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Rist BL, Witte SA, Schultz ZD. Machine Learning Classification of Integrin-Expression-Based Magnetic Sorted SW 620 Cells by Simultaneous O-PTIR and SERS. Anal Chem 2024; 96:17184-17191. [PMID: 39412786 DOI: 10.1021/acs.analchem.4c02685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
Immortalized cell lines are commonly used for in vitro studies such as drug efficacy, toxicology, and life cycle due to their cost effectiveness and accessibility; however, subpopulations within a cell line can arise from random mutations or asynchronous cell cycles which may lead to results that make interpretation difficult. A method that could classify these differences and separate unique subpopulations would increase our understanding of heterogeneous cellular responses. In the present work, we explore spectroscopic signals associated with subpopulations of cells magnetically sorted on the basis of α5β1 integrin binding to cyclic-RGDfC which mimics fibronectin in the extracellular matrix. SW620 colon cancer cells were incubated with cyclic-RGDfC functionalized gold-coated, iron core nanoparticles and magnetically sorted. The subpopulations from the sort were imaged (N = 10 positive and N = 10 negative, number of cells) via simultaneous surface-enhanced Raman scattering (SERS) and optical-photothermal infrared spectroscopy (O-PTIR). Pearson correlations of the standard peptide-protein interaction in the SERS channel allowed for visualization of the cyclic RGDfC-integrin α5β1 interaction. Partial least-squares discriminant analysis of the O-PTIR spectra collected from cell maps successfully classified the positively or negatively sorted cells. These results demonstrate that biochemical changes within a single cell line can be sorted via an integrin-activity-based assay using simultaneous SERS and O-PTIR.
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Affiliation(s)
- Blair L Rist
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Spencer A Witte
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Zachary D Schultz
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
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Aria H, Azizi M, Nazem S, Mansoori B, Darbeheshti F, Niazmand A, Daraei A, Mansoori Y. Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development. Heliyon 2024; 10:e35208. [PMID: 39170516 PMCID: PMC11337742 DOI: 10.1016/j.heliyon.2024.e35208] [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: 02/10/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.
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Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdieh Azizi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Mansoori
- Pediatrics Department, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Darbeheshti
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abdolreza Daraei
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
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Chen G, Han R, Wang L, Ma W, Zhang W, Lu Z, Wang L. Establishment of patient-derived organoids and a characterization based drug discovery platform for treatment of gastric cancer. Cancer Cell Int 2024; 24:288. [PMID: 39143546 PMCID: PMC11323579 DOI: 10.1186/s12935-024-03460-9] [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: 02/02/2024] [Accepted: 07/25/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation. METHODS Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy. RESULTS We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib. CONCLUSION The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.
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Affiliation(s)
- Guo Chen
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China
| | - Ruidong Han
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Li Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China
| | - Wen Ma
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wenli Zhang
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Zifan Lu
- Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China.
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, China.
| | - Lei Wang
- Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
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Chen P, Wu HY. Network pharmacology- and molecular docking-based exploration of the molecular mechanism underlying Jianpi Yiwei Recipe treatment of gastric cancer. World J Gastrointest Oncol 2024; 16:2988-2998. [PMID: 39072163 PMCID: PMC11271781 DOI: 10.4251/wjgo.v16.i7.2988] [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: 02/26/2024] [Revised: 04/26/2024] [Accepted: 05/14/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) is widely used as an important complementary and alternative healthcare system for cancer treatment in Asian countries. Network pharmacology, which utilizes various database platforms and computer software to study the interactions between complex drug components in vivo, is particularly useful for studying the pharmacodynamic mechanisms of multi-pathway and multi-target Chinese medicines. AIM To explore the potential targets and function of Jianpi Yiwei Recipe treatment of gastric cancer (GC) through network pharmacology and molecular docking. METHODS Data on the components of Jianpi Yiwei Recipe (Radix Astragali, Radix Codonopsis, Agrimonia eupatoria, Atractylodes macrocephala Koidz., Poria cocos, stir-baked rhizoma dioscoreae, Amomum villosum Lour., fried Fructus Aurantii, pericarpium citri reticulatae, Rhizoma Pinelliae Preparata, and Radix Glycyrrhizae Preparata) were collected and screened by using the TCM systems pharmacology database and analysis platform (TCMSP). Then the targets of these compounds were predicted. GC-related targets were screened using the GeneCards database. Venn diagram was used to identify common targets. An active ingredient-core target interaction network and a protein-protein interaction (PPI) network were built. Moreover, we performed gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on the core targets and validated them by molecular docking. RESULTS TCMSP screening revealed 11 active components and 184 targets, whereas GeneCards found 10118 disease-related targets, with 180 shared targets between them. Topology analysis of the PPI network identified 38 targets, including ATK1, TP53, and tumor necrosis factor, as key targets for the treatment of GC by Jianpi Yiwei Recipe. Quercetin, naringenin, luteolin, etc., may be the main active components of Jianpi Yiwei Recipe. GO enrichment analysis identified 2809, 1218, and 553 functions related to biological process, molecular function, and cellular component, respectively. KEGG pathway enrichment analysis revealed 167 related pathways, mainly involved in cancer, endocrine resistance, and AGE-RAGE signaling in diabetic complication. Validation with molecular docking analysis showed docking of key active components with core targets. CONCLUSION Jianpi Yiwei Recipe plays a therapeutic role in GC through multiple components, targets, and pathways. These findings form a basis for follow-up exploration of Jianpi Yiwei Recipe in the treatment of GC.
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Affiliation(s)
- Peng Chen
- Traditional Chinese Medicine, The First Teaching Hospital of Tianjin University, Tianjin 300193, China
| | - Huan-Yu Wu
- Traditional Chinese Medicine, The First Teaching Hospital of Tianjin University, Tianjin 300193, China
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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Ramović Hamzagić A, Gazdić Janković M, Cvetković D, Nikolić D, Nikolić S, Milivojević Dimitrijević N, Kastratović N, Živanović M, Miletić Kovačević M, Ljujić B. Machine Learning Model for Prediction of Development of Cancer Stem Cell Subpopulation in Tumurs Subjected to Polystyrene Nanoparticles. TOXICS 2024; 12:354. [PMID: 38787133 PMCID: PMC11125870 DOI: 10.3390/toxics12050354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024]
Abstract
Cancer stem cells (CSCs) play a key role in tumor progression, as they are often responsible for drug resistance and metastasis. Environmental pollution with polystyrene has a negative impact on human health. We investigated the effect of polystyrene nanoparticles (PSNPs) on cancer cell stemness using flow cytometric analysis of CD24, CD44, ABCG2, ALDH1 and their combinations. This study uses simultaneous in vitro cell lines and an in silico machine learning (ML) model to predict the progression of cancer stem cell (CSC) subpopulations in colon (HCT-116) and breast (MDA-MB-231) cancer cells. Our findings indicate a significant increase in cancer stemness induced by PSNPs. Exposure to polystyrene nanoparticles stimulated the development of less differentiated subpopulations of cells within the tumor, a marker of increased tumor aggressiveness. The experimental results were further used to train an ML model that accurately predicts the development of CSC markers. Machine learning, especially genetic algorithms, may be useful in predicting the development of cancer stem cells over time.
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Affiliation(s)
- Amra Ramović Hamzagić
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marina Gazdić Janković
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Danijela Cvetković
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Dalibor Nikolić
- Institute for Information Technologies Kragujevac, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Sandra Nikolić
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | | | - Nikolina Kastratović
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marko Živanović
- Institute for Information Technologies Kragujevac, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marina Miletić Kovačević
- Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Biljana Ljujić
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
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Wyszatko K, Janzen N, Silva LR, Kwon L, Komal T, Ventura M, Venugopal C, Singh SK, Valliant JF, Sadeghi S. 89Zr-labeled ImmunoPET targeting the cancer stem cell antigen CD133 using fully-human antibody constructs. EJNMMI Res 2024; 14:29. [PMID: 38498285 PMCID: PMC10948676 DOI: 10.1186/s13550-024-01091-9] [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: 11/22/2023] [Accepted: 03/04/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND Cancer stem cells play an important role in driving tumor growth and treatment resistance, which makes them a promising therapeutic target to prevent cancer recurrence. Emerging cancer stem cell-targeted therapies would benefit from companion diagnostic imaging probes to aid in patient selection and monitoring response to therapy. To this end, zirconium-89-radiolabeled immunoPET probes that target the cancer stem cell-antigen CD133 were developed using fully human antibody and antibody scFv-Fc scaffolds. RESULTS ImmunoPET probes [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1), [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3), and [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) were radiolabeled with zirconium-89 (radiochemical yield 42 ± 5%, 97 ± 2%, 86 ± 12%, respectively) and each was isolated in > 97% radiochemical purity with specific activities of 120 ± 30, 270 ± 90, and 200 ± 60 MBq/mg, respectively. In vitro binding assays showed a low-nanomolar binding affinity of 0.6 to 1.1 nM (95% CI) for DFO-RW03IgG (CA = 0.7 ± 0.1), 0.3 to 1.9 nM (95% CI) for DFO-RW03IgG (CA = 3.0 ± 0.3), and 1.5 to 3.3 nM (95% CI) for DFO-RW03scFv - Fc (C/A = 0.3). Biodistribution studies found that [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) exhibited the highest tumor uptake (23 ± 4, 21 ± 2, and 23 ± 4%ID/g at 24, 48, and 72 h, respectively) and showed low uptake (< 6%ID/g) in all off-target organs at each timepoint (24, 48, and 72 h). Comparatively, [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1) and [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3) both reached maximum tumor uptake (16 ± 3%ID/g and 16 ± 2%ID/g, respectively) at 96 h p.i. and showed higher liver uptake (10.2 ± 3%ID/g and 15 ± 3%ID/g, respectively) at that timepoint. Region of interest analysis to assess PET images of mice administered [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) showed that this probe reached a maximum tumor uptake of 22 ± 1%ID/cc at 96 h, providing a tumor-to-liver ratio that exceeded 1:1 at 48 h p.i. Antibody-antigen mediated tumor uptake was demonstrated through biodistribution and PET imaging studies, where for each probe, co-injection of excess unlabeled RW03IgG resulted in > 60% reduced tumor uptake. CONCLUSIONS Fully human CD133-targeted immunoPET probes [89Zr]-DFO-RW03IgG and [89Zr]-DFO-RW03scFv - Fc accumulate in CD133-expressing tumors to enable their delineation through PET imaging. Having identified [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) as the most attractive construct for CD133-expressing tumor delineation, the next step is to evaluate this probe using patient-derived tumor models to test its detection limit prior to clinical translation.
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Affiliation(s)
- Kevin Wyszatko
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Nancy Janzen
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Luis Rafael Silva
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Luke Kwon
- Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada
| | - Teesha Komal
- Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada
| | - Manuela Ventura
- Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada
| | - Chitra Venugopal
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Sheila K Singh
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - John F Valliant
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Saman Sadeghi
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada.
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Ke C, Zhou H, Xia T, Xie X, Jiang B. GTP binding protein 2 maintains the quiescence, self-renewal, and chemoresistance of mouse colorectal cancer stem cells via promoting Wnt signaling activation. Heliyon 2024; 10:e27159. [PMID: 38468952 PMCID: PMC10926081 DOI: 10.1016/j.heliyon.2024.e27159] [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: 04/05/2023] [Revised: 02/19/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and the second most deadly cancer across the globe. Colorectal cancer stem cells (CCSCs) fuel CRC growth, metastasis, relapse, and chemoresistance. A complete understanding of the modulatory mechanisms of CCSC biology is essential for developing efficacious CRC treatment. In the current study, we characterized the expression and function of GTP binding protein 2 (GTPBP2) in a chemical-induced mouse CRC model. We found that GTPBP2 was expressed at a higher level in CD133+CD44+ CCSCs compared with other CRC cells. Using a lentivirus-based Cas9/sgRNA system, GTPBP2 expression was ablated in CRC cells in vitro. GTPBP2 deficiency caused the following effects on CCSCs: 1) Significantly accelerating proliferation and increasing the proportions of cells at G1, S, and G2/M phase; 2) Impairing resistance to 5-Fluorouracil; 3) Weakening self-renewal but not impacting cell migration. In addition, GTPBP2 deficiency remarkably decreased β-catenin expression while increasing β-catenin phosphorylation in CCSCs. These effects of GTPBP2 were present in CCSCs but not in other CRC cell populations. The Wnt agonist SKL2001 completely abolished these changes in GTPBP2-deficient CCSCs. When GTPBP2-deficient CCSCs were implanted in nude mice, they exhibited consistent changes compared with GTPBP2-expressing CCSCs. Collectively, this study indicates that GTPBP2 positively modulates Wnt signaling to reinforce the quiescence, self-renewal, and chemoresistance of mouse CCSCs. Therefore, we disclose a novel mechanism underlying CCSC biology and GTPBP2 could be a therapeutic target in future CRC treatment.
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Affiliation(s)
- Chao Ke
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Hongjian Zhou
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Tian Xia
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Xingwang Xie
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Bin Jiang
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
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Ortega Duran M, Shaheed SU, Sutton CW, Shnyder SD. A Proteomic Investigation to Discover Candidate Proteins Involved in Novel Mechanisms of 5-Fluorouracil Resistance in Colorectal Cancer. Cells 2024; 13:342. [PMID: 38391955 PMCID: PMC10886605 DOI: 10.3390/cells13040342] [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: 12/20/2023] [Revised: 01/31/2024] [Accepted: 02/10/2024] [Indexed: 02/24/2024] Open
Abstract
One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.
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Affiliation(s)
- Mario Ortega Duran
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
| | - Sadr ul Shaheed
- Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9BQ, UK;
| | - Christopher W. Sutton
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
| | - Steven D. Shnyder
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
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10
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Shih JW, Wu ATH, Mokgautsi N, Wei PL, Huang YJ. Preclinical Repurposing of Sitagliptin as a Drug Candidate for Colorectal Cancer by Targeting CD24/ CTNNB1/ SOX4-Centered Signaling Hub. Int J Mol Sci 2024; 25:609. [PMID: 38203779 PMCID: PMC10778938 DOI: 10.3390/ijms25010609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, β-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.
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Affiliation(s)
- Jing-Wen Shih
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; (J.-W.S.); (N.M.)
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
| | - Alexander T. H. Wu
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Ntlotlang Mokgautsi
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; (J.-W.S.); (N.M.)
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Po-Li Wei
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
| | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
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11
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Huang CH, Pai PC, Lei KF. Investigation of Stem Cell-Like Characteristics and Immune Cell Interaction of Tumor Cells Survived from Continuous Shear Flow Environment. Adv Biol (Weinh) 2024; 8:e2300332. [PMID: 37752715 DOI: 10.1002/adbi.202300332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/25/2023] [Indexed: 09/28/2023]
Abstract
When tumor cells are released from a primary tumor into the bloodstream or lymphatic circulation system, they are exposed to a continuous shear flow environment. This environment exerts physical stresses on the tumor cells, which can activate apoptotic pathways. However, certain tumor cells have the ability to adapt to these mechanical stresses, enhancing their likelihood of survival and promoting metastasis. In this study, these tumor cells survived from shear flow environment are examined and revealed to closely link to stem cell-like characteristics. Higher gene expression levels of self-renewal and differentiation markers and enhanced abilities of migration, spheroid formation, and colony formation are shown. Moreover, the interaction between immune cells and the surviving cells is investigated. The results show that the surviving cells possess immune escape capabilities, implying their ability to evade immune surveillance. Additionally, these surviving cells display characteristics reminiscent of stem cells. This study holds great importance in advancing the understanding of tumor biology. By comprehending the behavior and properties of these surviving cells, new therapeutic strategies can be developed to specifically target circulating tumor cells (CTCs) and enhance cancer treatment outcomes.
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Affiliation(s)
- Chia-Hao Huang
- Department of Biomedical Engineering, Chang Gung University, Taoyuan, 33302, Taiwan
| | - Ping-Ching Pai
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, 33305, Taiwan
| | - Kin Fong Lei
- Department of Biomedical Engineering, Chang Gung University, Taoyuan, 33302, Taiwan
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, 33305, Taiwan
- Department of Electrical & Electronic Engineering, Yonsei University, Seoul, 03722, South Korea
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12
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Erisik D, Ozdil B, Acikgoz E, Asker Abdikan CS, Yesin TK, Aktug H. Differences and Similarities between Colorectal Cancer Cells and Colorectal Cancer Stem Cells: Molecular Insights and Implications. ACS OMEGA 2023; 8:30145-30157. [PMID: 37636966 PMCID: PMC10448492 DOI: 10.1021/acsomega.3c02681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023]
Abstract
Malignant tumors are formed by diverse groups of cancer cells. Cancer stem cells (CSCs) are a subpopulation of heterogeneous cells identified in tumors that have the ability to self-renew and differentiate. Colorectal cancer (CRC), the third most frequent malignant tumor, is progressively being supported by evidence suggesting that CSCs are crucial in cancer development. We aim to identify molecular differences between CRC cells and CRC CSCs, as well as the effects of those differences on cell behavior in terms of migration, EMT, pluripotency, morphology, cell cycle/control, and epigenetic characteristics. The HT-29 cell line (human colorectal adenocarcinoma) and HT-29 CSCs (HT-29 CD133+/CD44+ cells) were cultured for 72 h. The levels of E-cadherin, KLF4, p53, p21, p16, cyclin D2, HDAC9, and P300 protein expression were determined using immunohistochemistry staining. The migration of cells was assessed by employing the scratch assay technique. Additionally, the scanning electron microscopy method was used to examine the morphological features of the cells, and their peripheral/central elemental ratios were compared with the help of EDS. Furthermore, a Muse cell cycle kit was utilized to determine the cell cycle analysis. The HT-29 CSC group exhibited high levels of expression for E-cadherin, p53, p21, p16, cyclin D2, HDAC9, and P300, whereas KLF4 was found to be high in the HT-29. The two groups did not exhibit any statistically significant differences in the percentages of cell cycle phases. The identification of specific CSC characteristics will allow for earlier cancer detection and the development of more effective precision oncology options.
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Affiliation(s)
- Derya Erisik
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Berrin Ozdil
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
- Department
of Histology and Embryology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey
| | - Eda Acikgoz
- Department
of Histology and Embryology, Faculty of Medicine, Yuzuncu Yil University, Van 65080, Turkey
| | | | - Taha Kadir Yesin
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Huseyin Aktug
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
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13
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Lv S, Liu Y, Xie C, Xue C, Du S, Yao J. Emerging role of interactions between tumor angiogenesis and cancer stem cells. J Control Release 2023; 360:468-481. [PMID: 37391031 DOI: 10.1016/j.jconrel.2023.06.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/16/2023] [Accepted: 06/27/2023] [Indexed: 07/02/2023]
Abstract
Tumor angiogenesis and cancer stem cells (CSCs) are two major hallmarks of solid tumors. They have long received attention for their critical roles in tumor progression, metastasis and recurrence. Meanwhile, plenty of evidence indicates the close association between CSCs and tumor vasculature. CSCs are proven to promote tumor angiogenesis, and the highly vascularized tumor microenvironment further maintains CSCs growth in return, thereby forming a hard-breaking vicious circle to promote tumor development. Hence, though monotherapy targeting tumor vasculature or CSCs has been extensively studied over the past decades, the poor prognosis has been limiting the clinical application. This review summarizes the crosstalk between tumor vasculature and CSCs with emphasis on small-molecule compounds and the associated biological signaling pathways. We also highlight the importance of linking tumor vessels to CSCs to disrupt the CSCs-angiogenesis vicious circle. More precise treatment regimens targeting tumor vasculature and CSCs are expected to benefit future tumor treatment development.
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Affiliation(s)
- Shuai Lv
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Yufei Liu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Changheng Xie
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Chenyang Xue
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Shi Du
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
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14
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Peña M, Mesas C, Perazzoli G, Martínez R, Porres JM, Doello K, Prados J, Melguizo C, Cabeza L. Antiproliferative, Antioxidant, Chemopreventive and Antiangiogenic Potential of Chromatographic Fractions from Anemonia sulcata with and without Its Symbiont Symbiodinium in Colorectal Cancer Therapy. Int J Mol Sci 2023; 24:11249. [PMID: 37511009 PMCID: PMC10379856 DOI: 10.3390/ijms241411249] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/06/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Anemonia sulcata may be a source of marine natural products (MNPs) due to the antioxidant and antitumor activity of its crude homogenates shown in vitro in colon cancer cells. A bioguided chromatographic fractionation assay of crude Anemonia sulcata homogenates with and without its symbiont Symbiodinium was performed to characterize their bioactive composition and further determine their biological potential for the management of colorectal cancer (CRC). The 20% fractions retained the in vitro antioxidant activity previously reported for homogenates. As such, activation of antioxidant and detoxifying enzymes was also evaluated. The 40% fractions showed the greatest antiproliferative activity in T84 cells, synergistic effects with 5-fluoruracil and oxaliplatin, overexpression of apoptosis-related proteins, cytotoxicity on tumorspheres, and antiangiogenic activity. The predominantly polar lipids and toxins tentatively identified in the 20% and 40% fractions could be related to their biological activity in colon cancer cells although further characterizations of the active fractions are necessary to isolate and purify the bioactive compounds.
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Affiliation(s)
- Mercedes Peña
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
| | - Cristina Mesas
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
| | - Rosario Martínez
- Department of Physiology, Institute of Nutrition and Food Technology (INyTA), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Jesús M Porres
- Department of Physiology, Institute of Nutrition and Food Technology (INyTA), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Kevin Doello
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
- Medical Oncology Service, Virgen de las Nieves Hospital, 18016 Granada, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
| | - Laura Cabeza
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
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15
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Sai S, Koto M, Yamada S. Basic and translational research on carbon-ion radiobiology. Am J Cancer Res 2023; 13:1-24. [PMID: 36777517 PMCID: PMC9906076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 11/16/2022] [Indexed: 02/14/2023] Open
Abstract
Carbon-ion beam irradiation (IR) has evident advantages over the conventional photon beams in treating tumors. It releases enormous amount of energy in a well-defined range with insignificant scatter in surrounding tissues based on well-localized energy deposition. Over the past 28 years, more than 14,000 patients with various types of cancer have been treated by carbon ion radiotherapy (CIRT) with promising results at QST. I have provided an overview of the basic and translational research on carbon-ion radiobiology including mechanisms underlying high linear energy transfer (LET) carbon-ion IR-induced cell death (apoptosis, autophagy, senescence, mitotic catastrophe etc.) and high radiocurability produced by carbon-ion beams in combination with DNA damaging drugs or with molecular-targeted drugs, micro-RNA therapeutics and immunotherapy. Additionally, I have focused on the application of these treatment in human cancer cells, especially cancer stem cells (CSCs). Finally, I have summarized the current studies on the application of basic carbon-ion beam IR according to the cancer types and clinical outcomes.
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Affiliation(s)
- Sei Sai
- Department of Charged Particle Therapy Research, Institute of Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
| | - Masashi Koto
- Department of Charged Particle Therapy Research, Institute of Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)Chiba, Japan,QST Hospital, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
| | - Shigeru Yamada
- QST Hospital, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
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16
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Patel SG, Patel A, Patel N, Raiya B, Vora H, Jain N. Investigating the resistance mechanism of 5-fluorouracil in colorectal cancer based on surface markers of cancer stemness and cytokine level: A pre-clinical study. J Cancer Res Ther 2023; 19:S560-S568. [PMID: 38384019 DOI: 10.4103/jcrt.jcrt_1299_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/04/2022] [Indexed: 02/23/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is the deadliest malignancy in the world. The first-line chemotherapy used for CRC is 5-fluorouracil (5-FU). 5-FU completely eradicates rapidly proliferating and terminally differentiated tumor cells but fails to target cancer stem cells (CSCs). As a result, the tumor may shrink temporarily, but remnant CSC multiplies and forms a tumor again more aggressively. The recurrence and resistance lead to metastasis. METHODOLOGY CRC was induced in 12 Sprague-Dawley (RPCP/IAEC/2019-20/R2) rats by 1,2 dimethyl hydrazine. Later, animals were treated with 5-FU for 7 weeks at a 10 mg/kg dose by the subcutaneous route. At the end of treatment, half population was sacrificed (6), whereas the remaining half (6) was left without treatment of 5-FU for 5 weeks and then sacrificed. Parameters such as body weight, complete blood count (CBC), immune cell subset (CD4, CD8, and NK cells), colon length to weight index, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level, occult blood in stool, tumor multiplicity, and liver metastasis were estimated. In addition, the dissected colon was fixed in formalin and sent to the histology lab for hematoxylin-eosin staining and immunohistochemistry at both intervals. RESULTS All blood and tissue-based markers have shown significant differences (p < 0.05) between the animals sacrificed at the end of the 27th week and the end of the 32nd week for 5-FU treatment. CONCLUSION It can be concluded that 5-FU up-regulates inflammatory cytokines and cell surface markers of CSC that promote CRC stemness via the Wnt/β-catenin pathway. Also, involvement of Nf-κB, fibronectin, MMP-9, and RANKL leads to tumorigenesis, disease aggressiveness, metastasis, and resistance.
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Affiliation(s)
- Samir G Patel
- Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, Changa, India
| | - Alkeshkumar Patel
- Department of Pharmacology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, Changa, India
| | - Nupur Patel
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Birva Raiya
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Hemangini Vora
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Neeraj Jain
- Department of Biological Sciences, P D Patel Institute of Applied Sciences, Charotar University of Science & Technology, Changa, Anand, Gujarat, India
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17
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Gu Y, Bobrin V, Zhang D, Sun B, Ng CK, Chen SPR, Gu W, Monteiro MJ. RGD-Coated Polymer Nanoworms for Enriching Cancer Stem Cells. Cancers (Basel) 2022; 15:cancers15010234. [PMID: 36612229 PMCID: PMC9818073 DOI: 10.3390/cancers15010234] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/24/2022] [Accepted: 12/25/2022] [Indexed: 01/04/2023] Open
Abstract
Cancer stem cells (CSCs) are primarily responsible for tumour drug resistance and metastasis; thus, targeting CSCs can be a promising approach to stop cancer recurrence. However, CSCs are small in numbers and readily differentiate into matured cancer cells, making the study of their biological features, including therapeutic targets, difficult. The use of three-dimensional (3D) culture systems to enrich CSCs has some limitations, including low sphere forming efficiency, enzymatic digestion that may damage surface proteins, and more importantly no means to sustain the stem properties. A responsive 3D polymer extracellular matrix (ECM) system coated with RGD was used to enrich CSCs, sustain stemness and avoid enzymatic dissociation. RGD was used as a targeting motif and a ligand to bind integrin receptors. We found that the system was able to increase sphere forming efficiency, promote the growth of spheric cells, and maintain stemness-associated properties compared to the current 3D culture. We showed that continuous culture for three generations of colon tumour spheroid led to the stem marker CD24 gradually increasing. Furthermore, the new system could enhance the cancer cell sphere forming ability for the difficult triple negative breast cancer cells, MBA-MD-231. The key stem gene expression for colon cancer also increased with the new system. Further studies indicated that the concentration of RGD, especially at high doses, could inhibit stemness. Taken together, our data demonstrate that our RGD-based ECM system can facilitate the enrichment of CSCs and now allow for the investigation of new therapeutic approaches for colorectal cancer or other cancers.
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Affiliation(s)
- Yushu Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Valentin Bobrin
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Dayong Zhang
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Department of Clinical Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Bing Sun
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Chun Ki Ng
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Sung-Po R. Chen
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Correspondence: (W.G.); (M.J.M.)
| | - Michael J. Monteiro
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Correspondence: (W.G.); (M.J.M.)
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18
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Pramanik A, Xu Z, Ingram N, Coletta PL, Millner PA, Tyler AII, Hughes TA. Hyaluronic-Acid-Tagged Cubosomes Deliver Cytotoxics Specifically to CD44-Positive Cancer Cells. Mol Pharm 2022; 19:4601-4611. [PMID: 35938983 PMCID: PMC9727730 DOI: 10.1021/acs.molpharmaceut.2c00439] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Delivery of chemotherapy drugs specifically to cancer cells raises local drug doses in tumors and therefore kills more cancer cells while reducing side effects in other tissues, thereby improving oncological and quality of life outcomes. Cubosomes, liquid crystalline lipid nanoparticles, are potential vehicles for delivery of chemotherapy drugs, presenting the advantages of biocompatibility, stable encapsulation, and high drug loading of hydrophobic or hydrophilic drugs. However, active targeting of drug-loaded cubosomes to cancer cells, as opposed to passive accumulation, remains relatively underexplored. We formulated and characterized cubosomes loaded with potential cancer drug copper acetylacetonate and functionalized their surfaces using click chemistry coupling with hyaluronic acid (HA), the ligand for the cell surface receptor CD44. CD44 is overexpressed in many cancer types including breast and colorectal. HA-tagged, copper-acetylacetonate-loaded cubosomes have an average hydrodynamic diameter of 152 nm, with an internal nanostructure based on the space group Im3m. These cubosomes were efficiently taken up by two CD44-expressing cancer cell lines (MDA-MB-231 and HT29, representing breast and colon cancer) but not by two CD44-negative cell lines (MCF-7 breast cancer and HEK-293 kidney cells). HA-tagged cubosomes caused significantly more cell death than untargeted cubosomes in the CD44-positive cells, demonstrating the value of the targeting. CD44-negative cells were equally relatively resistant to both, demonstrating the specificity of the targeting. Cell death was characterized as apoptotic. Specific targeting and cell death were evident in both 2D culture and 3D spheroids. We conclude that HA-tagged, copper-acetylacetonate-loaded cubosomes show great potential as an effective therapeutic for selective targeting of CD44-expressing tumors.
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Affiliation(s)
- Arindam Pramanik
- School
of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom,
| | - Zexi Xu
- School
of Food Science and Nutrition, University
of Leeds, Leeds LS2 9JT, United Kingdom
| | - Nicola Ingram
- School
of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom
| | | | - Paul A Millner
- School
of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Arwen I I Tyler
- School
of Food Science and Nutrition, University
of Leeds, Leeds LS2 9JT, United Kingdom,
| | - Thomas A Hughes
- School
of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom,
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19
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Alkhatib H, Rubinstein AM, Vasudevan S, Flashner-Abramson E, Stefansky S, Chowdhury SR, Oguche S, Peretz-Yablonsky T, Granit A, Granot Z, Ben-Porath I, Sheva K, Feldman J, Cohen NE, Meirovitz A, Kravchenko-Balasha N. Computational quantification and characterization of independently evolving cellular subpopulations within tumors is critical to inhibit anti-cancer therapy resistance. Genome Med 2022; 14:120. [PMID: 36266692 PMCID: PMC9583500 DOI: 10.1186/s13073-022-01121-y] [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: 01/20/2022] [Accepted: 09/28/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Drug resistance continues to be a major limiting factor across diverse anti-cancer therapies. Contributing to the complexity of this challenge is cancer plasticity, in which one cancer subtype switches to another in response to treatment, for example, triple-negative breast cancer (TNBC) to Her2-positive breast cancer. For optimal treatment outcomes, accurate tumor diagnosis and subsequent therapeutic decisions are vital. This study assessed a novel approach to characterize treatment-induced evolutionary changes of distinct tumor cell subpopulations to identify and therapeutically exploit anticancer drug resistance. METHODS In this research, an information-theoretic single-cell quantification strategy was developed to provide a high-resolution and individualized assessment of tumor composition for a customized treatment approach. Briefly, this single-cell quantification strategy computes cell barcodes based on at least 100,000 tumor cells from each experiment and reveals a cell-specific signaling signature (CSSS) composed of a set of ongoing processes in each cell. RESULTS Using these CSSS-based barcodes, distinct subpopulations evolving within the tumor in response to an outside influence, like anticancer treatments, were revealed and mapped. Barcodes were further applied to assign targeted drug combinations to each individual tumor to optimize tumor response to therapy. The strategy was validated using TNBC models and patient-derived tumors known to switch phenotypes in response to radiotherapy (RT). CONCLUSIONS We show that a barcode-guided targeted drug cocktail significantly enhances tumor response to RT and prevents regrowth of once-resistant tumors. The strategy presented herein shows promise in preventing cancer treatment resistance, with significant applicability in clinical use.
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Affiliation(s)
- Heba Alkhatib
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Ariel M Rubinstein
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Swetha Vasudevan
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Efrat Flashner-Abramson
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Shira Stefansky
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Sangita Roy Chowdhury
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Solomon Oguche
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel
| | - Tamar Peretz-Yablonsky
- Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, 9103401, Jerusalem, Israel
| | - Avital Granit
- Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, 9103401, Jerusalem, Israel
| | - Zvi Granot
- Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, 91120, Jerusalem, Israel
| | - Ittai Ben-Porath
- Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, 91120, Jerusalem, Israel
| | - Kim Sheva
- The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka University Medical Center, Ben Gurion University of the Negev, Faculty of Medicine, 8410101, Beer Sheva, Israel
| | - Jon Feldman
- Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, 9103401, Jerusalem, Israel
| | - Noa E Cohen
- School of Software Engineering and Computer Science, Azrieli College of Engineering, 9103501, Jerusalem, Israel
| | - Amichay Meirovitz
- The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka University Medical Center, Ben Gurion University of the Negev, Faculty of Medicine, 8410101, Beer Sheva, Israel.
| | - Nataly Kravchenko-Balasha
- The institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, 9103401, Jerusalem, Israel.
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Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma. Biomed Pharmacother 2022; 153:113465. [DOI: 10.1016/j.biopha.2022.113465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 11/20/2022] Open
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21
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Firouzi J, Sotoodehnejadnematalahi F, Shokouhifar A, Rahimi M, Sodeifi N, Sahranavardfar P, Azimi M, Janzamin E, Safa M, Ebrahimi M. Silibinin exhibits anti-tumor effects in a breast cancer stem cell model by targeting stemness and induction of differentiation and apoptosis. BIOIMPACTS : BI 2022; 12:415-429. [PMID: 36381630 PMCID: PMC9596878 DOI: 10.34172/bi.2022.23336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 08/27/2021] [Accepted: 09/18/2021] [Indexed: 06/16/2023]
Abstract
Introduction: Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres. Methods: The effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC50 dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice. Results: The results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold. Conclusion: The present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.
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Affiliation(s)
- Javad Firouzi
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | | | - Alireza Shokouhifar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Mahsa Rahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Niloufar Sodeifi
- Department of Pathology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran 16635-148, Iran
| | - Parisa Sahranavardfar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Masoumeh Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Ehsan Janzamin
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Majid Safa
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
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22
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Bagheri R, Rassouli FB, Gholamhosseinian H, Ebrahimi K, Mahdavi S, Goudarzi S, Iranshahi M, Rafatpanah H, Keramati MR. Radiation Response of Human Leukemia/Lymphoma Cells was Improved by 7-Geranyloxycoumarin. Dose Response 2022; 20:15593258221124479. [PMID: 36158737 PMCID: PMC9500271 DOI: 10.1177/15593258221124479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objectives Adult T-cell leukemia/lymphoma (ATLL) is a blood neoplasm with specific geographic distribution. Although radiotherapy is a palliative treatment that provides long-term local control, single use of radiation leads to complications for patients. To introduce a novel multimodal approach against ATLL, we investigated combinatorial effects of 7-geranyloxycoumarin and radiation in vitro. Methods Viability of MT-2 cells was determined by resazurin assay upon administration of 7-geranyloxycoumarin alone and followed by radiation. Then, apoptosis was detected by annexin V and propidium iodide, and the expression of candidate genes was analyzed by qPCR. Results Findings revealed significant (P<.0001) improvement in radiation effects upon 7-geranyloxycoumarin pretreatment, most notably when cells were pretreated with 5 µg/ml 7-geranyloxycoumarin for 96 h, exposed to 6 Gy radiation and recovered for 48 h. These results were confirmed by flow cytometry, as the percentage of early and late apoptotic cells was increased after combinatorial treatment. In addition, significant (P< .0001) changes in CD44, c-MYC, cFLIPL, BMI-1, NF-κB (Rel A), and P53 expression was induced by 7-geranyloxycoumarin and radiation. Conclusions Current research indicated, for the first time, that combinatorial use of 7-geranyloxycoumarin and ionizing radiation could be considered as an effective therapeutic modality for ATLL.
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Affiliation(s)
- Ramin Bagheri
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B. Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hamid Gholamhosseinian
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Keyhan Ebrahimi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shakiba Mahdavi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Sajad Goudarzi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Center, Inflammation and inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keramati
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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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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Yu PC, Liu D, Han ZX, Liang F, Hao CY, Lei YT, Guo CR, Wang WH, Li XH, Yang XN, Li CZ, Yu Y, Fan YZ. Thymopentin-Mediated Inhibition of Cancer Stem Cell Stemness Enhances the Cytotoxic Effect of Oxaliplatin on Colon Cancer Cells. Front Pharmacol 2022; 13:779715. [PMID: 35242031 PMCID: PMC8886222 DOI: 10.3389/fphar.2022.779715] [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: 09/19/2021] [Accepted: 01/31/2022] [Indexed: 12/02/2022] Open
Abstract
Thymopentin (TP5) is an immunomodulatory pentapeptide that has been widely used in malignancy patients with immunodeficiency due to radiotherapy and chemotherapy. Here, we propose that TP5 directly inhibits the stemness of colon cancer cells HCT116 and therefore enhances the cytotoxicity of oxaliplatin (OXA) in HCT116 cells. In the absence of serum, TP5 was able to induce cancer stemness reduction in cultured HCT116 cells and significantly reduced stemness-related signals, such as the expression of surface molecular markers (CD133, CD44 and CD24) and stemness-related genes (ALDH1, SOX2, Oct-4 and Nanog), and resulted in altered Wnt/β-catenin signaling. Acetylcholine receptors (AchRs) are implicated in this process. OXA is a common chemotherapeutic agent with therapeutic effects in various cancers. Although TP5 had no direct effect on the proliferation of HCT116, this pentapeptide significantly increased the sensitivity of HCT116 to OXA, where the effect of TP5 on the stemness of colon cancer cells through stimulation of AchRs may contribute to this process. Our results provide a promising strategy for increasing the sensitivity of colon cancer cells to chemotherapeutic agents by incorporating immunomodulatory peptides.
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Affiliation(s)
- Peng-Cheng Yu
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Di Liu
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zeng-Xiang Han
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Three Departments of Oncology, Weifang Traditional Chinese Medicine Hospital, Weifang, China
| | - Fang Liang
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cui-Yun Hao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yun-Tao Lei
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chang-Run Guo
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wen-Hui Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xing-Hua Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiao-Na Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chang-Zhu Li
- State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha, China
| | - Ye Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ying-Zhe Fan
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Abdelrahman AE, El-Azony A, Elsebai E, Ibrahim HM. Prognostic Impact of LGR5, Prox1, and Notch1 Biomarkers in Stage II to III Colon Cancer. Appl Immunohistochem Mol Morphol 2022; 30:126-135. [PMID: 34657081 DOI: 10.1097/pai.0000000000000983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/14/2021] [Indexed: 11/26/2022]
Abstract
The potentiation and activation of Wnt signaling pathways are now assumed to mediate the self-renewal and proliferation of colon cancer stem cells that are responsible for therapeutic resistance, tumor relapse, and metastasis. We aimed to evaluate LGR5, Prox1, and Notch1 immunohistochemical expression in stage II to III colon cancer. Their predictive role of tumor relapse, overall survival, and disease-free survival was statistically analyzed. Our results revealed that high LGR5 expression was identified in 56.7% of the patients, LGR5 expression was significantly associated with left-sided tumors (P<0.001). Moreover, its expression was significantly associated with the unfavorable tumor characteristics including high grade, deep invasion (pT), lymph node metastasis, and advanced tumor stage (P<0.001 for each). High Prox1 expression was observed in 65% of the cases, and its expression was significantly associated with tumor grade, lymph node metastasis, and the advanced tumor stage (P=0.004, 0.009, 0.016, respectively). Positive Notch1 expression was identified in 35% of patients, and it was inversely associated with high grade lymph node metastasis, deep invasion (pT), and advanced tumor stage (P<0.001 for each). During the follow-up period, the tumor relapse was significantly associated with high LGR5, high Prox1, and negative Notch1 expression. Shorter overall survival and disease-free survival were significantly associated with high LGR5, high Prox1, and negative Notch1 expression. High LGR5, high Prox1, and negative Notch1 expression are unfavorable prognostic factors in colon cancer. Prox1 is a crucial regulator of Notch-independent LGR5+ stem cells that is mostly responsible for relapse and therapeutic resistance in stage II to III colon cancer.
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Affiliation(s)
| | - Ahmed El-Azony
- Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Eman Elsebai
- Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Identification, Culture and Targeting of Cancer Stem Cells. Life (Basel) 2022; 12:life12020184. [PMID: 35207472 PMCID: PMC8879966 DOI: 10.3390/life12020184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.
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Wu AT, Yeh YC, Huang YJ, Mokgautsi N, Lawal B, Huang TH. Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 95:153797. [PMID: 34802869 DOI: 10.1016/j.phymed.2021.153797] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 09/24/2021] [Accepted: 10/07/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts (CAFs) facilitate the generation of cancer stem-like cells (CSCs) and drug resistance. Glycogen synthase kinase-3 (GSK) associated signaling pathways have been implicated in the generation of CSCs and represent a target for therapeutics development. HYPOTHESIS Gamma-mangostin (gMG) isolated from Garcinia mangostana was evaluated for its ability to downregulate GSK3β-associated signaling in CRC cells and overcome CAF-induced 5-fluorouracil resistance and CSC generation. METHODS Bioinformatics analysis, in silico molecular docking, in vitro assays, including cell viability tests, colony- and tumor sphere-formation assays, transwell migration assays, ELISA, SDS-PAGE, Western blotting, miR expression, qPCR, and flow cytometry, as well as in vivo mouse xenograft models were used to evaluate the antitumor effects of gMG. RESULTS Bioinformatics analyses indicated that GSK3β/CDK6/β-catenin mRNA signature was significantly higher in colon cancer patients. Additional algorithms predicted a higher miR-26b level was associated with significantly higher survival in CRC patients and GSK3β and CDK6 as targets of miR-26b-5p. To validate these findings in vitro, we showed that CAF-cocultured CRC cells expressed an increased expression of GSK3β, β-catenin, CDK6, and NF-κB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3β-associated signaling pathways while concomitantly increased the miR-26b-5p level. Using a xenograft mouse model of CAFs cocultured HCT116 tumorspheres, we showed that gMG treatment reduced tumor growth and overcame CAF-induced 5-fluorouracil resistance. CONCLUSIONS Pharmacological intervention with gMG suppressed CRC carcinogenesis and stemness via downregulating GSK3/β-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.
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Affiliation(s)
- Alexander Th Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; International PhD Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei 11031, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Yuan-Chieh Yeh
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, 20401, Taiwan; Program in Molecular Medicine, School of Life Sciences, National Yang Ming University, Taipei 11221, Taiwan
| | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Department of Surgery, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ntlotlang Mokgautsi
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute for Cancer Biology & Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute for Cancer Biology & Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333, Taiwan; School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan; Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Department & Graduate Institute of Chemical Engineering & Graduate Institute of Biochemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan.
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He Y, Liu S, Newburg DS. Musarin, a novel protein with tyrosine kinase inhibitory activity from Trametes versicolor, inhibits colorectal cancer stem cell growth. Biomed Pharmacother 2021; 144:112339. [PMID: 34656057 DOI: 10.1016/j.biopha.2021.112339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer is the second deadly cancer in the world. Trametes versicolor is a traditional Chinese medicinal mushroom with a long history of being used to regulate immunity and prevent cancer. Trametes versicolor mushroom extract demonstrates strongly cell growth inhibitory activity on human colorectal tumor cells. In this study, we characterized a novel 12-kDa protein that named musarin, which was purified from Trametes versicolor mushroom extract and showed significant growth inhibition on multiple human colorectal cancer cell lines in vitro. The protein sequence of musarin was determined through enzyme digestion and MS/MS analysis. Furthermore, Musarin, in particular, strongly inhibits aggressive human colorectal cancer stem cell-like CD24+CD44+ HT29 proliferation in vitro and in a NOD/SCID murine xenograft model. Through whole transcription profile and gene enrichment analysis of musarin-treated CSCs-like cells, major signaling pathways and network modulated by musarin have been enriched, including the bioprocess of the Epithelial-Mesenchymal Transition, the EGFR-Ras signaling pathway and enzyme inhibitor activity. Musarin demonstrated tyrosine kinase inhibitory activity in vitro. Musarin strongly attenuated EGFR expression and down-regulated phosphorylation level, thereby slowing cancer cells proliferation. In addition, oral ingestion of musarin significantly inhibited CD24+CD44+ HT29 generated tumor development in SCID/NOD mice with less side effects in microgram doses. Targeting self-renewal aggressive stem-cell like cancer cell proliferation, with higher water solubility and lower cytotoxicity, musarin has shown strong potence to be developed as a promising novel therapeutic drug candidate against colorectal cancers, especially those that acquire chemo-resistance.
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Affiliation(s)
- YingYing He
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; School of Chemical Science & Technology, Yunnan University, Kunming, Yunnan 650091, China
| | - Shubai Liu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
| | - David S Newburg
- University of Cincinnati College of Medicine, 130 Panzeca Way, Cincinnati, OH 45267, USA.
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Altundag Ö, Canpinar H, Çelebi-Saltik B. Methionine affects the expression of pluripotency genes and protein levels associated with methionine metabolism in adult, fetal, and cancer stem cells. J Cell Biochem 2021; 123:406-416. [PMID: 34783058 DOI: 10.1002/jcb.30180] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/01/2021] [Accepted: 11/05/2021] [Indexed: 01/07/2023]
Abstract
Intracellular and extracellular regulatory factors promote the potency and self-renewal property of stem cells. Methionine is fundamental for protein synthesis and regulation of methylation reactions. Specifically, methionine metabolism in embryonic and fetal development processes regulates gene expression profile/epigenetic identity of stem cells to achieve pluripotency and cellular functions. We aimed to reveal the differences in methionine metabolism of bone marrow (BM)-mesenchymal stem cells (MSCs), umbilical cord blood (UCB)-MSCs, and cancer stem cells (CSCs), which reflect different metabolic profiles and developmental stages of stem cells. UCB-MSC, BM-MSCs, and breast CSCs were treated with different doses (0, 10, 25, 50, and 100 µM) of l-methionine. Cell surface marker and cell cycle assessment were performed by flow cytometry. Changes in gene expressions (OCT3/4, NANOG, DMNT1, DNMT3A, and DNMT3B, MAT2A, and MAT2B) with methionine supplementation were examined by quantitative real-time polymerase chain reaction and the changes in histone methylation (H3K4me3, H3K27me3) levels were demonstrated by western blot analysis. S-adenosylmethionine//S-adenosylhomocysteine (SAM/SAH) levels were evaluated by enzyme-linked immunosorbent assay. Cells that were exposed to different concentrations of l-methionine, were mostly arrested in the G0/G1 phase for each stem cell group. It was evaluated that BM-MSCs increased all gene expressions in the culture medium-containing 100 µM methionine, in addition to SAM/SAH levels. On the other hand, UCB-MSCs were found to increase OCT3/4, NANOG, and DNMT1 gene expressions and decrease MAT2A and MAT2B expressions in the culture medium containing 10 µM methionine. Moreover, an increase was observed in the He3K4me3 methylation profile. In addition, OCT3/4, NANOG, DNMT1, and MAT2B gene expressions in CSCs increased starting from the addition of 25 µM methionine. An increase was determined in H3K4me3 protein expression at 50 and 100 µM methionine-supplemented culture condition. This study demonstrates that methionine plays a critical role in metabolism and epigenetic regulation in different stem cell groups.
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Affiliation(s)
- Özlem Altundag
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Sihhiye, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Sihhiye, Turkey
| | - Hande Canpinar
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Sihhiye, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Sihhiye, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Sihhiye, Turkey
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Li M, Shi M, Xu Y, Qiu J, Lv Q. Histone Methyltransferase KMT2D Regulates H3K4 Methylation and is Involved in the Pathogenesis of Ovarian Cancer. Cell Transplant 2021; 30:9636897211027521. [PMID: 34705580 PMCID: PMC8554562 DOI: 10.1177/09636897211027521] [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] [Indexed: 01/08/2023] Open
Abstract
To investigate the function of histone-lysine N-methyltransferase 2D (KMT2D) on the methylation of H3 lysine 4 (H3K4) in the progression of Ovarian cancer (OV). KMT2D, ESR1 and H3K4me expressions in surgical resected tumors and tumor adjacent tissues of OV from 198 patients were determined using immunohistochemistry (IHC). Human OV cell lines including SKOV3, HO-8910 cells and normal ovarian epithelial cell line IOSE80 were employed for in vitro experiment, and BALB/C female nude mice were used for in vivo study. qRT-PCR and Western blotting were implemented for measuring the KMT2D, ESR1, PTGS2, STAT3, VEGFR2, H3K4me and ELF3 levels. Chromatin immunoprecipitation (ChIP) analysis was used for studying the binding between ESR1 and H3K4me. Edu staining assay was executed to determine cell viability, and colony formation and cell invasion assay. The immunofluorescence method was utilized for the visualization of protein expression and distribution in cells. In this study, KMT2D, ESR1 and H3K4me were found upregulated in OV progression. Mutated H3K4me could inhibit the proliferation, colony formation and invasion ability of OV cells. Mutated H3K4me could also hinder the ESR1 in SKOV3 expressions and HO-8910 cells, which would further mediate PTGS2/STAT3/VEGF pathway. In vivo studies also demonstrated that mutated H3K4me inhibited OV progression via targeting ESR1. All the ChIP-PCR analysis indicated the moderator effect of H3K4me on ESR1. Our findings indicated that ESR1 played an important role in the OV progression. Besides, H3K4me could promote cell proliferation and inhibit apoptosis of OV cells. Meanwhile, it could also targets the ESR1 production to enhance the migration and invasion of OV cells, which was through the activation of ESR1-ELF3-PTGS2-STAT3-VEGF cascade signaling pathway.
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Affiliation(s)
- Ming Li
- Department of Pathology, the Affiliated Suzhou Municipal Hospital of Nanjing Medical University, Suzhou, China
- Co-first author
| | - Mengdie Shi
- Department of obstetrics and gynecology, the Affiliated Suzhou Municipal Hospital of Nanjing Medical University, Suzhou, China
- Co-first author
| | - Ying Xu
- Department of obstetrics and gynecology, the Affiliated Suzhou Municipal Hospital of Nanjing Medical University, Suzhou, China
| | - Jianping Qiu
- Department of obstetrics and gynecology, the Affiliated Suzhou Municipal Hospital of Nanjing Medical University, Suzhou, China
- Jianping Qiu, Department of obstetrics and gynecology, the Affiliated Suzhou Municipal Hospital of Nanjing Medical University, No.242 Guangji Road, Suzhou, 215008, China.
| | - Qing Lv
- Department of Breast Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
- Qing Lv, Department of Breast Surgery, Affiliated Hospital of Jiangnan University, No.1000 Hefeng Road, Wuxi, 214000, China.
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Huang JL, Oshi M, Endo I, Takabe K. Clinical relevance of stem cell surface markers CD133, CD24, and CD44 in colorectal cancer. Am J Cancer Res 2021; 11:5141-5154. [PMID: 34765317 PMCID: PMC8569346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 06/13/2023] Open
Abstract
Colon cancer stem cells (CSC) identified by cell surface markers CD133, CD24, and CD44, have been shown to be involved with tumor formation, chemotherapy resistance, and the progression of metastatic disease. Using an in silico translational approach, we hypothesize that a combination of these CSC markers has prognostic value in a large cohort of patients with colorectal cancer. Clinicopathologic and RNA expression data from a total of 594 colorectal cancer (CRC) patients from TCGA were analyzed. The expression of CD133, CD24, and CD44 was individually defined as "high" or "low" based on the median expression. Disease specific survival (DSS) and overall survival (OS) were not associated with tumors that are CD133-high or CD44-high alone. Patients with CD24-high tumors have significantly better DSS (P<0.001) and OS (P = 0.043). CD24-high, CD44-high and CD133-high tumors were associated with significantly greater EGFR, KRAS and Ki67 expression (all P<0.001). CD133, CD24 and CD44-high tumors were independently enriched for conventional stemness-related signaling pathways such as Wnt/β-catenin and Hedgehog signaling pathways. There was no survival difference linked to CD133-high/CD44-low patients, but CD44-high/CD24-low patients have worse DSS (P = 0.005) compared with CD44-low/CD24-high patients. CD133-high/CD24-low tumors show significant negative enrichment of MYC targets, E2F targets, G2M checkpoint and mitotic spindle gene sets, suggesting less cell proliferation in these tumors. Patients with CD133-high/CD24-low tumors have worse DSS (P = 0.004) and OS (P = 0.044), and are more likely to have early and late recurrences. In conclusion, we demonstrated that CD133-high/CD24-low tumors may predict colorectal cancer prognosis.
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Affiliation(s)
- Jing Li Huang
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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Garza-Treviño EN, Martínez-Rodríguez HG, Delgado-González P, Solís-Coronado O, Ortíz-Lopez R, Soto-Domínguez A, Treviño VM, Padilla-Rivas GR, Islas-Cisneros JF, Quiroz-Reyes AG, Said-Fernández SL. Chemosensitivity analysis and study of gene resistance on tumors and cancer stem cell isolates from patients with colorectal cancer. Mol Med Rep 2021; 24:721. [PMID: 34396431 PMCID: PMC8383037 DOI: 10.3892/mmr.2021.12360] [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: 02/23/2021] [Accepted: 06/29/2021] [Indexed: 11/09/2022] Open
Abstract
Colorectal cancer (CRC) is one of the main causes of mortality. Recent studies suggest that cancer stem cells (CSCs) can survive after chemotherapy and promote tumor invasiveness and aggression. According to a higher hierarchy complexity of CSC, different protocols for isolation, expansion, and characterization have been used; however, there are no available resistance biomarkers that allow predicting the clinical response of treatment 5‑fluorouracil (5FU) and oxaliplatin. Therefore, the primary aim of the present study was to analyze the expression of gene resistance on tumors and CSC‑derived isolates from patients CRC. In the present study, adenocarcinomas of the colon and rectum (CRAC) were classified based on an in vitro adenosine triphosphate‑based chemotherapy response assay, as sensitive and resistant and the percentage of CD24 and CD44 markers are evaluated by immunohistochemistry. To isolate resistant colon‑CSC, adenocarcinoma tissues resistant to 5FU and oxaliplatin were evaluated. Finally, all samples were sequenced using a custom assay with chemoresistance‑associated genes to find a candidate gene on resistance colon‑CSC. Results showed that 59% of the CRC tissue analyzed was resistant and had a higher percentage of CD44 and CD24 markers. An association was found in the expression of some genes between the tumor‑resistant tissue and CSC. Overall, isolates of the CSC population CD44+ resistant to 5FU and oxaliplatin demonstrated different expression profiles; however, the present study was able to identify overexpression of the KRT‑18 gene, in most of the isolates. In conclusion, the results of the present study showed overexpression of KRT‑18 in CD44+ cells is associated with chemoresistance to 5FU and oxaliplatin in CRAC.
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Affiliation(s)
- Elsa N. Garza-Treviño
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Herminia G. Martínez-Rodríguez
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Paulina Delgado-González
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Orlando Solís-Coronado
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Rocio Ortíz-Lopez
- Monterrey Institute of Technology and Higher Education, School of Medicine and Health Sciences, Monterrey, Nuevo Leon 64710, Mexico
| | - Adolfo Soto-Domínguez
- Department of Histology, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Víctor M. Treviño
- Monterrey Institute of Technology and Higher Education, School of Medicine and Health Sciences, Monterrey, Nuevo Leon 64710, Mexico
| | - Gerardo R. Padilla-Rivas
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Jose F. Islas-Cisneros
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Adriana G. Quiroz-Reyes
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
| | - Salvador L. Said-Fernández
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, University Hospital ‘Dr. Jose Eleuterio Gonzalez’, Monterrey, Nuevo Leon 64460, Mexico
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Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL. Pharmaceutics 2021; 13:pharmaceutics13071062. [PMID: 34371753 PMCID: PMC8309156 DOI: 10.3390/pharmaceutics13071062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/20/2022] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.
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34
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Quiroz-Reyes AG, Delgado-Gonzalez P, Islas JF, Gallegos JLD, Martínez Garza JH, Garza-Treviño EN. Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL. Pharmaceutics 2021; 13:1062. [DOI: https:/doi.org/10.3390/pharmaceutics13071062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.
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35
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She X, Qin S, Jing B, Jin X, Sun X, Lan X, An R. Radiotheranostic Targeting Cancer Stem Cells in Human Colorectal Cancer Xenografts. Mol Imaging Biol 2021; 22:1043-1053. [PMID: 32125599 DOI: 10.1007/s11307-019-01467-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE The aim of this study was to perform radiotheranostics with radioiodinated monoclonal antibodies (mAbs) for targeting cancer stem cells (CSCs) in human colorectal cancer xenografts and evaluate the relative advantage of a cocktail containing both [131I]CD133 mAb and [131I]CD44 mAb. PROCEDURES Tumor-bearing mice were randomly divided into eight groups: [131I]CD133mAb, [131I]CD44 mAb, [131I]IgG isotype control, radioiodinated mAb cocktail, CD133 mAb, CD44 mAb, unradioiodinated mAb cocktail, and saline groups. In vivo single photon emission computed tomography (SPECT) imaging was used to monitor dynamically changes in the CSC population after treatment. The radioactivity uptake of tumors was quantified ex vivo. The expression of CD133 and CD44 after treatment was also assessed by immunohistochemistry and western blot. Tumor growth curves and survival curves were generated to assess treatment efficacy. Cell apoptosis and proliferation in xenografts 30 days after treatment were measured by TdT-mediated dUTP-biotin nick end labeling (aka, TUNEL) and Ki67 staining. The expression levels of biomarkers in xenografts 30 days after treatment were measured by flow cytometry. RESULTS The radioimmunoimaging (RII) with in vivo SPECT showed that the CSC-targeting radioimmunotherapy (RIT) groups ([131I]CD133 mAb, [131I]CD44 mAb, and radioiodinated mAb cocktail groups) had intense accumulations of radiolabeled agents in the tumor areas. The ex vivo biodistribution confirmed these findings. In the CSC-targeting RIT groups, immunohistochemistry and western blot indicated significant reduction of specific target expression in the xenografts. The tumor growth curves and survival curves showed that the CSC-targeting RIT significantly inhibited tumor growth and prolonged mean survival, respectively. Significantly increased apoptosis and decreased proliferation in xenografts further confirmed the therapeutic efficacy of CSC-targeting RIT. Flow cytometry showed that the decreases in CSCs correlated with the presence of the corresponding antibodies. CONCLUSIONS Our results suggest that the CSC-targeting RIT can effectively reduce CSCs which consequently inhibits tumor development. The radioiodinated mAb cocktail may generate enhanced CSC-targeting specificity.
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Affiliation(s)
- Xianliang She
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Saimei Qin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Boping Jing
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xueyan Jin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xun Sun
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Rui An
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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Özerkan D, Erol A, Altuner EM, Canlı K, Kuruca DS. Some Bryophytes Trigger Cytotoxicity of Stem Cell-like Population in 5-Fluorouracil Resistant Colon Cancer Cells. Nutr Cancer 2021; 74:1012-1022. [PMID: 34151658 DOI: 10.1080/01635581.2021.1933098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Colorectal cancer is the third most common cancer worldwide. Cancer stem cells are known to play an important role in relapse, and metastases of the disease after chemotherapy. Investigation of new drugs, and their combinations targeting these cells and thus eliminating cancer is one of the most urgent needs of today's chemotherapy. The aim of the present study was to evaluate the effects of Bryophytes like Abietinella abietina (AA), Homolothecium sericeum (HS), Tortella tortuosa (TT), Syntrichia ruralis (SR), and Bryoerythrophyllum rubrum (BR) species extracted with ethyl alcohol on 5-fluorouracil(5-FU) resistant colorectal cancer cell lines (HCT116 and HT29). After extraction, stock solutions of bryophytes were prepared, and IC50 values were detected in drug-resistant cells obtained with 5-FU application. CD24+, CD44+/CD133+ surface markers and P-glycoprotein (P-gp) mediated efflux were isolated from both 5-FU treated cells and analyzed using the flow cytometry. In all bryophyte-treated groups, the binding Rho123low (low Rho fluorescence) and Rhohigh (high Rho fluorescence) were sorted from 5-FU resistant HCT116, and HT-29 cells. All types of bryophytes were found cytotoxic. Bryophyte extract reduced the percentage of Rholow cells in cultures incubated with 5-FU. In summary, the implementation of these bryophytes might be regarded as an effective approach for treatment of colorectal cancer due to their cytotoxic effect that decreases the recurrence of the disease.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1933098.
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Affiliation(s)
- Dilşad Özerkan
- Faculty of Health Sciences, Molecular Cancer Research Center, İstinye University, İstanbul, Turkey
| | - Ayşe Erol
- Department of Medical Biology, Faculty of Medicine, İstanbul University, İstanbul, Turkey
| | - Ergin Murat Altuner
- Department of Biology, Faculty of Science and Literature, Kastamonu University, Kastamonu, Turkey
| | - Kerem Canlı
- Department of Biology, Faculty of Sciences, Dokuz Eylül University, İzmir, Turkey
| | - Dürdane Serap Kuruca
- Department of Physiology, Faculty of Medicine, Istanbul University, İstanbul, Turkey
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Ren Y, Deng R, Cai R, Lu X, Luo Y, Wang Z, Zhu Y, Yin M, Ding Y, Lin J. TUSC3 induces drug resistance and cellular stemness via Hedgehog signaling pathway in colorectal cancer. Carcinogenesis 2021; 41:1755-1766. [PMID: 32338281 DOI: 10.1093/carcin/bgaa038] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/08/2020] [Accepted: 04/16/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor suppressor candidate 3 (TUSC3) is a coding gene responsible for N-glycosylation of many critical proteins. TUSC3 gene plays an oncogenic role in colorectal cancer (CRC), however, the role of TUSC3 in drug resistance of CRC is still unclear. The aim of this study is to investigate the biological function and molecular mechanism of TUSC3 in CRC drug resistance. The expression of TUSC3 in CRC is positively correlated to tumor stage in 90 paired clinical samples, and negatively associated with overall survival and disease-free survival of CRC patients. In vitro, TUSC3 promotes the formation of stemness and induces the drug resistance to 5-fluorouracil and cis-dichlorodiammineplatinum(II) in CRC cells. The tissue microarray assay and bioinformatic analysis indicate that TUSC3 may promote the expression of CD133 and ABCC1 via Hedgehog signaling pathway. Treatment of Hedgehog signaling pathway agonist or inhibitor in TUSC3-silenced or TUSC3-overexpressed cells reverse the effects of TUSC3 in cellular stemness phenotype and drug resistance. Meanwhile, coimmunoprecipitation and immunofluorescence assays indicate a tight relationship between TUSC3 and SMO protein. Our data suggest that TUSC3 promotes the formation of cellular stemness and induces drug resistance via Hedgehog signaling pathway in CRC.
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Affiliation(s)
- Yansong Ren
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Ruxia Deng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Rui Cai
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Xiansheng Lu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Yuejun Luo
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Ziyuan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Yuchen Zhu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Mengyuan Yin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
| | - Jie Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, PR China.,Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, Guangdong Province, PR China
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Sung TC, Huang WL, Ban LK, Lee HHC, Wang JH, Su HY, Jen SH, Chang YH, Yang JM, Higuchi A, Ye Q. Enrichment of cancer-initiating cells from colon cancer cells through porous polymeric membranes by a membrane filtration method. J Mater Chem B 2021; 8:10577-10585. [PMID: 33124643 DOI: 10.1039/d0tb02312d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer-initiating cells (CICs) or cancer stem cells (CSCs) are primarily responsible for tumor initiation, growth, and metastasis and represent a few percent of the total tumor cell population. We designed a membrane filtration protocol to enrich CICs (CSCs) from the LoVo colon cancer cell line via nylon mesh filter membranes with 11 and 20 μm pore sizes and poly(lactide-co-glycolic acid)/silk screen (PLGA/silk screen) porous membranes (pore sizes of 20-30 μm). The colon cancer cell solution was filtered through the membranes to obtain a permeate solution. Subsequently, the cell culture medium was filtered through the membranes to collect the recovery solution where the cells attached to the membranes were rinsed off into the recovery solution. Then, the membranes were cultivated in the cultivation medium to collect the migrated cells from the membranes. The cells migrated from any membrane had higher expression of the CSC surface markers CD44 and CD133, had higher colony formation levels, and produced more carcinoembryonic antigen (CEA) than the colon cancer cells cultivated on conventional tissue culture plates (control). We established a method to enrich the CICs (CSCs) of colon cancer cells from migrated cells through porous polymeric membranes by the membrane filtration protocol developed in this study.
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Affiliation(s)
- Tzu-Cheng Sung
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd., Jhongli, Taoyuan, 32001, Taiwan. and School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang 325027, China
| | - Wei-Lun Huang
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd., Jhongli, Taoyuan, 32001, Taiwan.
| | - Lee-Kiat Ban
- Department of Surgery, Hsinchu Cathay General Hospital, No. 678, Sec 2, Zhonghua Rd., Hsinchu, 30060, Taiwan
| | - Henry Hsin-Chung Lee
- Department of Surgery, Hsinchu Cathay General Hospital, No. 678, Sec 2, Zhonghua Rd., Hsinchu, 30060, Taiwan and Graduate Institute of Translational and Interdisciplinary Medicine, National Central University, No. 300, Jhongda Rd., Jhongli, Taoyuan, 32001, Taiwan
| | - Jia-Hua Wang
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd., Jhongli, Taoyuan, 32001, Taiwan.
| | - Her-Young Su
- Department of Obstetrics and Gynecology, Bobson Yuho Women and Children's Clinic, No. 182, Zhuangjing S. Rd., Zhubei City, Hsinchu 302, Taiwan
| | - Shih Hsi Jen
- Department of Obstetrics and Gynecology, Taiwan Landseed Hospital, 77, Kuangtai Road, Pingjen City, Taoyuan 32405, Taiwan
| | - Yen-Hsiang Chang
- Department of General Dentistry, Chang Gung Memorial Hospital, Guishan, Taoyuan 333, Taiwan
| | - Jen-Ming Yang
- Department of Chemical and Materials Engineering, Chang Gung University, Guishan, Taoyuan 333, Taiwan.
| | - Akon Higuchi
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd., Jhongli, Taoyuan, 32001, Taiwan. and School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang 325027, China and Department of Chemical Engineering and R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan and Center for Emergent Matter Science, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan and Wenzhou Institute, University of Chinese Academy of Science, No. 16, Xinsan Road, Hi-tech Industry Park, Wenzhou, Zhejiang, China
| | - Qingsong Ye
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China and Skeletal Biology Research Center, OMFS, Massachusetts General Hospital & Harvard School of Dental Medicine, Boston, MA02114, USA and School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Ouyang J, Xie Z, Lei X, Tang G, Gan R, Yang X. Clinical crosstalk between microRNAs and gastric cancer (Review). Int J Oncol 2021; 58:7. [PMID: 33649806 PMCID: PMC7895535 DOI: 10.3892/ijo.2021.5187] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, there were over 1 million new gastric cancer (GC) patients in 2018 and GC has become the sixth most common cancer worldwide. GC caused 783,000 deaths worldwide in 2018, making it the third most deadly cancer type. miRNAs are short (~22 nucleotides in length) non‑coding RNA molecules, which can regulate gene expression passively at a post‑transcriptional level. There are more and more in‑depth studies on miRNAs. There are numerous conclusive evidences that there is an inseparable link between miRNAs and GC. miRNAs can affect the entire process of GC, including the oncogenesis, development, diagnosis, treatment and prognosis of GC. Although many miRNAs have been linked to GC, few can be applied to clinical practice. This review takes the clinical changes of GC as a clue and summarizes the miRNAs related to GC that have confirmed the mechanism of action in the past three years. Through in‑depth study and understanding of the mechanism of those miRNAs, we predict their possible clinical uses, and suggest some new insights to overcome GC.
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Affiliation(s)
- Jing Ouyang
- Institute of Pharmacy and Pharmacology, University of South China
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology, University of South China
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology, University of South China
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology, University of South China
| | - Runliang Gan
- Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoyan Yang
- Institute of Pharmacy and Pharmacology, University of South China
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40
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Du L, Cheng Q, Zheng H, Liu J, Liu L, Chen Q. Targeting stemness of cancer stem cells to fight colorectal cancers. Semin Cancer Biol 2021; 82:150-161. [PMID: 33631296 DOI: 10.1016/j.semcancer.2021.02.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/12/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Cancer initiating/ stem cells (CSCs) undergo self-renewal and differentiation that contributes to tumor initiation, recurrence and metastasis in colorectal cancer (CRC). Targeting of colorectal cancer stem cells (CCSCs) holds significant promise in eradicating cancer cells and ultimately curing patients with cancer. In this review, we will introduce the current progress of CCSC studies, including the specific surface markers of CCSCs, the intrinsic signaling pathways that regulate the stemness and differentiation characteristics of CCSCs, and the tumor organoid model for CCSC research. We will focus on how these studies will lead to the progress in targeting specific surface markers or signaling pathways on CCSCs by monoclonal antibodies, or by natural or synthetic compounds, or by immunotherapy. As CSCs are highly heterogeneous and plastic, we suggest that combinatory approaches that target the stemness network may represent an important strategy for eradicating cancers.
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Affiliation(s)
- Lei Du
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine. Beijing, 100101, China.
| | - Qi Cheng
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; The Graduate University of Chinese Academy of Sciences. Beijing, 100049, China
| | - Hao Zheng
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jinming Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lei Liu
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine. Beijing, 100101, China
| | - Quan Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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41
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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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42
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Curcumin may be a potential adjuvant treatment drug for colon cancer by targeting CD44. Int Immunopharmacol 2020; 88:106991. [PMID: 33182071 DOI: 10.1016/j.intimp.2020.106991] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 09/07/2020] [Accepted: 09/07/2020] [Indexed: 12/21/2022]
Abstract
Despite the considerable advances in treatment method development, the mortality rate related to colon cancer still ranks the fifth in all tumor-related diseases. Recently, there has been growing evidences supporting the existence of colon cancer stem cells (CSCs) might be one of the main causes for initiation, progression and recurrence of colon cancer. Curcumin has been shown to possess anticancer activities. It has also been suggested that curcumin was effective against colon CSCs by coupling with CD44, a robust marker and functional important molecule for colorectal CSC. In the present study, we confirmed that curcumin can inhibit the proliferation, colony formation, migration and tumor sphere formation of colon cancer cells. Results from real-time PCR and western blotting had suggested that curcumin could down-regulate the expression of CD44. Moreover, results from flow cytometry had further revealed that curcumin could decrease the proportion of CD44+ colon cancer cells. After the expression of CD44 had been knocked down by using siRNA, the inhibition effects of curcumin against CD44+ colon cancer cells were observed to be reduced significantly. Moreover, it had been observed that the cellular uptake of curcumin was significantly higher in CD44+ colon cancer cells. Results from flow cytometry had shown that curcumin could induce apoptosis in CD44+ colon cancer cells. Altogether, our results suggested that curcumin might be an adjuvant drug for the treatment of colorectal cancer by targeting CD44.
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Forster S, Radpour R. Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells. Front Oncol 2020; 10:569017. [PMID: 33240813 PMCID: PMC7680905 DOI: 10.3389/fonc.2020.569017] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/08/2020] [Indexed: 12/17/2022] Open
Abstract
The immune system is able to recognize and eliminate tumor cells. Some tumors, including colorectal cancer (CRC), induce immune tolerance via different mechanisms of “immunoediting” and “immune evasion” and can thus escape immune surveillance. The impact of immunotherapy on cancer has been investigated for many years, but so far, the application was limited to few cancer types. Immuno-oncological therapeutic strategies against metastatic colorectal cancer (mCRC), the adaptive immune system activating approaches, offer a high potential for adaptation to the great heterogeneity of CRC. Moreover, novel treatment approaches are currently being tested that might specifically target the disease initiating and maintaining population of colorectal cancer stem cells (CSCs). In this review, we aim to summarize the current state of immune-oncology and tumor immunotherapy of patients with mCRC and discuss different therapeutic modalities that focus on the activation of tumor-specific T-cells and their perspectives such as tumor vaccination, checkpoint inhibition, and adoptive T-cell transfer or on the eradication of colorectal CSCs.
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Affiliation(s)
- Stefan Forster
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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44
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Hamid FB, Gopalan V, Matos M, Lu CT, Lam AKY. Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma. Int J Mol Sci 2020; 21:ijms21207766. [PMID: 33092235 PMCID: PMC7589365 DOI: 10.3390/ijms21207766] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/10/2020] [Accepted: 10/18/2020] [Indexed: 12/11/2022] Open
Abstract
The aim of the present study was to isolate and investigate the genetic heterogeneities in single circulating tumour cells (CTCs) from patients with colorectal carcinoma (CRC). Twenty-eight single CTCs were collected from eight patients with CRC using a negative immunomagnetic enrichment method. After validation with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in 3 colon cancer cell lines, a panel of 19 genes were used to analyse the single CTCs (n = 28), primary colorectal carcinoma tissues (n = 8) and colon carcinoma cells (n = 6) using real-time qPCR. Genetic heterogeneities were assessed by comparing gene expression profiles of single CTCs from the different patients and in the same patient, respectively. Genetic profiling of the single CTCs showed extensive heterogeneities of the selected genes among the CTCs. Hierarchical clustering analyses exhibited two clusters of CTCs with differentially expressed genes, which highlighted different modifications from the primary carcinomas. Further, the genetic heterogeneities were observed between different patients or in the same patient. Finally, AKT1 expression was significantly (p = 0.0129) higher in single CTCs from CRC of advanced pathological stages (III or IV) CRC than in CTCs from CRC of early stages (I or II). Our findings suggest that single-cell genetic analysis can monitor the genetic heterogeneities and guide the personalised therapeutic targets in clinical sectors.
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Affiliation(s)
- Faysal Bin Hamid
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
- Correspondence: (V.G.); (A.K.L.)
| | - Marco Matos
- Oncology, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia;
| | - Cu-Tai Lu
- Colorectal Surgery, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia;
| | - Alfred King-yin Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
- Correspondence: (V.G.); (A.K.L.)
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45
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Wang TW, Chern E, Hsu CW, Tseng KC, Chao HM. SIRT1-Mediated Expression of CD24 and Epigenetic Suppression of Novel Tumor Suppressor miR-1185-1 Increases Colorectal Cancer Stemness. Cancer Res 2020; 80:5257-5269. [PMID: 33046442 DOI: 10.1158/0008-5472.can-19-3188] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 07/19/2020] [Accepted: 10/05/2020] [Indexed: 12/16/2022]
Abstract
NAD-dependent deacetylase sirtuin-1 (SIRT1) is a class III histone deacetylase that positively regulates cancer-related pathways such as proliferation and stress resistance. SIRT1 has been shown to promote progression of colorectal cancer and is associated with cancer stemness, yet the precise mechanism between colorectal cancer stemness and SIRT1 remains to be further clarified. Here we report that SIRT1 signaling regulates colorectal cancer stemness by enhancing expression of CD24, a colorectal cancer stemness promoter. A novel miRNA, miR-1185-1, suppressed the expression of CD24 by targeting its 3'UTR (untranslated region) and could be inhibited by SIRT1 via histone deacetylation. Targeting SIRT1 by RNAi led to elevated H3 lysine 9 acetylation on the promoter region of miR-1185-1, which increased expression of miR-1185-1 and further repressed CD24 translation and colorectal cancer stemness. In a mouse xenograft model, overexpression of miR-1185-1 in colorectal cancer cells substantially reduced tumor growth. In addition, expression of miR-1185-1 was downregulated in human colorectal cancer tissues, whereas expression of CD24 was increased. In conclusion, this study not only demonstrates the essential roles of a SIRT1-miR-1185-1-CD24 axis in both colorectal cancer stemness properties and tumorigenesis but provides a potential therapeutic target for colorectal cancer treatment. SIGNIFICANCE: A novel tumor suppressor miR-1185-1 is involved in molecular regulation of CD24- and SIRT1-related cancer stemness networks, marking it a potential therapeutic target in colorectal cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5257/F1.large.jpg.
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Affiliation(s)
- Teh-Wei Wang
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Edward Chern
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
| | - Chao-Wei Hsu
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Kuo-Chang Tseng
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Hsiao-Mei Chao
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan. .,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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46
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Neog Bora P, Baruah VJ, Borkotokey S, Gogoi L, Mahanta P, Sarmah A, Kumar R, Moretti S. Identifying the Salient Genes in Microarray Data: A Novel Game Theoretic Model for the Co-Expression Network. Diagnostics (Basel) 2020; 10:E586. [PMID: 32823765 PMCID: PMC7460294 DOI: 10.3390/diagnostics10080586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/05/2020] [Accepted: 08/10/2020] [Indexed: 12/16/2022] Open
Abstract
Microarray techniques are used to generate a large amount of information on gene expression. This information can be statistically processed and analyzed to identify the genes useful for the diagnosis and prognosis of genetic diseases. Game theoretic tools are applied to analyze the gene expression data. Gene co-expression networks are increasingly used to explore the system-level functionality of genes, where the roles of the genes in building networks in addition to their independent activities are also considered. In this paper, we develop a novel microarray network game by constructing a gene co-expression network and defining a game on this network. The notion of the Link Relevance Index (LRI) for this network game is introduced and characterized. The LRI successfully identifies the relevant cancer biomarkers. It also enables identifying salient genes in the colon cancer dataset. Network games can more accurately describe the interactions among genes as their basic premises are to consider the interactions among players prescribed by a network structure. LRI presents a tool to identify the underlying salient genes involved in cancer or other metabolic syndromes.
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Affiliation(s)
- Papori Neog Bora
- Department of Mathematics, Dibrugarh University, Dibrugarh 786004, India;
| | - Vishwa Jyoti Baruah
- Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh 786004, India
| | - Surajit Borkotokey
- Department of Mathematics, Dibrugarh University, Dibrugarh 786004, India;
| | - Loyimee Gogoi
- Department of Applied Mathematics, Northwestern Polytechnical University, Xi’an 710072, China;
| | - Priyakshi Mahanta
- Centre for Computer Science and Applications, Dibrugarh University, Dibrugarh 786004, India; (P.M.); (A.S.)
| | - Ankumon Sarmah
- Centre for Computer Science and Applications, Dibrugarh University, Dibrugarh 786004, India; (P.M.); (A.S.)
| | - Rajnish Kumar
- Economics Group, Queen’s Management School, Queen’s University, Belfast BT9 5EE, UK
| | - Stefano Moretti
- Université Paris-Dauphine, PSL Research University, CNRS, LAMSADE, 75016 Paris, France;
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47
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Zhao L, Liu C, Yan S, Hu G, Xiang K, Xiang H, Yu H. LINC00657 promotes colorectal cancer stem-like cell invasion by functioning as a miR-203a sponge. Biochem Biophys Res Commun 2020; 529:500-506. [PMID: 32703458 DOI: 10.1016/j.bbrc.2020.04.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/12/2020] [Indexed: 02/09/2023]
Abstract
Recently, the role of long non-coding RNAs (lncRNAs) in regulating multiple cancer types has attracted increasing interest because of their involvement in cell metastasis in different cancer types. Previous studies indicated that LINC00657 may work as an oncogene in gastric and colon cancer. However, the functional role and mechanistic action of LINC00657 on colorectal cancer (CRC) remains unknown. Therefore, in this study, the role of LINC00657 in CRC was evaluated. Our results showed that LINC00657 was enriched in CRC stem-like cells (CSCs) and significantly promoted CSCs invasion ability. LINC00657 expression resulted frequently up-regulated in CRC patient tissue, and high expression of LINC00657 was correlated with an advanced clinical stage, lymph node metastasis, distant metastasis and poor overall survival of CRC patients. Furthermore, LINC00657 worked as a competing endogenous RNA (ceRNA) for miR-203a, antagonizing its function as a tumor suppressor and leading to the de-repression of CSCs invasion. Collectively, our observations revealed that LINC00657 is involved in CRC invasion by acting as a competing endogenous RNA. Thus, LINC00657 may serve as a potential prognostic factor and/or therapeutic target for CRC.
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Affiliation(s)
- Lian Zhao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, 410013, China
| | - Chao Liu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Shipeng Yan
- Department of Cancer Prevention and Control, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Gui Hu
- Department of Gastroenterological Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Kaimin Xiang
- Department of Gastroenterological Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Hong Xiang
- Center for Experimental Medical Research, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Haibo Yu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, 410011, China.
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48
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Im H, Lee J, Ryu KY, Yi JY. Integrin αvβ3-Akt signalling plays a role in radioresistance of melanoma. Exp Dermatol 2020; 29:562-569. [PMID: 32298492 DOI: 10.1111/exd.14102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023]
Abstract
Melanoma is a deadly type of skin cancer that is particularly difficult to treat owing to its resistance to radiation therapy. Here, we attempted to determine the key proteins responsible for melanoma radioresistance, with the aim of improving disease response to radiation therapy. Two melanoma cell lines, SK-Mel5 and SK-Mel28, with different radiosensitivities were analysed via RNA-Seq (Quant-Seq) and target proteins with higher abundance in the more radioresistant cell line, SK-Mel28, identified. Among these proteins, integrin αvβ3, a well-known molecule in cell adhesion, was selected for analysis. Treatment of SK-Mel28 cells with cilengitide, an integrin αvβ3 inhibitor, as well as γ-irradiation resulted in more significant cell death than γ-irradiation alone. In addition, Akt, a downstream signal transducer of integrin αvβ3, showed high basic activation in SK-Mel28 and was significantly decreased upon co-treatment with cilengitide and γ-irradiation. MK-2206, an Akt inhibitor, exerted similar effects on the SK-Mel28 cell line following γ-irradiation. Our results collectively demonstrate that the integrin αvβ3-Akt signalling pathway contributes to radioresistance in SK-Mel28 cells, which may be manipulated to improve therapeutic options for melanoma.
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Affiliation(s)
- Hyuntaik Im
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.,Department of Life Science, University of Seoul, Seoul, Korea
| | - Jeeyong Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Kwon-Yul Ryu
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Jae Youn Yi
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 01/27/2025] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania.
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
Collapse
MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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