatment thanks to the deep tissue penetration of ultrasound. However, its clinical translation suffers from the potential damages to healthy tissues and the resistance of tumors, particularly from cancer stem-like cells (CSCs), to the ultrasound. To address these challenges, we designed a novel glutathione (GSH)-activated nanomedicine to simultaneously enhance the safety and efficacy of SDT by in situ regulating the generation of reactive oxygen species (ROS) and copper metabolism. This nanomedicine, Es@CuTCPP, was created by loading elesclomol (Es) onto CuTCPP nanosheets. By accumulating this nanomedicine in tumors, the Cu(II)-TCPP is reduced to the highly sonosensitive Cu(I)-TCPP by the intra-tumoral-overexpressed GSH, leading to the production of abundant ROS upon ultrasound exposure, which effectively kills large amounts of tumor cells. Concurrently, the released copper ions react with co-released Es to form a CuEs complex, which induces cuproptosis of CSCs surviving the ROS attack by disrupting cellular copper metabolism, evidently amplifying the effectiveness of SDT. This work presents the first paradigm of a GSH-activated and cuproptosis-enhanced SDT approach, offering a promising novel strategy for cancer therapy.
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Affiliation(s)
- Jinhong Bing
- State Key Laboratory of High-performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai, 200050, PR China
| | - Bangguo Zhou
- Department of Radiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR China
| | - Minqi Chen
- Digestive Endoscopy Center, Shanghai Fourth People's Hospital to Tongji University, Shanghai, 200081, PR China
| | - Yucui Shen
- Digestive Endoscopy Center, Shanghai Fourth People's Hospital to Tongji University, Shanghai, 200081, PR China
| | - Min Zhou
- Digestive Endoscopy Center, Shanghai Fourth People's Hospital to Tongji University, Shanghai, 200081, PR China
| | - Han Lin
- State Key Laboratory of High-performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai, 200050, PR China
| | - Wencheng Wu
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, PR China.
| | - Jianlin Shi
- State Key Laboratory of High-performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai, 200050, PR China.
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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3
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Yang L, Yi Y, Mei Z, Huang D, Tang S, Hu L, Liu L. Circular RNAs in cancer stem cells: Insights into their roles and mechanisms (Review). Int J Mol Med 2025; 55:50. [PMID: 39930823 PMCID: PMC11781527 DOI: 10.3892/ijmm.2025.5491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/03/2025] [Indexed: 02/14/2025] Open
Abstract
Cancer stem cells (CSCs) represent a small, yet pivotal subpopulation of tumor cells that play significant roles in tumor initiation, progression and therapeutic resistance. Circular RNAs (circRNAs) are a distinct class of RNAs characterized by their closed‑loop structures, lacking 5' to 3'ends. There is growing evidence that circRNAs are integral to the development and regulation of CSCs. Aberrant expression of circRNAs in CSCs can contribute to oncogenic properties and drug resistance. Specifically, oncogenic circRNAs modulate CSC behavior via key signaling pathways, thereby promoting CSC self‑renewal and maintenance, as well as tumor progression. This review summarizes the latest research on the functional roles and regulatory mechanisms of circRNAs in CSC behavior and discusses potential applications and challenges of targeting circRNAs in CSCs. Understanding the intricate interactions between circRNAs and CSCs may lead to novel therapeutic strategies that effectively combat treatment resistance and improve patient outcomes.
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Affiliation(s)
- Lunyu Yang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Yuling Yi
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Zhu Mei
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Dongmei Huang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Sitian Tang
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Liyi Hu
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
| | - Ling Liu
- Department of Medical Laboratory, Chongqing Liangjiang New Area People's Hospital, Chongqing 401121, P.R. China
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Chang CH, Tsai CC, Tsai FM, Chu TY, Hsu PC, Kuo CY. EpCAM Signaling in Oral Cancer Stem Cells: Implications for Metastasis, Tumorigenicity, and Therapeutic Strategies. Curr Issues Mol Biol 2025; 47:123. [PMID: 39996844 PMCID: PMC11854592 DOI: 10.3390/cimb47020123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
Oral cancer, a subtype of head and neck cancer, poses significant global health challenges owing to its late diagnosis and high metastatic potential. The epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein, has emerged as a critical player in cancer biology, particularly in oral cancer stem cells (CSCs). This review highlights the multifaceted roles of EPCAM in regulating oral cancer metastasis, tumorigenicity, and resistance to therapy. EpCAM influences key pathways, including Wnt/β-catenin and EGFR, modulating CSC self-renewal, epithelial-to-mesenchymal transition (EMT), and immune evasion. Moreover, EpCAM has been implicated in metabolic reprogramming, epigenetic regulation, and crosstalk with other signaling pathways. Advances in EpCAM-targeting strategies, such as monoclonal antibodies, chimeric antigen receptor (CAR) T/NK cell therapies, and aptamer-based systems hold promise for personalized cancer therapies. However, challenges remain in understanding the precise mechanism of EpCAM in CSC biology and its translation into clinical applications. This review highlights the need for further investigation into the role of EPCAM in oral CSCs and its potential as a therapeutic target to improve patient outcomes.
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Affiliation(s)
- Chuan-Hsin Chang
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Chung-Che Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Fu-Ming Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Tin-Yi Chu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Po-Chih Hsu
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
- Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
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Wang H, He W, Elizondo-Riojas MA, Zhou X, Lee TJ, Gorenstein DG. Development and Characterization of CD44-Targeted X-Aptamers with Enhanced Binding Affinity for Cancer Therapeutics. Bioengineering (Basel) 2025; 12:113. [PMID: 40001633 PMCID: PMC11852163 DOI: 10.3390/bioengineering12020113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
CD44, a pivotal cell surface molecule, plays a crucial role in many cellular functions, including cell-cell interactions, adhesion, and migration. It serves as a receptor for hyaluronic acid and is involved in lymphocyte activation, recirculation, homing, and hematopoiesis. Moreover, CD44 is a commonly used cancer stem cell marker associated with tumor progression and metastasis. The development of CD44 aptamers that specifically target CD44 can be utilized to target CD44-positive cells, including cancer stem cells, and for drug delivery. Building on the primary sequences of our previously selected thioaptamers (TAs) and observed variations, we developed a bead-based X-aptamer (XA) library by conjugating drug-like ligands (X) to the 5-positions of certain uridines on a complete monothioate backbone. From this, we selected an XA with high affinity to the CD44 hyaluronic acid binding domain (HABD) from a large combinatorial X-aptamer library modified with N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (ADDA). This XA demonstrated an enhanced binding affinity for the CD44 protein up to 23-fold. The selected CD44 X-aptamers (both amine form and ADDA form) also showed enhanced binding affinity to CD44-overexpressing human ovarian cancer IGROV cells. Secondary structure predictions of CD44 using MFold identified several binding motifs and smaller constructs of various stem-loop regions. Among our identified binding motifs, X-aptamer motif 3 and motif 5 showed enhanced binding affinity to CD44-overexpressing human ovarian cancer IGROV cells with ADDA form, compared to the binding affinities with amine form and scrambled sequence. The effect of ADDA as a binding affinity enhancer was not uniform within the aptamer, highlighting the importance of optimal ligand positioning. The incorporation of ADDA not only broadened the XA's chemical diversity but also increased the binding surface area, offering enhanced specificity. Therefore, the strategic use of site-directed modifications allows for fine-tuning aptamer properties and offers a flexible, generalizable framework for developing high-performance aptamers that target a wide range of molecules.
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Affiliation(s)
- Hongyu Wang
- Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Weiguo He
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Miguel-Angel Elizondo-Riojas
- Centro Universitario Contra el Cáncer, Hospital Universitario “Dr. José Eleuterio González”, Universidad Autonoma de Nuevo León, Monterrey 64460, NL, Mexico
| | - Xiaobo Zhou
- Center for Computational Systems Medicine, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Tae Jin Lee
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - David G. Gorenstein
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
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Wang W, Lokman NA, Barry SC, Oehler MK, Ricciardelli C. LGR5: An emerging therapeutic target for cancer metastasis and chemotherapy resistance. Cancer Metastasis Rev 2025; 44:23. [PMID: 39821694 PMCID: PMC11742290 DOI: 10.1007/s10555-024-10239-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
Cancer stem cells play an important role in tumor progression and chemotherapy resistance. Leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) has been identified as a cancer stem cell marker in several cancer types. LGR5 is involved in cancer development and progression via several pathways including WNT/β-catenin signaling pathway. LGR5 plays a role in tumor progression by promoting cancer cell migration, invasion, metastasis, and angiogenesis in many cancers including colorectal, brain, gastric, and ovarian cancer. This review summarises the current knowledge on the expression and functional role of LGR5 in cancers, the molecular mechanisms regulated by LGR5, and the relationship between LGR5 and chemotherapy resistance. The review also includes highlights potential strategies to inhibit LGR5 expression and function. The majority of functional studies have shown that LGR5 plays an important role in promoting cancer progression, metastasis and chemotherapy resistance however, in some contexts LGR5 can also activate tumor-suppressive pathways and LGR5 negative cells can also promote cancer progression. The review highlights that targeting LGR5 is a promising anti-cancer treatment but the functional effect of LGR5 on tumor cells is complex may be dependent on cancer type, tumor microenvironment and cross-talk with other molecules in the LGR5 signaling pathway.
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Affiliation(s)
- Wanqi Wang
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, 5005, Australia
| | - Noor A Lokman
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, 5005, Australia
| | - Simon C Barry
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, 5005, Australia
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, 5005, Australia
| | - Martin K Oehler
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, 5005, Australia
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, 5000, Australia
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, 5005, Australia.
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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Fakhrioliaei A, Tanhaei S, Pakmehr S, Noori Shakir M, Qasim MT, Hariri M, Nouhi Kararoudi A, Valilo M. Potential Role of Nrf2, HER2, and ALDH in Cancer Stem Cells: A Narrative Review. J Membr Biol 2024; 257:3-16. [PMID: 38356054 DOI: 10.1007/s00232-024-00307-2] [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: 12/08/2023] [Accepted: 01/16/2024] [Indexed: 02/16/2024]
Abstract
Cancer is one of the main causes of death among humans, second only to cardiovascular diseases. In recent years, numerous studies have been conducted on the pathophysiology of cancer, and it has been established that this disease is developed by a group of stem cells known as cancer stem cells (CSCs). Thus, cancer is considered a stem cell disease; however, there is no comprehensive consensus about the characteristics of these cells. Several different signaling pathways including Notch, Hedgehog, transforming growth factor-β (TGF-β), and WNT/β-catenin pathways cause the self-renewal of CSCs. CSCs change their metabolic pathways in order to access easy energy. Therefore, one of the key objectives of researchers in cancer treatment is to destroy CSCs. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the protection of CSCs from reactive oxygen species (ROS) and chemotherapeutic agents by regulating antioxidants and detoxification enzymes. Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family, which contributes to the protection of cancer cells against treatment and implicated in the invasion, epithelial-mesenchymal transition (EMT), and tumorigenesis. Aldehyde dehydrogenases (ALDHs) are highly active in CSCs and protect the cells against damage caused by active aldehydes through the regulation of aldehyde metabolism. On the other hand, ALDHs promote the formation and maintenance of tumor cells and lead to drug resistance in tumors through the activation of various signaling pathways, such as the ALDH1A1/HIF-1α/VEGF axis and Wnt/β-catenin, as well as changing the intracellular pH value. Given the growing body of information in this field, in the present narrative review, we attempted to shed light on the function of Nrf2, HER2, and ALDH in CSCs.
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Affiliation(s)
| | | | | | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Maryam Hariri
- Department of Pathobiology, Auburn University, Auburn, AL, 36832, USA
| | - Alireza Nouhi Kararoudi
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Mohammad Valilo
- Dpartment of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Hao B, Dong H, Xiong R, Song C, Xu C, Li N, Geng Q. Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma. Comput Biol Med 2024; 171:108183. [PMID: 38422959 DOI: 10.1016/j.compbiomed.2024.108183] [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: 11/04/2023] [Revised: 01/20/2024] [Accepted: 02/18/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND As one of the common subtypes of non-small lung cancer, lung squamous cell carcinoma (LUSC) patients with advanced stage have few choices of treatment strategies. Therefore, it is urgent to discover genes that are associated with the survival and efficacy of immunotherapies. METHOD Differential gene expression analyses were conducted using TCGA LUSC bulk-sequencing and single-cell RNA-sequencing data. Prognostic genes were identified from the TCGA LUSC cohort. Protein expression validation and survival analyses were performed. Experiments were conducted to explore the underlying mechanisms. In addition, the correlation between gene expression and pathological response to adjuvant immunochemotherapy was also investigated. RESULTS After a series of bioinformatic analyses, solute carrier family 2 member 1(SLC2A1), encoding glucose transporter-1 (GLUT1), was found to be differentially expressed between tumor and normal tissues. GLUT1 was subsequently identified as an independent prognostic factor for LUSC. GSEA analysis revealed the glycolysis metabolism pathway of KEGG enriched in SLC2A1high tumor tissues. LASSO analyses revealed that tumor tissues with high expression of SLC2A1 were associated with high levels of protein lactylation. We found that SLC2A1 was preferentially expressed by SPP1+ macrophages in the tumor microenvironment, and the expression of SLC2A1 was associated with the abundance of SPP1+ macrophages. Immunofluorescence demonstrated GLUT1 and HIF1α colocalization in tumor-infiltrating macrophages. In vitro experiments showed HIF-1α-induced macrophage polarization under hypoxia, and GLUT1 inhibition blocked this polarization. In addition, SLC2A1 was negatively associated with the common immune checkpoint molecules, such as programmed cell death 1(PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and lymphocyte activating 3 (LAG3), while showed a positive association with CD44. Finally, we observed that there was a significant correlation between pre-adjuvant-treatment GLUT1 expression and the pathological response. CONCLUSION SLC2A1 expression was differentially upregulated in tumor tissues, and elevated GLUT1 expression was associated with worse survival and poor pathological response to adjuvant immunochemotherapy. Upregulation of GLUT1 promoted macrophage polarization into the M2 phenotype. The findings will contribute to guiding the treatment selection for LUSC patients and providing personalized immunotherapy strategies.
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Affiliation(s)
- Bo Hao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
| | - Huixing Dong
- Department of Pulmonary and Critical Care Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 200336, China.
| | - Rui Xiong
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
| | - Congkuan Song
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
| | - Chenzhen Xu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China.
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Omran MM, Fouda MS, Mekkawy SA, Tabll AA, Abdelaziz AG, Omran AM, Emran TM. Molecular Biomarkers and Signaling Pathways of Cancer Stem Cells in Colorectal Cancer. Technol Cancer Res Treat 2024; 23:15330338241254061. [PMID: 38794896 PMCID: PMC11128179 DOI: 10.1177/15330338241254061] [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: 11/23/2023] [Revised: 03/27/2018] [Indexed: 05/26/2024] Open
Abstract
Colorectal cancer (CRC) is the third most frequently found cancer in the world, and it is frequently discovered when it is already far along in its development. About 20% of cases of CRC are metastatic and incurable. There is more and more evidence that colorectal cancer stem cells (CCSCs), which are in charge of tumor growth, recurrence, and resistance to treatment, are what make CRC so different. Because we know more about stem cell biology, we quickly learned about the molecular processes and possible cross-talk between signaling pathways that affect the balance of cells in the gut and cancer. Wnt, Notch, TGF-β, and Hedgehog are examples of signaling pathway members whose genes may change to produce CCSCs. These genes control self-renewal and pluripotency in SCs and then decide the function and phenotype of CCSCs. However, in terms of their ability to create tumors and susceptibility to chemotherapeutic drugs, CSCs differ from normal stem cells and the bulk of tumor cells. This may be the reason for the higher rate of cancer recurrence in patients who underwent both surgery and chemotherapy treatment. Scientists have found that a group of uncontrolled miRNAs related to CCSCs affect stemness properties. These miRNAs control CCSC functions like changing the expression of cell cycle genes, metastasis, and drug resistance mechanisms. CCSC-related miRNAs mostly control signal pathways that are known to be important for CCSC biology. The biomarkers (CD markers and miRNA) for CCSCs and their diagnostic roles are the main topics of this review study.
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Affiliation(s)
- Mohamed M. Omran
- Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Manar S. Fouda
- Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Sara A. Mekkawy
- Molecular Biotechnology Program, Faculty of Science, Helwan University, Cairo, Egypt
| | - Ashraf A. Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Dokki, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - Ahmed G. Abdelaziz
- Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Azza M. Omran
- Clinical Pharma Program, Faculty of Pharmacy, Delta University, Dakahlia, Egypt
| | - Tarek M. Emran
- Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt
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11
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Patel HV, Joshi JS, Shah FD. A clinicopathological exploration of Hedgehog signaling: implications in oral carcinogenesis. J Cancer Res Clin Oncol 2023; 149:16525-16535. [PMID: 37712962 DOI: 10.1007/s00432-023-05383-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/30/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Hedgehog Signaling, a basic cancer stem cell pathway, plays a major role during the embryonic development, is known to play a quiescent role in adults. However, aberrant activation of Hedgehog signaling in adults is known to play a role in cancer development. Hence, the aim of the study was to identify the role of Hedgehog signaling pathway in the Oral cancers. MATERIALS AND METHODS The expression of Hedgehog signaling pathway was evaluated in 124 patients through the quantitative real-time PCR. The association between the gene expression and clinico-pathological parameters were analyzed using the Pearson chi-square test and survival analysis was carried out using Kaplan-Meier analysis. RESULTS SHH and GLI1 was found to be significantly associated with the Lymph Node Status and SUFU was significantly associated with the Age. SMO and SUFU were found to have a worse prognosis in oral cancer patients. According to our findings, IHH plays a critical role in the activation of the HH signaling pathway in oral cancer. CONCLUSION These findings back up the use of the Hedgehog signaling pathway as a biomarker for early disease prediction in oral cancer, as well as its role in tumor aggressiveness and invasiveness.
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Affiliation(s)
- Hitarth V Patel
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, 380016, India
| | - Jigna S Joshi
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, 380016, India
| | - Franky D Shah
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, 380016, India.
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12
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Brisset M, Mehlen P, Meurette O, Hollande F. Notch receptor/ligand diversity: contribution to colorectal cancer stem cell heterogeneity. Front Cell Dev Biol 2023; 11:1231416. [PMID: 37860822 PMCID: PMC10582728 DOI: 10.3389/fcell.2023.1231416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/21/2023] [Indexed: 10/21/2023] Open
Abstract
Cancer cell heterogeneity is a key contributor to therapeutic failure and post-treatment recurrence. Targeting cell subpopulations responsible for chemoresistance and recurrence seems to be an attractive approach to improve treatment outcome in cancer patients. However, this remains challenging due to the complexity and incomplete characterization of tumor cell subpopulations. The heterogeneity of cells exhibiting stemness-related features, such as self-renewal and chemoresistance, fuels this complexity. Notch signaling is a known regulator of cancer stem cell (CSC) features in colorectal cancer (CRC), though the effects of its heterogenous signaling on CRC cell stemness are only just emerging. In this review, we discuss how Notch ligand-receptor specificity contributes to regulating stemness, self-renewal, chemoresistance and cancer stem cells heterogeneity in CRC.
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Affiliation(s)
- Morgan Brisset
- Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia
- Centre for Cancer Research, The University of Melbourne, Melbourne, VIC, Australia
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Patrick Mehlen
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Olivier Meurette
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Frédéric Hollande
- Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia
- Centre for Cancer Research, The University of Melbourne, Melbourne, VIC, Australia
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13
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Chandra J, Molugulu N, Annadurai S, Wahab S, Karwasra R, Singh S, Shukla R, Kesharwani P. Hyaluronic acid-functionalized lipoplexes and polyplexes as emerging nanocarriers for receptor-targeted cancer therapy. ENVIRONMENTAL RESEARCH 2023; 233:116506. [PMID: 37369307 DOI: 10.1016/j.envres.2023.116506] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/17/2023] [Accepted: 06/23/2023] [Indexed: 06/29/2023]
Abstract
Cancer is an intricate disease that develops as a response to a combination of hereditary and environmental risk factors, which then result in a variety of changes to the genome. The cluster of differentiation (CD44) is a type of transmembrane glycoprotein that serves as a potential biomarker for cancer stem cells (CSC) and viable targets for therapeutic intervention in the context of cancer therapy. Hyaluronic acid (HA) is a linear polysaccharide that exhibits a notable affinity for the CD44 receptor. This characteristic renders it a promising candidate for therapeutic interventions aimed at selectively targeting CD44-positive cancer cells. Treating cancer via non-viral vector-based gene delivery has changed the notion of curing illness through the incorporation of therapeutic genes into the organism. The objective of this review is to provide an overview of various hyaluronic acid-modified lipoplexes and polyplexes as potential drug delivery methods for specific forms of cancer by effectively targeting CD44.
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Affiliation(s)
- Jyoti Chandra
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nagashekhara Molugulu
- School of Pharmacy, Monash University, Bandar Sunway, Jalan Lagoon Selatan, 47500, Malaysia
| | - Sivakumar Annadurai
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Ritu Karwasra
- Central Council for Research in Unani Medicine (CCRUM), Ministry of AYUSH, Government of India, Janakpuri, New Delhi 110058, India
| | - Surender Singh
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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14
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Wang F, Zhao J, Zhang C, Yang B, Tian T, Tian M, Meng N, Xie W, Liu G, Zhu X, Su M, He Z, Liu Y, Tang D, Li Y. Effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells. Discov Oncol 2023; 14:156. [PMID: 37639070 PMCID: PMC10462592 DOI: 10.1007/s12672-023-00779-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND 3D cancer stem cell (CSC) cultures are widely used as in vitro tumor models. In this study, we determined the effects of enriching HCT116 tumor spheres initially cultured in serum-free medium with different concentrations of serum, focusing on the effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells (CCSCs). METHODS CCSCs were enriched in standard serum-free medium and serum-free medium with different concentrations of serum for 1 week. The expression of CSC-associated markers in CCSCs, and the presence and relative proportion of CSCs (CD133/CD44 cell sorting) were then determined to elucidate the effect of the microserum environment on the preservation of CSC-related features. Further, the tumorigenic capacity of CCSCs was evaluated in an immunodeficiency mouse model. RESULTS Our data indicated that a significantly greater number of spheres with a greater size range and high viability without drastic alteration in biological and structural features, which maintained self-renewal potential after sequential passages were formed after serum supplementation. Real-time analysis showed that both serum spheres and serum-free spheres displayed similar expression patterns for key stemness genes. Serum spheres showed higher expression of the CSC surface markers CD133 and CD44 than did CSCs spheres cultured in serum-free medium. Adherent cultures in complete medium could adapt to the serum-containing microenvironment faster and showed higher proliferation ability. The addition of serum induced EMT and promoted the migration and invasion of serum globular cells. Compared with serum-free cells and adherent cells, serum spheres showed higher tumor initiation ability. CONCLUSIONS Microserum environment stimulation could be an effective strategy for reliable enrichment of intact CCSCs, and a more efficient CSC enrichment method.
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Affiliation(s)
- Feiqing Wang
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin City, 300072 China
| | - Jianing Zhao
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Chike Zhang
- Department of Hematology Oncology, Affiliated Hospital of Guizhou Medical University, No. 4 Bei Jing Road, Yunyan District, Guiyang, 550004 Guizhou Province China
| | - Bo Yang
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Tingting Tian
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Mengxian Tian
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Na Meng
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Wei Xie
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Guangyang Liu
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Xiaodong Zhu
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Min Su
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004 Guizhou Province China
| | - Zhixu He
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004 Guizhou Province China
| | - Yang Liu
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004 Guizhou Province China
| | - Dongxin Tang
- Clinical Medical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Bao Shan North Road, Yunyan District, Guiyang, 550001 Guizhou Province China
| | - Yanju Li
- Department of Hematology Oncology, Affiliated Hospital of Guizhou Medical University, No. 4 Bei Jing Road, Yunyan District, Guiyang, 550004 Guizhou Province China
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15
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Du T, Wu Z, Wu Y, Liu Y, Song Y, Ma L. CD44 Is Associated with Poor Prognosis of ccRCC and Facilitates ccRCC Cell Migration and Invasion through HAS1/MMP9. Biomedicines 2023; 11:2077. [PMID: 37509716 PMCID: PMC10377257 DOI: 10.3390/biomedicines11072077] [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: 06/04/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND In many solid tumors, CD44 has been identified as a cancer stem cell marker as well as an important molecular in cancer progression and metastasis, making it attractive for potential therapeutic applications. However, our knowledge of the biological function and mechanism of CD44 in clear cell renal cell carcinoma (ccRCC) is limited. METHODS In this study, the expression, prognostic values and functional enrichment analysis of CD44 in ccRCC were analyzed using public databases. Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemical (IHC) assays were taken to detect CD44 expression in ccRCC tissues. The effects of CD44 on the proliferation, migration and invasion of ccRCC cells were investigated by gain-of-function and loss-of-function experiments. Subcutaneous models further confirmed the role of CD44 in tumor growth. The relationship between CD44, HAS1 and MMP9 was investigated to uncover the regulatory mechanism of CD44 in ccRCC. RESULTS CD44 was significantly upregulated in ccRCC and associated with poor overall survival (OS). Based on the functional enrichment analysis and PPI network, we found that CD44 had associations with ECM interaction and focal adhesion pathway. Clinical ccRCC sample validation revealed that CD44 mRNA and protein expression were significantly increased in ccRCC tissues, and strong CD44 staining was observed in four metastatic ccRCC cases. In vitro experiments showed that CD44 overexpression promoted cell proliferation, migration and invasion. In vivo experiments also demonstrated that CD44 overexpression accelerated tumor formation in mice. Finally, we found that CD44 regulates the expression of HAS1 in ccRCC, which is essential for the secretion of MMP9 and cell migratory ability. CONCLUSION The upregulation of CD44 mRNA and protein expressions in ccRCC is indicative of unfavorable clinical prognoses. The CD44/HAS1/MMP9 axis is believed to exert a significant influence on the regulation of ECM degradation and ccRCC metastasis.
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Affiliation(s)
- Tan Du
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Zonglong Wu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Yaqian Wu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Yunchong Liu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Yimeng Song
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Lulin Ma
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
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16
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Desette A, Guichet PO, Emambux S, Masliantsev K, Cortes U, Ndiaye B, Milin S, George S, Faigner M, Tisserand J, Gaillard A, Brot S, Wager M, Tougeron D, Karayan-Tapon L. Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular Features. Cell Mol Gastroenterol Hepatol 2023; 16:757-782. [PMID: 37482243 PMCID: PMC10520365 DOI: 10.1016/j.jcmgh.2023.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND & AIMS Brain metastases (BMs) from colorectal cancer (CRC) are associated with significant morbidity and mortality, with chemoresistance and short overall survival. Migrating cancer stem cells with the ability to initiate BM have been described in breast and lung cancers. In this study, we describe the identification and characterization of cancer stem cells in BM from CRC. METHODS Four brain metastasis stem cell lines from patients with colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) were obtained by mechanical dissociation of patient's tumors and selection of cancer stem cells by appropriate culture conditions. BM-SC-CRCs were characterized in vitro by clonogenic and limiting-dilution assays, as well as immunofluorescence and Western blot analyses. In ovo, a chicken chorioallantoic membrane (CAM) model and in vivo, xenograft experiments using BALB/c-nude mice were realized. Finally, a whole exome and RNA sequencing analyses were performed. RESULTS BM-SC-CRC formed metaspheres and contained tumor-initiating cells with self-renewal properties. They expressed stem cell surface markers (CD44v6, CD44, and EpCAM) in serum-free medium and CRC markers (CK19, CK20 and CDX-2) in fetal bovine serum-enriched medium. The CAM model demonstrated their invasive and migratory capabilities. Moreover, mice intracranial xenotransplantation of BM-SC-CRCs adequately recapitulated the original patient BM phenotype. Finally, transcriptomic and genomic approaches showed a significant enrichment of invasiveness and specific stemness signatures and highlighted KMT2C as a potential candidate gene to potentially identify high-risk CRC patients. CONCLUSIONS This original study represents the first step in CRC BM initiation and progression comprehension, and further investigation could open the way to new therapeutics avenues to improve patient prognosis.
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Affiliation(s)
- Amandine Desette
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France.
| | - Pierre-Olivier Guichet
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
| | - Sheik Emambux
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Service d'oncologie médicale, CHU de Poitiers, Poitiers, France
| | - Konstantin Masliantsev
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
| | - Ulrich Cortes
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
| | - Birama Ndiaye
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
| | - Serge Milin
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Service d'Anatomie et de Cytologie Pathologiques, CHU de Poitiers, Poitiers, France
| | - Simon George
- MGX-Montpellier GenomiX, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Mathieu Faigner
- Service d'oncologie médicale, CHU de Poitiers, Poitiers, France
| | | | - Afsaneh Gaillard
- Université de Poitiers, CHU de Poitiers, INSERM, LNEC, Poitiers, France
| | - Sébastien Brot
- Université de Poitiers, CHU de Poitiers, INSERM, LNEC, Poitiers, France
| | - Michel Wager
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Service de Neurochirurgie, CHU de Poitiers, Poitiers, France
| | - David Tougeron
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Service d'hépato-gastro-entérologie, CHU de Poitiers, Poitiers, France
| | - Lucie Karayan-Tapon
- Université de Poitiers, CHU Poitiers, ProDiCeT, UR 24144, Poitiers, France; Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
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Lama Tamang R, Kumar B, Patel SM, Thapa I, Ahmad A, Kumar V, Ahmad R, Becker DF, Bastola D(K, Dhawan P, Singh AB. Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling. Cells 2023; 12:1883. [PMID: 37508547 PMCID: PMC10377831 DOI: 10.3390/cells12141883] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. METHODS A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. RESULTS PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. CONCLUSIONS PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.
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Affiliation(s)
- Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Sagar M. Patel
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Ishwor Thapa
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Alshomrani Ahmad
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Vikas Kumar
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Donald F. Becker
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Dundy (Kiran) Bastola
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
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Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: Therapeutic implications. World J Stem Cells 2023; 15:323-341. [PMID: 37342220 PMCID: PMC10277968 DOI: 10.4252/wjsc.v15.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/26/2023] Open
Abstract
Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs' resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.
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Affiliation(s)
- Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Sana Hachem
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jana Ismael
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon.
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19
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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20
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Zhou G, Lv X, Zhong X, Ying W, Li W, Feng Y, Xia Q, Li J, Jian S, Leng Z. Suspension culture strategies to enrich colon cancer stem cells. Oncol Lett 2023; 25:116. [PMID: 36844615 PMCID: PMC9950343 DOI: 10.3892/ol.2023.13702] [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: 01/06/2021] [Accepted: 11/16/2021] [Indexed: 02/09/2023] Open
Abstract
How to efficiently obtain high-purity cancer stem cells (CSCs) has been the basis of CSC research, but the optimal conditions for serum-free suspension culture of CSCs are still unclear. The present study aimed to define the optimal culture medium composition and culture time for the enrichment of colon CSCs via suspension culture. Suspension cell cultures of colon cancer DLD-1 cells were prepared using serum-free medium (SFM) containing variable concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to produce spheroids. Culture times were set at 10, 20 and 30 days. A total of nine different concentrations of EGF and bFGF were added to SFM to generate nine experimental groups. The proportions of CD44+, CD133+, and CD44+CD133+ double-positive spheroid cells were detected via flow cytometry. mRNA expression of stemness-, epithelial-mesenchymal transition- and Wnt/β-catenin pathway-associated genes was determined via reverse transcription-quantitative PCR. Self-renewal ability was evaluated by a sphere-forming assay. Tumorigenesis was studied in vitro using a colony formation assay and in vivo via subcutaneous cell injection in nude mice. It was found that the highest expression proportions of CD133+ and CD44+ spheroid cells were observed in group (G)9 (20 ng/ml EGF + 20 ng/ml bFGF) at 30 days (F=123.554 and 99.528, respectively, P<0.001), CD133+CD44+ cells were also observed in G9 at 30 days (and at 10 days in G3 and 20 days in G6; F=57.897, P<0.001). G9 at 30 days also displayed the highest expression of Krüppel-like factor 4, leucine-rich repeat-containing G protein-coupled receptor 5, CD44, CD133, Vimentin and Wnt-3a (F=22.682, 25.401, 3.272, 7.852, 13.331 and 17.445, respectively, P<0.001) and the lowest expression of E-cadherin (F=10.851, P<0.001). G9 at 30 days produced the highest yield of cell spheroids, as determined by a sphere forming assay (F=19.147, P<0.001); colony formation assays also exhibited the greatest number of colonies derived from G9 spheroids at 30 days (F=60.767, P<0.01), which also generated the largest mean tumor volume in the subcutaneous tumorigenesis xenograft model (F=12.539, P<0.01). In conclusion, 20 ng/ml EGF + 20 ng/ml bFGF effectively enriched colon CSCs when added to suspension culture for 30 days, and conferred the highest efficiency compared with other combinations.
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Affiliation(s)
- Guojun Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaojiang Lv
- Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaorong Zhong
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Wei Ying
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Wenbo Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Yanchao Feng
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Qinghua Xia
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China
| | - Jianshui Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Shunhai Jian
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Professor Shunhai Jian, Department of Pathology, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan 637000, P.R. China, E-mail:
| | - Zhengwei Leng
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Correspondence to: Professor Zhengwei Leng, Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, 234, Fujiang Road, Nanchong, Sichuan 637000, P.R. China, E-mail:
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21
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Polymer Thin Film Promotes Tumor Spheroid Formation via JAK2-STAT3 Signaling Primed by Fibronectin-Integrin α5 and Sustained by LMO2-LDB1 Complex. Biomedicines 2022; 10:biomedicines10112684. [DOI: 10.3390/biomedicines10112684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex vivo, which remains restricted due to the low availability and diversity of CSCs. To address this limitation, a functional polymer thin-film (PTF) platform was invented to induce the transformation of cancer cells into tumorigenic spheroids. In this study, we demonstrated the functionality of a new PTF, polymer X, using a streamlined production process. Polymer X induced the formation of tumor spheroids with properties of CSCs, as revealed through the upregulated expression of CSC-related genes. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in the cancer cells cultured on polymer X was upregulated by the fibronectin-integrin α5-Janus kinase 2 (JAK2) axis and maintained by the cytosolic LMO2/LBD1 complex. In addition, STAT3 signaling was critical in spheroid formation on polymer X. Our PTF platform allows the efficient generation of tumor spheroids from cancer cells, thereby overcoming the existing limitations of cancer research.
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22
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Regulation of the Cancer Stem Phenotype by Long Non-Coding RNAs. Cells 2022; 11:cells11152352. [PMID: 35954194 PMCID: PMC9367355 DOI: 10.3390/cells11152352] [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: 07/04/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer stem cells are a cell population within malignant tumors that are characterized by the ability to self-renew, the presence of specific molecules that define their identity, the ability to form malignant tumors in vivo, resistance to drugs, and the ability to invade and migrate to other regions of the body. These characteristics are regulated by various molecules, such as lncRNAs, which are transcripts that generally do not code for proteins but regulate multiple biological processes through various mechanisms of action. LncRNAs, such as HOTAIR, H19, LncTCF7, LUCAT1, MALAT1, LINC00511, and FMR1-AS1, have been described as key regulators of stemness in cancer, allowing cancer cells to acquire this phenotype. It has been proposed that cancer stem cells are clinically responsible for the high recurrence rates after treatment and the high frequency of metastasis in malignant tumors, so understanding the mechanisms that regulate the stem phenotype could have an impact on the improvement of cancer treatments.
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23
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Zheng S, Luo J, Xie S, Lu S, Liu Q, Xiao H, Luo W, Huang Y, Liu K. Tumor budding of cervical squamous cell carcinoma: epithelial-mesenchymal transition-like cancer stem cells? PeerJ 2022; 10:e13745. [PMID: 35860042 PMCID: PMC9291004 DOI: 10.7717/peerj.13745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/27/2022] [Indexed: 01/17/2023] Open
Abstract
Recent evidence indicates that cancer stem cells (CSCs) are the origin of cancers. Scientists have identified CSCs in various tumors and have suggested the existence of a variety of states of CSCs. The existence of epithelial-mesenchymal transition (EMT)-like CSCs has been confirmed in vitro, but they have not been identified in vivo. Tumor budding was defined as single cell or clusters of ≤ 5 cells at the invasive front of cancers. Such tumor budding is hypothesized to be closely related to EMT and linked to CSCs, especially to those migrating at the invasive front. Therefore, tumor budding has been proposed to represent EMT-like stem cells. However, this hypothesis has not yet been proven. Thus, we studied the expression of EMT markers, certain CSC markers of tumor budding, and the tumor center of cervical squamous cell carcinoma (CxSCC). We performed tissue chip analyses of 95 primary CxSCCs from patients. Expression of EMT and CSC markers (E-cadherin, β-catenin, vimentin, Ki67, CD44, SOX2 , and ALDH1A1) in a set of tumor samples on tissue chips (87 cases of tumor budding/the main tumor body) were evaluated by immunohistochemistry. We found that the cell-membranous expression of β-catenin was stronger in the main tumor body than in tumor buds. Compared with the main tumor body, tumor buds had reduced proliferative activity as measured by Ki67. Moreover, vimentin expression was high and E-cadherin expression was low in tumor buds. Expression of EMT-related markers suggested that tumor buds were correlated with EMT. We noted that CxSCC tumor buds had a CD44negative/low/SOX2high/ALDH1A1high staining pattern, indicating that tumor buds of CxSCC present CSC-like immunophenotypic features. Taken together, our data indicate that tumor buds in CxSCC may represent EMT-like CSCs in vivo.
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Affiliation(s)
- Shaoqiu Zheng
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Jing Luo
- Department of Pelvic Radiotherapy, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Shoucheng Xie
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Shanming Lu
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Qinghua Liu
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Huanqin Xiao
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Wenjuan Luo
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Yanfang Huang
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
| | - Kun Liu
- Department of Pathology, Meizhou People’s Hospital, Meizhou, Guangdong, China
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24
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Cancer stem cell marker expression and methylation status in patients with colorectal cancer. Oncol Lett 2022; 24:231. [PMID: 35720495 PMCID: PMC9185140 DOI: 10.3892/ol.2022.13352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/29/2022] [Indexed: 11/21/2022] Open
Abstract
The number of individuals diagnosed with colorectal cancer (CRC) has been on an alarming upward trajectory over the past decade. In some countries, this cancer represents one of the most frequently diagnosed types of neoplasia. Therefore, it is an important demand to study the pathology underlying this disease to gain insights into the mechanism of resistance to treatment. Resistance of tumors to chemotherapy and tumor aggressiveness have been associated with a minor population of neoplastic cells, which are considered to be responsible for tumor recurrence. These types of neoplastic cells are known as cancer stem cells, which have been previously reported to serve an important role in pathogenesis of this malignant disease. Slovakia has one of the highest incidence rates of CRC worldwide. In the present study, the aim was to classify the abundance of selected stem cell markers (CD133, CD166 and Lgr5) in CRC tumors using flow cytometry. In addition, the methylation status of selected genomic regions of CRC biomarkers (ADAMTS16, MGMT, PROM1 (CD133), LGR5 and ALCAM) was investigated by pyrosequencing in a cohort of patients from Martin University Hospital, Martin, Slovakia. Samples from both primary tumors and metastatic tumors were tested. Analysis of DNA methylation in the genomic regions of indicated five CRC biomarkers was also performed, which revealed the highest levels of methylation in the A disintegrin and metalloproteinase with thrombospondin motifs 16 and O6-methyguanine-DNA methyl transferase genes, whereas the lowest levels of methylation were found in genes expressing prominin-1, leucine-rich repeat-containing G-protein-coupled receptor 5 and activated leukocyte cell adhesion molecule. Furthermore, tumor tissues from metastases showed significantly higher levels of CD133+ cells compared with that in primary tumors. Higher levels of CD133+ cells correlated with TNM stage and the invasiveness of CRC into the lymphatic system. Although relatively small number of samples was processed, CD133 marker was consider to be important marker in pathology of CRC.
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Sun J, Ye L, Shi Y, Wang X, Zhao X, Ren S, Fan J, Shao H, Qin B. MiR-6511b-5p suppresses metastasis of pMMR colorectal cancer through methylation of CD44 by directly targeting BRG1. Clin Transl Oncol 2022; 24:1940-1953. [PMID: 35590122 PMCID: PMC9418090 DOI: 10.1007/s12094-022-02845-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/19/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE Distal metastases are a major cause of poor prognosis in colorectal cancer patients. Approximately 95% of metastatic colorectal cancers are defined as DNA mismatch repair proficient (pMMR). Our previous study found that miR-6511b-5p was downregulated in pMMR colorectal cancer. However, the mechanism of miR-6511b-5p in pMMR colorectal cancer metastases remain unclear. METHODS We first used quantitative real-time PCR to evaluate the role of miR-6511b-5p in colorectal cancer. Second, we conducted invasion assays and wound healing assays to investigate the role of miR-6511b-5p and CD44 in colorectal cancer cells metastases. Third, luciferase reporter assay, in situ hybridization (ISH), and immunohistochemistry assays were performed to study the relationship between miR-6511b-5p and BRG1. Finally, real-time quantitative PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed to analyze the relationship between BRG1 and CD44 in colorectal cancer. RESULTS We found that lower expression of miR-6511b-5p appeared more often in pMMR colorectal cancer patients compared with dMMR (mismatch repair deficient) cases, and was positively correlated with metastases. In vitro, overexpression of miR-6511b-5p inhibited metastasis by decreasing CD44 expression via directly targeting BRG1 in colorectal cancer. Furthermore, BRG1 knockdown decreased the expression of CD44 by promoting CD44 methylation in colorectal cancer cells. CONCLUSION Our data suggest that miR-6511b-5p may act as a promising biomarker and treatment target for pMMR colorectal cancer, particularly in metastatic patients. Mechanistically, miR-6511b-5p suppresses invasion and migration of colorectal cancer cells through methylation of CD44 via directly targeting BRG1.
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Affiliation(s)
- JinMing Sun
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Ling Ye
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yuan Shi
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - XingWei Wang
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - XiaFei Zhao
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - ShengYong Ren
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - JunWei Fan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - HuanZhang Shao
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
| | - BingYu Qin
- Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
- Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
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26
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Sánchez-Díez M, Alegría-Aravena N, López-Montes M, Quiroz-Troncoso J, González-Martos R, Menéndez-Rey A, Sánchez-Sánchez JL, Pastor JM, Ramírez-Castillejo C. Implication of Different Tumor Biomarkers in Drug Resistance and Invasiveness in Primary and Metastatic Colorectal Cancer Cell Lines. Biomedicines 2022; 10:1083. [PMID: 35625820 PMCID: PMC9139065 DOI: 10.3390/biomedicines10051083] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/28/2022] [Accepted: 05/04/2022] [Indexed: 12/04/2022] Open
Abstract
Protein expression profiles are directly related to the different properties of cells and are conditioned by the cellular niche. As an example, they are the cause of the characteristic cell plasticity, epithelium-mesenchymal transition (EMT), and drug resistance of cancer cells. This article characterizes ten biomarkers related to these features in three human colorectal cancer cell lines: SW-480, SW-620, and DLD-1, evaluated by flow cytometry; and in turn, resistance to oxaliplatin is studied through dose-response trials. The main biomarkers present in the three studied lines correspond to EpCAM, CD-133, and AC-133, with the latter two in low proportions in the DLD-1 line. The biomarker CD166 is present in greater amounts in SW-620 and DLD-1 compared to SW-480. Finally, DLD-1 shows high values of Trop2, which may explain the aggressiveness and resistance of these cells to oxaliplatin treatments, as EpCAM is also highly expressed. Exposure to oxaliplatin slows cell growth but also helps generate resistance to the treatment. In conclusion, the response of the cell lines is variable, due to their genetic variability, which will condition protein expression and cell growth. Further analyses in this area will provide important information for better understanding of patients' cellular response and how to prevent resistance.
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Affiliation(s)
- Marta Sánchez-Díez
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
| | - Nicolás Alegría-Aravena
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
| | - Marta López-Montes
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
| | - Josefa Quiroz-Troncoso
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
| | - Raquel González-Martos
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
| | - Adrián Menéndez-Rey
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
| | | | - Juan Manuel Pastor
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
| | - Carmen Ramírez-Castillejo
- CTB (CTB-UPM) Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (N.A.-A.); (M.L.-M.); (J.Q.-T.); (R.G.-M.); (A.M.-R.)
- Grupo de Sistemas Complejos, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
- ETSIAAB, Departamento Biotecnología-Biología Vegetal, Universidad Politécnica de Madrid, IdISSC, 28040 Madrid, Spain
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Guo T, Zhang Z, Zhu L, Chen W, Ding Y, Li W, Huang Y, Huang J, Pan X. TRIM55 suppresses malignant biological behavior of lung adenocarcinoma cells by increasing protein degradation of Snail1. Cancer Biol Ther 2022; 23:17-26. [PMID: 34974792 PMCID: PMC8812808 DOI: 10.1080/15384047.2021.2004835] [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] [Indexed: 11/07/2022] Open
Abstract
Up until now, cancer refractoriness and distal organ metastatic disease remain as major obstacles for oncologists to achieve satisfactory therapeutic effects for lung adenocarcinoma patients. Previous studies indicated that TRIM55, which participates in the natural development of muscle and cardiovascular system, plays a protective role in hepatocellular carcinoma (HCC) pathogenesis. Therefore, in this study, we aimed to unveil the detailed molecular mechanism of TRIM55 and identify the potential target for lung adenocarcinoma patients. Surgical samples and lung cancer cell lines were collected to detect the TRIM55 expression for patients with or without lymph node/distal organ metastasis. Cellular functional assays including transwell assay, wound healing assay, cellular survivability assay, etc. as well as ubiquitination assay were performed to evaluate the impact of TRIM55/Snail1 regulatory network via the UPP pathway on lung cancer tumor cell migration and chemo-resistance. Lung cancer tissues and tumor cell lines exhibited significantly lower levels of TRIM55 expression. Functional study further indicated that TRIM55 inhibited chemo-resistance, migration, and cancer stem-cell like phenotype of tumor cells. Further detailed molecular experiments indicated that TRIM55 promoted degradation of Snail1 via the UPP pathway, which played an interesting role in the regulation of cancer cell malignancy. This study provided novel theory that TRIM55 acted as a potential tumor suppressor by inhibition of tumor cell malignancy through enhancement of Snail1 degradation via the UPP pathway. Our research will inspire further exploration on TRIM55 to promote therapeutic effects for lung adenocarcinoma patients.
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Affiliation(s)
- Tianxing Guo
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Zhenlong Zhang
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Lihuan Zhu
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Wenshu Chen
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Yun Ding
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Wujin Li
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Yangyun Huang
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Jianyuan Huang
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
| | - Xiaojie Pan
- Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou China
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AbdelMageed M, Ismail HTH, Olsson L, Lindmark G, Hammarström ML, Hammarström S, Sitohy B. Clinical Significance of Stem Cell Biomarkers EpCAM, LGR5 and LGR4 mRNA Levels in Lymph Nodes of Colon Cancer Patients. Int J Mol Sci 2021; 23:403. [DOI: https:/doi.org/10.3390/ijms23010403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan-Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA copies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12-year follow-up (p = 0.022, p = 0.005 and p = 0.011, respectively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.
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Affiliation(s)
- Manar AbdelMageed
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Hager Tarek H. Ismail
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Lina Olsson
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
| | - Gudrun Lindmark
- Institution of Clinical Sciences, Lund University, SE-25187 Helsingborg, Sweden
| | - Marie-Louise Hammarström
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
| | - Sten Hammarström
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
| | - Basel Sitohy
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
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29
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AbdelMageed M, Ismail HTH, Olsson L, Lindmark G, Hammarström ML, Hammarström S, Sitohy B. Clinical Significance of Stem Cell Biomarkers EpCAM, LGR5 and LGR4 mRNA Levels in Lymph Nodes of Colon Cancer Patients. Int J Mol Sci 2021; 23:403. [PMID: 35008827 PMCID: PMC8745090 DOI: 10.3390/ijms23010403] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 12/26/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022] Open
Abstract
The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan-Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA copies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12-year follow-up (p = 0.022, p = 0.005 and p = 0.011, respectively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.
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Affiliation(s)
- Manar AbdelMageed
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Hager Tarek H. Ismail
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Lina Olsson
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
| | - Gudrun Lindmark
- Institution of Clinical Sciences, Lund University, SE-25187 Helsingborg, Sweden;
| | - Marie-Louise Hammarström
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
| | - Sten Hammarström
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
| | - Basel Sitohy
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, SE-90185 Umeå, Sweden; (M.A.); (H.T.H.I.); (L.O.); (M.-L.H.); (S.H.)
- Department of Radiation Sciences, Oncology, Umeå University, SE-90185 Umeå, Sweden
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Jiang X, Liang L, Chen G, Liu C. Modulation of Immune Components on Stem Cell and Dormancy in Cancer. Cells 2021; 10:2826. [PMID: 34831048 PMCID: PMC8616319 DOI: 10.3390/cells10112826] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis.
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Affiliation(s)
| | | | | | - Caigang Liu
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang 110004, China; (X.J.); (L.L.); (G.C.)
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31
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Kantapan J, Paksee S, Duangya A, Sangthong P, Roytrakul S, Krobthong S, Suttana W, Dechsupa N. A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells. BMC Complement Med Ther 2021; 21:189. [PMID: 34217266 PMCID: PMC8254241 DOI: 10.1186/s12906-021-03363-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 06/21/2021] [Indexed: 12/19/2022] Open
Abstract
Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03363-6.
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Affiliation(s)
- Jiraporn Kantapan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Siwaphon Paksee
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Aphidet Duangya
- Interdisciplinary Program of Biotechnology, Graduate School, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Padchanee Sangthong
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand.,Research Center on Chemistry for Development of Health Promoting Products from Northern Resources, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sittiruk Roytrakul
- Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand
| | - Sucheewin Krobthong
- National Omics Center (NOC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand
| | - Wipob Suttana
- Department of Biomedical Science, School of Health Science, Mae Fah Luang University, Chiang Rai, 57100, Thailand
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
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32
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Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition. Biomolecules 2021; 11:biom11070956. [PMID: 34209658 PMCID: PMC8301972 DOI: 10.3390/biom11070956] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities.
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Ghaderi F, Jokar N, Gholamrezanezhad A, Assadi M, Ahmadzadehfar H. Toward radiotheranostics in cancer stem cells: a promising initial step for tumour eradication. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00444-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Kopenhaver J, Crutcher M, Waldman SA, Snook AE. The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission. Expert Opin Biol Ther 2021; 21:1335-1345. [PMID: 33977849 DOI: 10.1080/14712598.2021.1929167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and is the second leading cause of cancer-related death in the United States. Despite advances in early detection, ~25% of patients are late stage, and treated patients have <12% chance of survival after five years. Tumor relapse and metastasis are the main causes of patient death. Cancer stem cells (CSCs) are a rare population of cancer cells characterized by properties of self-renewal, chemo- and radio-resistance, tumorigenicity, and high plasticity. These qualities make CSCs particularly important for metastasic seeding, DNA-damage resistance, and tumor repopulating.Areas Covered: The following review article focuses on the role of CRC-SCs in tumor initiation, metastasis, drug resistance, and tumor relapse, as well as on potential therapeutic options for targeting CSCs.Expert Opinion: Current studies are underway to better isolate and discriminate CSCs from normal stem cells and to produce CSC-targeted therapeutics. The intestinal receptor, guanylate cyclase C (GUCY2C) could potentially provide a unique therapeutic target for both non-stem cells and CSCs alike in colorectal cancer through immunotherapies. Indeed, immunotherapies targeting CSCs have the potential to break the treatment-recurrence cycle in the management of advanced malignancies.
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Affiliation(s)
- Jessica Kopenhaver
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
| | - Madison Crutcher
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States.,Department of Surgery, Thomas Jefferson University, Philadelphia, United States
| | - Scott A Waldman
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
| | - Adam E Snook
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, United States
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35
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Hervieu C, Christou N, Battu S, Mathonnet M. The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials. Cancers (Basel) 2021; 13:1092. [PMID: 33806312 PMCID: PMC7961892 DOI: 10.3390/cancers13051092] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/23/2021] [Accepted: 02/27/2021] [Indexed: 02/06/2023] Open
Abstract
The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient's overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.
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Affiliation(s)
- Céline Hervieu
- EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France; (C.H.); (N.C.); (S.B.)
| | - Niki Christou
- EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France; (C.H.); (N.C.); (S.B.)
- Department of General, Endocrine and Digestive Surgery, University Hospital of Limoges, 87025 Limoges CEDEX, France
| | - Serge Battu
- EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France; (C.H.); (N.C.); (S.B.)
| | - Muriel Mathonnet
- EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France; (C.H.); (N.C.); (S.B.)
- Department of General, Endocrine and Digestive Surgery, University Hospital of Limoges, 87025 Limoges CEDEX, France
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The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031424. [PMID: 33572600 PMCID: PMC7867000 DOI: 10.3390/ijms22031424] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
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37
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Belayneh YM, Amare GG, Meharie BG. Updates on the molecular mechanisms of aspirin in the prevention of colorectal cancer: Review. J Oncol Pharm Pract 2021; 27:954-961. [PMID: 33427041 DOI: 10.1177/1078155220984846] [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] [Indexed: 01/15/2023]
Abstract
Colorectal cancer is one of the commonest malignancies worldwide. The estimated lifetime risk of the disease is about 5% with an incidence of one million new cases and 600,000 deaths worldwide every year. It is estimated that in 2019, approximately 134,490 new cases of colorectal cancer will be diagnosed with 49,190 mortalities. Though the disease is regarded as a disorder of the more developed world, the occurrence is steadily increasing in many developing countries. Since chronic inflammation is a known aggravating risk factor for colorectal cancer, anti-inflammatory agents such as aspirin have been used to prevent the development of colorectal cancer and related mortality. The potential mechanisms for the effect of aspirin in the prevention of colorectal cancer have been proposed and broadly classified as cyclooxygenase (COX) dependent and COX-independent. Some of the primary effectors of COX-dependent mechanisms in carcinogenesis are likely to be prostaglandins. In contrast to the reversible action of other nonsteroidal anti-inflammatory drugs, aspirin is known to irreversibly inactivate COX enzymes to suppress production of prostaglandins. COX-independent mechanisms of anticancer effects of aspirin include down-regulation of nuclear factor kappa B activity and Akt activation, modulation of Bcl-2 and Bax family proteins, suppression of vascular endothelial growth factor, induction of apoptosis, disruption of DNA repair mechanisms, and induction of spermidine/spermine N1-acetyltransferase that modulates polyamine catabolism.
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Affiliation(s)
- Yaschilal Muche Belayneh
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Gedefew Getnet Amare
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Birhanu Geta Meharie
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
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38
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Javed Z, Javed Iqbal M, Rasheed A, Sadia H, Raza S, Irshad A, Koch W, Kukula-Koch W, Głowniak-Lipa A, Cho WC, Sharifi-Rad J. Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer. Front Oncol 2021; 10:607607. [PMID: 33489917 PMCID: PMC7817854 DOI: 10.3389/fonc.2020.607607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.
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Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Muhammad Javed Iqbal
- Department of Biotechnology, Faculty of Sciences, University of Sialkot, Sialkot, Pakistan
| | - Amna Rasheed
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Shahid Raza
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Asma Irshad
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Wojciech Koch
- Chair and Department of Food and Nutrition, Medical University of Lublin, Lublin, Poland
| | | | - Anna Głowniak-Lipa
- Department of Cosmetology, University of Information Technology and Management in Rzeszów, Rzeszów, Poland
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
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Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol 2020; 9:36. [PMID: 33303029 PMCID: PMC7727191 DOI: 10.1186/s40164-020-00192-0] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 11/21/2020] [Indexed: 12/15/2022] Open
Abstract
CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.
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Affiliation(s)
- Hanxiao Xu
- Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Mengke Niu
- Department of Medical Oncology, The Affiliated Tumor Hospital of Zhengzhou University: Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Kongming Wu
- Department of Medical Oncology, The Affiliated Tumor Hospital of Zhengzhou University: Henan Cancer Hospital, Zhengzhou, 450008, China. .,Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Aiguo Liu
- Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Oswald JT, Patel H, Khan D, Jeorje NN, Golzar H, Oswald EL, Tang S. Drug Delivery Systems Using Surface Markers for Targeting Cancer Stem Cells. Curr Pharm Des 2020; 26:2057-2071. [PMID: 32250211 DOI: 10.2174/1381612826666200406084900] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022]
Abstract
The innate abilities of cancer stem cells (CSCs), such as multi-drug resistance, drug efflux, quiescence and ionizing radiation tolerance, protect them from most traditional chemotherapeutics. As a result, this small subpopulation of persistent cells leads to more aggressive and chemoresistant cancers, causing tumour relapse and metastasis. This subpopulation is differentiated from the bulk tumour population through a wide variety of surface markers expressed on the cell surface. Recent developments in nanomedicine and targeting delivery methods have given rise to new possibilities for specifically targeting these markers and preferentially eliminating CSCs. Herein, we first summarize the range of surface markers identifying CSC populations in a variety of cancers; then, we discuss recent attempts to actively target CSCs and their niches using liposomal, nanoparticle, carbon nanotube and viral formulations.
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Affiliation(s)
- James T Oswald
- School Of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Haritosh Patel
- School Of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Daid Khan
- School Of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Ninweh N Jeorje
- School Of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Hossein Golzar
- Department of Chemistry & Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Erin L Oswald
- School Of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Shirley Tang
- Department of Chemistry & Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
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Yan X, Han D, Chen Z, Han C, Dong W, Han L, Zou L, Zhang J, Liu Y, Chai J. RUNX2 interacts with BRG1 to target CD44 for promoting invasion and migration of colorectal cancer cells. Cancer Cell Int 2020; 20:505. [PMID: 33071648 PMCID: PMC7559818 DOI: 10.1186/s12935-020-01544-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 09/07/2020] [Indexed: 12/16/2022] Open
Abstract
Background Cancer stem cells (CSCs) play an important role in tumor invasion and metastasis. CD44 is the most commonly used marker of CSCs, with the potential to act as a determinant against the invasion and migration of CSCs and as the key factor in epithelial-mesenchymal transition (EMT)-like changes that occur in colorectal cancer (CRC). Runt-related transcription factor-2 (RUNX2) is a mesenchymal stem marker for cancer that is involved in stem cell biology and tumorigenesis. However, whether RUNX2 is involved in CSC and in inducing EMT-like changes in CRC remains uncertain, warranting further investigation. Methods We evaluated the role of RUNX2 in the invasion and migration of CRC cells as a promoter of CD44-induced stem cell- and EMT-like modifications. For this purpose, western blotting was employed to analyze the expression of differential proteins in CRC cells. We conducted sphere formation, wound healing, and transwell assays to investigate the biological functions of RUNX2 in CRC cells. Cellular immunofluorescence and coimmunoprecipitation (co-IP) assays were performed to study the relationship between RUNX2 and BRG1. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) were performed to analyze the expressions of RUNX2, BRG1, and CD44 in the CRC tissues. Results We found that RUNX2 could markedly induce the CRC cell sphere-forming ability and EMT. Interestingly, the RUNX2-mediated EMT in CRC cell may be associated with the activation of CD44. Furthermore, RUNX2 was found to interact with BRG1 to promote the recruitment of RUNX2 to the CD44 promoter. Conclusions Our cumulative findings suggest that RUNX2 and BRG1 can form a compact complex to regulate the transcription and expression of CD44, which has possible involvement in the invasion and migration of CRC cells.
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Affiliation(s)
- Xiaodong Yan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 China
| | - Dali Han
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Zhiqiang Chen
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100069 China
| | - Chao Han
- Department of Gastrointestinal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000 Shanxi Province China
| | - Wei Dong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Li Han
- Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Lei Zou
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Jianbo Zhang
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Yan Liu
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong Province China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440 Ji-Yan Road, Jinan, 250117 Shandong Province China.,Tianjin Medical University, Tianjin, 300070 China
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Rezaee M, Gheytanchi E, Madjd Z, Mehrazma M. Clinicopathological Significance of Tumor Stem Cell Markers ALDH1 and CD133 in Colorectal Carcinoma. IRANIAN JOURNAL OF PATHOLOGY 2020; 16:40-50. [PMID: 33391379 PMCID: PMC7691712 DOI: 10.30699/ijp.2020.127441.2389] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/23/2020] [Indexed: 12/15/2022]
Abstract
Background & Objective: Colorectal cancer (CRC) is the third most common cancer worldwide with a high mortality rate. The main causes of death in patients are recurrence and metastasis which are mainly attributed to the small subpopulation of cells within tumors called cancer stem cells (CSCs). This study aimed to evaluate the correlation between the expression of ALDH1 and CD133 as CSC associated markers and clinicopathological characteristics in CRC. Methods: In this cross-sectional study, a total of 483 CRC tumor samples were immunohistochemically stained for detection of CD133 and ALDH1 markers. Correlations of marker expression with clinicopathological factors were also evaluated. Results: There was a significant correlation between the luminal intensity of CD133 and neural invasion (P=0.05) and between the cytoplasmic intensity of CD133 and metastasis (P=0.05). In terms of H-score, a positive significant relation was observed between cytoplasmic expression of CD133 and lymph node (P=0.02), neural (P=0.04) and vascular invasion (P=0.02). The ALDH1 cytoplasmic expression showed a significant correlation with tumor size (P=0.001). Conclusion: Our findings showed that increased expression of CD133 and ALDH1 is associated with tumor progression and worse outcomes in CRC patients. These markers can be good candidates for localized targeting of CSCs using antibodies. Future researches need to be improved approaches for early detection of CRC, and treatment monitoring for CRC and other cancers.
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Affiliation(s)
- Maryam Rezaee
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mitra Mehrazma
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Pathology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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Schulte am Esch J, Windmöller BA, Hanewinkel J, Storm J, Förster C, Wilkens L, Krüger M, Kaltschmidt B, Kaltschmidt C. Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition. Cancers (Basel) 2020; 12:cancers12092582. [PMID: 32927768 PMCID: PMC7564713 DOI: 10.3390/cancers12092582] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The aim of this study was to gain a better understanding of cancer stem cells, which are a small subpopulation of tumor cells with high plasticity driving tumor growth and metastasis. Here we isolated two novel colorectal cancer cell lines originating from a rectal neuroendocrine carcinoma and a colorectal adenocarcinoma, depicting stem-like properties. These in vitro models offer the possibility to evaluate pathophysiological mechanisms in order to develop tailored therapeutic strategies for distinct colorectal malignancies. Investigations revealed gene copy number gain of the N-myc proto-oncogene for both. Accordingly, inhibition of the protein–protein interaction of myc and N-myc proto-oncogenes with the myc-associated factor X utilizing small molecule KJ-Pyr-9, exhibited a significant reduction in survival of both cell lines by the induction of apoptosis. Consequently, the blockage of these interactions may serve as a possible treatment strategy for colorectal cancer cell lines with gene copy number gain of the N-myc proto-oncogene. Abstract Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.
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Affiliation(s)
- Jan Schulte am Esch
- Department of General and Visceral Surgery, Protestant Hospital of Bethel Foundation, 33611 Bielefeld, Germany;
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
| | - Beatrice Ariane Windmöller
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Department of Cell Biology, University of Bielefeld, 33611 Bielefeld, Germany;
- Correspondence: ; Tel.: +49-0521-106-5629
| | - Johannes Hanewinkel
- Department of Cell Biology, University of Bielefeld, 33611 Bielefeld, Germany;
| | - Jonathan Storm
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Department of Cell Biology, University of Bielefeld, 33611 Bielefeld, Germany;
| | - Christine Förster
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Institute of Pathology, KRH Hospital Nordstadt, affiliated with the Protestant Hospital of Bethel Foundation, 30167 Hannover, Germany
| | - Ludwig Wilkens
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Institute of Pathology, KRH Hospital Nordstadt, affiliated with the Protestant Hospital of Bethel Foundation, 30167 Hannover, Germany
| | - Martin Krüger
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Department of Internal Medicine and Gastroenterology, Protestant Hospital of Bethel Foundation, 33611 Bielefeld, Germany
| | - Barbara Kaltschmidt
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Department of Cell Biology, University of Bielefeld, 33611 Bielefeld, Germany;
- Molecular Neurobiology, University of Bielefeld, 33615 Bielefeld, Germany
| | - Christian Kaltschmidt
- Forschungsverbund BioMedizin Bielefeld (FBMB), 33611 Bielefeld, Germany; (J.S.); (C.F.); (L.W.); (M.K.); (B.K.); (C.K.)
- Department of Cell Biology, University of Bielefeld, 33611 Bielefeld, Germany;
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Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauß A, Blaudszun AR, Yevsa T, Fricke S, Kossatz-Boehlert U. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol 2020; 11:1280. [PMID: 32849491 PMCID: PMC7426526 DOI: 10.3389/fimmu.2020.01280] [Citation(s) in RCA: 549] [Impact Index Per Article: 109.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
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Affiliation(s)
- Lia Walcher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Ann-Kathrin Kistenmacher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Reni Kitte
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Sarah Dluczek
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Alexander Strauß
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - André-René Blaudszun
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Stephan Fricke
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Uta Kossatz-Boehlert
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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Gzil A, Zarębska I, Jaworski D, Antosik P, Durślewicz J, Maciejewska J, Domanowska E, Skoczylas-Makowska N, Ahmadi N, Grzanka D, Szylberg Ł. The prognostic value of leucine-rich repeat-containing G-protein (Lgr5) and its impact on clinicopathological features of colorectal cancer. J Cancer Res Clin Oncol 2020; 146:2547-2557. [PMID: 32671503 PMCID: PMC7467967 DOI: 10.1007/s00432-020-03314-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 07/06/2020] [Indexed: 12/26/2022]
Abstract
Introduction Colorectal cancer (CRC) constitutes one of the most prevalent malignancies in the world. Recent research suggests that cancer stem cells (CSCs) are responsible for tumor cell’s malignant behavior in CRC. This study has been designed to determinate clinical implications of CSC markers: CD44, DCLK1, Lgr5, and ANXA2 in CRC. Materials and methods The study was performed on tissue samples which were collected from 89 patients undergoing colectomy. Formalin-fixed paraffin-embedded tissue blocks with representative tumor areas were identified and corded. Immunohistochemical staining was performed using anti-CD44, anti-LGR5, anti-ANXA2, and anti-DCLK1 antibodies. The H-score system was utilized to determine the immunointensity of CRC cells. Results The lower expression of Lgr5 was significantly correlated with the presence of lymph-node metastases (p = 0.011), while high expression of Lgr5 was statistically significant in vascular invasion in examined cancer tissue samples (p = 0.027). Moreover, a high H-score value of Lgr5 expression was significantly related to a reduced overall survival rate (p = 0.043). Conclusion Our results suggest a strong relationship between CSC marker Lgr5 and vascular invasion, presence of lymph-node metastasis, and overall poor survival. The presence of Lgr5 might be an unfavorable prognostic factor, and its high level in cancer tissue is related to an aggressive course. This marker could also be used to access the effectiveness of the treatment.
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Affiliation(s)
- Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland. .,Nicolaus Copernicus University, Toruń, Poland.
| | - Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Damian Jaworski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Joanna Maciejewska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Ewa Domanowska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Natalia Skoczylas-Makowska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Navid Ahmadi
- Chair and Department of Oncologic Pathology and Prophylactics, Greater Poland Cancer Center, Poznan University of Medical Sciences, Poznan, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.,Nicolaus Copernicus University, Toruń, Poland.,Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland.,Department of Tumor Pathology and Pathomorphology, Oncology Center, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
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Pádua D, Figueira P, Ribeiro I, Almeida R, Mesquita P. The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication. Front Cell Dev Biol 2020; 8:442. [PMID: 32626705 PMCID: PMC7314965 DOI: 10.3389/fcell.2020.00442] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.
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Affiliation(s)
- Diana Pádua
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paula Figueira
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Inês Ribeiro
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Raquel Almeida
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Patrícia Mesquita
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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Leng Z, Li Y, Zhou G, Lv X, Ai W, Li J, Hou L. Krüppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-β1/Smad/snail pathway. J Cell Mol Med 2020; 24:1866-1877. [PMID: 31830379 PMCID: PMC6991673 DOI: 10.1111/jcmm.14882] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 09/09/2019] [Accepted: 09/18/2019] [Indexed: 12/12/2022] Open
Abstract
Krüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells. Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5+ CD44+ EpCAM+ colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-β1 pathway, whereas enforced KLF4 overexpression activated TGF-β1, phosphorylation of Smad 2/3 and Snail expression, and restored stemness and mesenchymal phenotypes. Furthermore, TGF-β1 pathway inhibition invalidated KLF4-facilitated stemness and mesenchymal features without affecting KLF4 expression. The data from the current study are the first to demonstrate that KLF4 maintains stemness and mesenchymal properties through the TGF-β1/Smad/Snail pathway in Lgr5+ CD44+ EpCAM+ colorectal CSCs.
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Affiliation(s)
- Zhengwei Leng
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
- Cancer Stem Cells Research CenterAffiliated Hospital of North Sichuan Medical CollegeSichuanChina
| | - Yong Li
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
| | - Guojun Zhou
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
| | - Xiaojiang Lv
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
| | - Walden Ai
- Department of Biology, Chemistry and Environmental Health ScienceBenedict CollegeColumbiaSCUSA
| | - Jianshui Li
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
| | - Lingmi Hou
- Northeast Sichuan Acute Pancreatic Research CenterNorth Sichuan Medical CollegeSichuanChina
- Cancer Stem Cells Research CenterAffiliated Hospital of North Sichuan Medical CollegeSichuanChina
- Thyriod and Breast SurgeryAffiliated Hospital of North Sichuan Medical CollegeSichuanChina
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Conciatori F, Bazzichetto C, Falcone I, Ferretti G, Cognetti F, Milella M, Ciuffreda L. Colorectal cancer stem cells properties and features: evidence of interleukin-8 involvement. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:968-979. [PMID: 35582268 PMCID: PMC9019202 DOI: 10.20517/cdr.2019.56] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/13/2019] [Accepted: 09/20/2019] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) still remains a disease with high percentage of death, principally due to therapy resistance and metastasis. During the time the hypothesis has been reinforced that CRC stem cells (CRCSC) are involved in allowing intratumoral heterogeneity, drug escape mechanisms and secondary tumors. CRCSC are characterized by specific surface markers (i.e., CD44 and CD133), signaling pathways activation (i.e., Wnt and Notch) and gene expression (i.e., Oct4 and Snail), which confer to CRCSC self-renewal abilities and pluripotent capacity. Interleukin (IL)-8 is correlated to CRC progression, development of liver metastases and chemoresistance; moreover, IL-8 modulates not only stemness maintenance but also stemness promotion, such as epithelial-mesenchymal transition. This review wants to give a brief and up-to-date overview on IL-8 implication in CRCSC cues.
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Affiliation(s)
- Fabiana Conciatori
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Chiara Bazzichetto
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Italia Falcone
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Gianluigi Ferretti
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Francesco Cognetti
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona 37126, Italy
| | - Ludovica Ciuffreda
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy.,SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
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50
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A Shifty Target: Tumor-Initiating Cells and Their Metabolism. Int J Mol Sci 2019; 20:ijms20215370. [PMID: 31661927 PMCID: PMC6862122 DOI: 10.3390/ijms20215370] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/25/2019] [Accepted: 10/26/2019] [Indexed: 12/20/2022] Open
Abstract
Tumor-initiating cells (TICs), or cancer stem cells, constitute highly chemoresistant, asymmetrically dividing, and tumor-initiating populations in cancer and are thought to play a key role in metastatic and chemoresistant disease. Tumor-initiating cells are isolated from cell lines and clinical samples based on features such as sphere formation in stem cell medium and expression of TIC markers, typically a set of outer membrane proteins and certain transcription factors. Although both bulk tumor cells and TICs show an adaptive metabolic plasticity, TIC metabolism is thought to differ and likely in a tumor-specific and growth condition-dependent pattern. In the context of some common solid tumor diseases, we here review reports on how TIC isolation methods and markers associate with metabolic features, with some focus on oxidative metabolism, including fatty acid and lipid metabolism. These have emerged as significant factors in TIC phenotypes, and in tumor biology as a whole. Other sections address mitochondrial biogenesis and dynamics in TICs, and the influence of the tumor microenvironment. Further elucidation of the complex biology of TICs and their metabolism will require advanced methodologies.
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