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1
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Yang J, Aljitawi O, Van Veldhuizen P. Prostate Cancer Stem Cells: The Role of CD133. Cancers (Basel) 2022; 14:5448. [PMID: 36358865 PMCID: PMC9656005 DOI: 10.3390/cancers14215448] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/17/2022] [Accepted: 11/01/2022] [Indexed: 09/27/2023] Open
Abstract
Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. In this article, we focus on reviewing the role of CD133 in PCSC. Any other main stem cell biomarkers in PCSC reported from key publications, as well as about vital research progress of CD133 in CSCs of different cancers, will be selectively reviewed to help us inform the main topic.
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Affiliation(s)
| | - Omar Aljitawi
- Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Peter Van Veldhuizen
- Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
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2
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Pandrangi SL, Chittineedi P, Chalumuri SS, Meena AS, Neira Mosquera JA, Sánchez Llaguno SN, Pamuru RR, Mohiddin GJ, Mohammad A. Role of Intracellular Iron in Switching Apoptosis to Ferroptosis to Target Therapy-Resistant Cancer Stem Cells. Molecules 2022; 27:3011. [PMID: 35566360 PMCID: PMC9100132 DOI: 10.3390/molecules27093011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 02/07/2023] Open
Abstract
Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to ferroptosis to target cancer stem cells death thereby preventing cancer relapse. To the best of our knowledge, this is the first review to demonstrate the importance of intracellular iron in regulating the switching of tumor cells and therapy resistant CSCs from apoptosis to ferroptosis.
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Affiliation(s)
- Santhi Latha Pandrangi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Prasanthi Chittineedi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Sphoorthi Shree Chalumuri
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Avtar Singh Meena
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India;
| | - Juan Alejandro Neira Mosquera
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
- Faculty of Industry and Production Sciences, Quevedo State Technical University, km 11/2 via Santo Domingo, Quevedo 120301, Ecuador
| | - Sungey Naynee Sánchez Llaguno
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | | | - Gooty Jaffer Mohiddin
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | - Arifullah Mohammad
- Department of Agriculture Science, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli 17600, Malaysia
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Soleimani A, Dadjoo P, Avan A, Soleimanpour S, Rajabian M, Ferns G, Ryzhikov M, Khazaei M, Hassanian SM. Emerging roles of CD133 in the treatment of gastric cancer, a novel stem cell biomarker and beyond. Life Sci 2022; 293:120050. [PMID: 35026215 DOI: 10.1016/j.lfs.2021.120050] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 11/15/2022]
Abstract
Gastric cancer (GC) is an aggressive disease with one of the highest mortality rates in the world. In the early stage, most patients are asymptomatic and early diagnosis is difficult. Recently, cancer stem cells (CSCs) have been highlighted as crucial emerging factors in the initiation or invasiveness of solid tumors. CD133, a CSC marker, is highly expressed in various tumors including gastric cancer. CD133-positive cells showed elevated malignant biological behaviors and CD133 upregulation is related to chemoresistance, cancer relapse, and poor prognosis. CD133 also plays an important role in the progression of tumors and metastasis. This review summarizes the current knowledge of the role of CD133 expression in GC and aims to contribute at identifying promising new strategies for treatment and management of gastric cancer.
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Affiliation(s)
- Atena Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Dadjoo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Human Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rajabian
- Department of Biology, Payame Noor University, Po Box19395-3697, Tehran, Iran
| | - Gordon Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Mikhail Ryzhikov
- Saint Louis University, School of Medicine, Saint Louis, MO, USA
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Dai ZT, Xiang Y, Duan YY, Wang J, Li JP, Zhang HM, Cheng C, Wang Q, Zhang TC, Liao XH. MiR-17-5p and MKL-1 modulate stem cell characteristics of gastric cancer cells. Int J Biol Sci 2021; 17:2278-2293. [PMID: 34239355 PMCID: PMC8241736 DOI: 10.7150/ijbs.57338] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 05/22/2021] [Indexed: 12/13/2022] Open
Abstract
Effectively targeting cancer stem cells to treat cancer has great therapeutic prospects. However, the effect of microRNA miR-17/MKL-1 on gastric cancer stem cells has not been studied yet. This study preliminarily explored the mechanism of miR-17/MKL-1 in gastric cancer stem cells. Many previous reports have indicated that microRNA and EMT regulated cancer stem cell characteristics, and miR-17 and MKL-1 were involved as a critical gene in migration and invasion in the EMT pathway. Through RT-PCR, Western Blot, flow cytometry, immunofluorescence, sphere formation xenograft tumor assays and drug resistance, the role of miR-17-5p and MKL-1 on promoting stem cell-like properties of gastric cancer were verified in vivo and vitro. Next, MKL-1 targets CD44, EpCAM, and miR -17-5p promoter verified by luciferase assay and ChIP. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. It is found that MKL-1 promotes expression by targeting miR-17, CD44 and EpCAM promoters. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. These findings reveal new regulatory signaling pathways for gastric cancer stem cells, thus it give new insights on potential early diagnosis and/or molecular therapy for gastric cancer.
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Affiliation(s)
- Zhou-Tong Dai
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Hubei, 430014, P.R. China
| | - Yuan-Yuan Duan
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jun Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jia Peng Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Hui-Min Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Chao Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiong Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Tong-Cun Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.,Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, Tinajin, 300457, P.R. China
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
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The role of SOX family transcription factors in gastric cancer. Int J Biol Macromol 2021; 180:608-624. [PMID: 33662423 DOI: 10.1016/j.ijbiomac.2021.02.202] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/26/2021] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is a leading cause of death worldwide. GC is the third-most common cause of cancer-related death after lung and colorectal cancer. It is also the fifth-most commonly diagnosed cancer. Accumulating evidence has revealed the role of signaling networks in GC progression. Identification of these molecular pathways can provide new insight into therapeutic approaches for GC. Several molecular factors involved in GC can play both onco-suppressor and oncogene roles. Sex-determining region Y (Sry)-box-containing (SOX) family members are transcription factors with a well-known role in cancer. SOX proteins can bind to DNA to regulate cellular pathways via a highly conserved domain known as high mobility group (HMG). In the present review, the roles of SOX proteins in the progression and/or inhibition of GC are discussed. The dual role of SOX proteins as tumor-promoting and tumor-suppressing factors is highlighted. SOX members can affect upstream mediators (microRNAs, long non-coding RNAs and NF-κB) and down-stream mediators (FAK, HIF-1α, CDX2 and PTEN) in GC. The possible role of anti-tumor compounds to target SOX pathway members in GC therapy is described. Moreover, SOX proteins may be used as diagnostic or prognostic biomarkers in GC.
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Kim HS, Song HJ, Kim HU, Jeong IH, Koh HM, Shin JH, Jang BG. Expression profile of intestinal stem cell and cancer stem cell markers in gastric cancers with submucosal invasion. Pathol Res Pract 2021; 218:153336. [PMID: 33450435 DOI: 10.1016/j.prp.2020.153336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/29/2020] [Accepted: 12/30/2020] [Indexed: 11/16/2022]
Abstract
Cancer stem cells (CSCs) are believed to be responsible for tumor growth, invasion, and metastasis. Submucosal invasion, which greatly enhances metastasis risk, is a critical step in gastric cancer (GC) progression. To identify stem cell-related markers associated with submucosal invasion and lymph node (LN) metastasis in GCs, we investigated the expression of candidate CSC markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs that manifested submucosal invasion. We discovered that EPHB2 and LGR5 expression was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer, and the proportion of stem cell marker-positive cells substantially increased during submucosal invasion. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. Unexpectedly, no CSC markers showed any associations with LN metastasis, and only loss of EPHB2 expression was associated with increased LN metastasis. Treatment of RSPO2, a niche factor, along with Wnt 3a, to GC cells led to increased EPHB2 and LGR5 mRNA levels. RNA in situ hybridization confirmed specific RSPO2 expression in the smooth muscle cells of the muscularis mucosa, suggesting that RSPO2 is responsible for the increased expression of ISC markers in GC cells at the basal areas. In summary, no stem cell markers were associated with increased LN metastasis in early GCs. Conversely, isolated EPHB2 expression was associated with lower LN metastasis. EPHB2 and LGR5 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs, which was induced by a niche factor, RSPO2, from the muscularis mucosa.
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Affiliation(s)
- Hye Sung Kim
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Hyun Joo Song
- Department of Internal Medicine, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Heung Up Kim
- Department of Internal Medicine, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - In Ho Jeong
- Department of Surgery, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Hyun Min Koh
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Jung Hyub Shin
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Bo Gun Jang
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea.
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Pádua D, Figueira P, Ribeiro I, Almeida R, Mesquita P. The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication. Front Cell Dev Biol 2020; 8:442. [PMID: 32626705 PMCID: PMC7314965 DOI: 10.3389/fcell.2020.00442] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.
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Affiliation(s)
- Diana Pádua
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paula Figueira
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Inês Ribeiro
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Raquel Almeida
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Patrícia Mesquita
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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Pádua D, Barros R, Luísa Amaral A, Mesquita P, Filipa Freire A, Sousa M, Filipe Maia A, Caiado I, Fernandes H, Pombinho A, Filipe Pereira C, Almeida R. A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin. Cancers (Basel) 2020; 12:E495. [PMID: 32093282 PMCID: PMC7072720 DOI: 10.3390/cancers12020495] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/12/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.
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Affiliation(s)
- Diana Pádua
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Rita Barros
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Ana Luísa Amaral
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Patrícia Mesquita
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Ana Filipa Freire
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Mafalda Sousa
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - André Filipe Maia
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Inês Caiado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Hugo Fernandes
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
| | - António Pombinho
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Carlos Filipe Pereira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Raquel Almeida
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Biology Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
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Kumar P, Mistri TK. Transcription factors in SOX family: Potent regulators for cancer initiation and development in the human body. Semin Cancer Biol 2019; 67:105-113. [PMID: 31288067 DOI: 10.1016/j.semcancer.2019.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 06/17/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022]
Abstract
Transcription factors (TFs) have a key role in controlling the gene regulatory network that sustains explicit cell states in humans. However, an uncontrolled regulation of these genes potentially results in a wide range of diseases, including cancer. Genes of the SOX family are indeed crucial as deregulation of SOX family TFs can potentially lead to changes in cell fate as well as irregular cell growth. SOX TFs are a conserved group of transcriptional regulators that mediate DNA binding through a highly conserved high-mobility group (HMG) domain. Accumulating evidence demonstrates that cell fate and differentiation in major developmental processes are controlled by SOX TFs. Besides; numerous reports indicate that both up- and down-regulation of SOX TFs may induce cancer progression. In this review, we discuss the involvement of key TFs of SOX family in human cancers.
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Affiliation(s)
- Prasann Kumar
- The Division of Research and Development, Lovely Professional University, Jalandhar, Punjab, 144411, India; The Department of Agronomy, Lovely Professional University, Jalandhar, Punjab, 144411, India
| | - Tapan Kumar Mistri
- The Division of Research and Development, Lovely Professional University, Jalandhar, Punjab, 144411, India; The Department of Chemistry, Lovely Professional University, Jalandhar, Punjab, 144411, India.
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10
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Mizukami T, Kamachi H, Mitsuhashi T, Einama T, Hatanaka Y, Kamiyama T, Taketomi A. Cytoplasmic CD133 expression correlates with histologic differentiation and is a significant prognostic factor in extrahepatic bile duct cancer and gallbladder cancer. Oncol Lett 2018; 16:6423-6430. [PMID: 30405779 PMCID: PMC6202489 DOI: 10.3892/ol.2018.9499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 09/13/2018] [Indexed: 01/06/2023] Open
Abstract
Prominin-1 (CD133) is one of the most important stem cell markers among various malignant tumor types, but the clinicopathological significance of CD133 expression in intrahepatic cholangiocarcinoma remains controversial. To the best of our knowledge, there have been no reports on extrahepatic bile duct cancer (EHBDCA) and gallbladder cancer (GBCA). The present study examined the clinicopathological significance of CD133 expression in EHBDCA and GBCA. Immunohistochemistry was used to evaluate CD133 expression in resected specimens obtained from 82 patients with EHBDCA and GBCA, and this expression was compared with the clinicopathological parameters and survival data of the patients. Cytoplasmic CD133 expression was identified in 20 patients, and its incidence was significantly associated with histopathological grade (P=0.035), pT factor (P=0.020) and recurrence (P=0.046). Survival analysis revealed that cytoplasmic CD133 expression in patients was significantly associated with a poorer overall survival (OS) and relapse-free survival (RFS) compared with those without cytoplasmic expression (5-year OS rate, 11.6% vs. 39.1%; 3-year RFS rate, 12.5% vs. 42.0%, respectively). Multivariate analysis revealed that cytoplasmic CD133 expression was an independent prognostic factor for OS and RFS (P=0.0036 and P<0.0001, respectively). To the best of our knowledge, this is the first report demonstrating that cytoplasmic CD133 expression was associated with histologic differentiation, cancer progression, recurrence and poor prognosis in EHBDCA and GBCA. CD133 expression may be a useful marker for clinical prognosis in patients with EHBDCA and GBCA.
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Affiliation(s)
- Tatsuzo Mizukami
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
| | - Takahiro Einama
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Yutaka Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
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The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer. Oncogene 2018; 38:1764-1777. [PMID: 30382189 PMCID: PMC6408295 DOI: 10.1038/s41388-018-0553-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 08/03/2018] [Accepted: 09/14/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.
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Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review. Clin Transl Med 2018; 7:18. [PMID: 29984391 PMCID: PMC6035906 DOI: 10.1186/s40169-018-0198-1] [Citation(s) in RCA: 265] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/16/2018] [Indexed: 12/12/2022] Open
Abstract
Despite the abundant ongoing research efforts, cancer remains one of the most challenging diseases to treat globally. Due to the heterogenous nature of cancer, one of the major clinical challenges in therapeutic development is the cancer’s ability to develop resistance. It has been hypothesized that cancer stem cells are the cause for this resistance, and targeting them will lead to tumor regression. A pentaspan transmembrane glycoprotein, CD133 has been suggested to mark cancer stem cells in various tumor types, however, the accuracy of CD133 as a cancer stem cell biomarker has been highly controversial. There are numerous speculations for this, including differences in cell culture conditions, poor in vivo assays, and the inability of current antibodies to detect CD133 variants and deglycosylated epitopes. This review summarizes the most recent and relevant research regarding the controversies surrounding CD133 as a normal stem cell and cancer stem cell biomarker. Additionally, it aims to establish the overall clinical significance of CD133 in cancer. Recent clinical studies have shown that high expression of CD133 in tumors has been indicated as a prognostic marker of disease progression. As such, a spectrum of immunotherapeutic strategies have been developed to target these CD133pos cells with the goal of translation into the clinic. This review compiles the current therapeutic strategies targeting CD133 and discusses their prognostic potential in various cancer subtypes.
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Affiliation(s)
- Paige M Glumac
- Department of Pharmacology, University of Minnesota Medical School, Nils Hasselmo Hall 3-104, 312 Church St. SE, Minneapolis, MN, 55455, USA
| | - Aaron M LeBeau
- Department of Pharmacology, University of Minnesota Medical School, Nils Hasselmo Hall 3-104, 312 Church St. SE, Minneapolis, MN, 55455, USA.
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Yu B, Gu D, Zhang X, Li J, Liu B, Xie J. GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer. Oncotarget 2018; 8:27412-27427. [PMID: 28404967 PMCID: PMC5432345 DOI: 10.18632/oncotarget.16174] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/24/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance.
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Affiliation(s)
- Beiqin Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Department of Pediatrics, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Dongsheng Gu
- Department of Pediatrics, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiaoli Zhang
- Department of Pediatrics, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jianfang Li
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jingwu Xie
- Department of Pediatrics, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Yu B, Gu D, Zhang X, Liu B, Xie J. The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. J Genet Genomics 2017; 44:375-383. [PMID: 28847472 DOI: 10.1016/j.jgg.2017.04.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 03/20/2017] [Accepted: 04/13/2017] [Indexed: 12/17/2022]
Abstract
Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil (5Fu)-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually succumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer cells following 5Fu treatment have elevated expression of hedgehog (Hg) target genes GLI1 and GLI2, suggestive of Hh signaling activation. Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated GLI2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation of ABCG2. ABCG2 can rescue the GLI2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2-associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy (containing 5Fu). Taken together, we have identified a molecular mechanism by which gastric cancer cells gain 5Fu resistance.
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Affiliation(s)
- Beiqin Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Dongsheng Gu
- Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiaoli Zhang
- Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Jingwu Xie
- Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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15
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Song Y, Wang Y, Tong C, Xi H, Zhao X, Wang Y, Chen L. A unified model of the hierarchical and stochastic theories of gastric cancer. Br J Cancer 2017; 116:973-989. [PMID: 28301871 PMCID: PMC5396111 DOI: 10.1038/bjc.2017.54] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 01/16/2017] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a life-threatening disease worldwide. Despite remarkable advances in treatments for GC, it is still fatal to many patients due to cancer progression, recurrence and metastasis. Regarding the development of novel therapeutic techniques, many studies have focused on the biological mechanisms that initiate tumours and cause treatment resistance. Tumours have traditionally been considered to result from somatic mutations, either via clonal evolution or through a stochastic model. However, emerging evidence has characterised tumours using a hierarchical organisational structure, with cancer stem cells (CSCs) at the apex. Both stochastic and hierarchical models are reasonable systems that have been hypothesised to describe tumour heterogeneity. Although each model alone inadequately explains tumour diversity, the two models can be integrated to provide a more comprehensive explanation. In this review, we discuss existing evidence supporting a unified model of gastric CSCs, including the regulatory mechanisms of this unified model in addition to the current status of stemness-related targeted therapy in GC patients.
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Affiliation(s)
- Yanjing Song
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yao Wang
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Chuan Tong
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Hongqing Xi
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xudong Zhao
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yi Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
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Expression of NUAK2 in gastric cancer tissue and its effects on the proliferation of gastric cancer cells. Exp Ther Med 2016; 13:676-680. [PMID: 28352350 DOI: 10.3892/etm.2016.3983] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 08/16/2016] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to analyze the expression and effects of NUAK2 in gastric cancer and adjacent normal gastric tissues. The protein expression levels of NUAK2 were detected by western blot analysis. The effects of NUAK2 expression on the proliferation of gastric cancer cells was detected using an MTT and BrdU incorporation assay. Furthermore, the effects of NUAK2 on proliferation and cancer stem cell markers, both protein and microRNA (miRNA), were investigated by western blot analysis and miRNA microarrays, respectively. The results demonstrated that NUAK2 was able to significantly promote the proliferation of SGC-7901 gastric cancer cells. In addition, NUAK2 overexpression decreased the percentage of cells in the G1 phase and increased the percentage of cells in the S phase. Western blot analysis and miRNA microarrays revealed that overexpression of NUAK2 resulted in increased expression levels of proliferation markers, including c-myc, proliferating cell nuclear antigen, cyclin-dependent kinase 2, miRNA 21, and gastric cancer stem cell markers, including aldehyde dehydrogenase 1, CD44 and CD133. In conclusion, NUAK2 expression differed between the tumor and normal gastric tissues. NUAK2 was able to promote the proliferation of gastric cancer cells and regulate their cell cycle. Proliferation and cancer stem cell markers were upregulated by NUAK2 expression. Therefore, the results from the present study suggest that NUAK2 may be a promising target for gastric cancer therapy in the future.
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17
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CD133 overexpression correlates with clinicopathological features of gastric cancer patients and its impact on survival: a systematic review and meta-analysis. Oncotarget 2016; 6:42019-27. [PMID: 26503471 PMCID: PMC4747206 DOI: 10.18632/oncotarget.5714] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 10/09/2015] [Indexed: 12/12/2022] Open
Abstract
Background CD133 is one of the most commonly used markers of cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CD133 in gastric cancer remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta-analysis to elucidate the correlation of CD133 overexpression with prognosis and clinicopathological features of GC patients. Methods A search in the Cochrane Library, Pubmed, Medline, Web of Knowledge and Chinese CNKI, CBM (up to Jun 30, 2015) was performed using the following keywords gastric cancer, CD133, AC133, prominin-1, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Outcomes included overall survival and various clinicopathological features. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted the data, and assessed the methodological quality of the included studies, and then RevMan 5.2.0 software was used for meta-analysis. Results A total of 603 gastric cancer patients from 8 studies were included. The results of the meta-analyses showed that, there were significant differences of CD133 expression in the following comparisons: gastric cancer tissues vs. normal esophageal tissue (OR = 3.49, 95% CI [2.48, 490], P < 0.00001), lymph node metastasis vs. non-lymph node metastasis (OR = 2.75, 95% CI [1.99, 3.81], P < 0.00001), distant metastasis vs. non-distant metastasis (OR = 2.38, 95%CI [1.47, 3.85], P < 0.0004), clinical stages III~IV vs. clinical stages I~II (OR = 2.83, 95% CI [2.13, 3.76], P < 0.00001), as well as the accumulative 5-year overall survival rates of CD133-positive vs. CD133-negative patients (OR = 0.23, 95% CI [0.16, 0.33], P < 0.00001). Conclusion Overexpression of CD133 is associated with lymph node metastasis, distant metastasis, poor TNM stage. Additionally, CD133-positive gastric cancer patients had worse prognosis. Our results indicate that CD133 may be involved in the carcinogenesis of gastric cancer. Evaluation of cytoplasmic CD133 overexpression in gastric cancer tissue sections may be useful in the future as a novel prognostic factor. Nevertheless, due to the poor quality and small sample size of included trials, more well-designed multi-center randomized controlled trials should be performed.
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Park JW, Park JM, Park DM, Kim DY, Kim HK. Stem Cells Antigen-1 Enriches for a Cancer Stem Cell-Like Subpopulation in Mouse Gastric Cancer. Stem Cells 2016; 34:1177-87. [DOI: 10.1002/stem.2329] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/23/2015] [Accepted: 12/08/2015] [Indexed: 01/06/2023]
Affiliation(s)
- Jun Won Park
- Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics; National Cancer Center; Goyang Gyeonggi Republic of Korea
- Department of Veterinary Pathology, Department of Veterinary Pathology, College of Veterinary Medicine; Seoul National University; Seoul Republic of Korea
| | - Jung Min Park
- Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics; National Cancer Center; Goyang Gyeonggi Republic of Korea
| | - Dong Min Park
- Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics; National Cancer Center; Goyang Gyeonggi Republic of Korea
| | - Dae-Yong Kim
- Department of Veterinary Pathology, Department of Veterinary Pathology, College of Veterinary Medicine; Seoul National University; Seoul Republic of Korea
| | - Hark Kyun Kim
- Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics; National Cancer Center; Goyang Gyeonggi Republic of Korea
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Gastric cancer stem cells: evidence, potential markers, and clinical implications. J Gastroenterol 2016; 51:313-26. [PMID: 26428661 DOI: 10.1007/s00535-015-1125-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/13/2015] [Indexed: 02/04/2023]
Abstract
Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.
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DNA Damage in CD133-Positive Cells in Barrett's Esophagus and Esophageal Adenocarcinoma. Mediators Inflamm 2016; 2016:7937814. [PMID: 27069317 PMCID: PMC4812016 DOI: 10.1155/2016/7937814] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 01/21/2016] [Accepted: 02/17/2016] [Indexed: 01/13/2023] Open
Abstract
Barrett's esophagus (BE) caused by gastroesophageal reflux is a major risk factor of Barrett's esophageal adenocarcinoma (BEA), an inflammation-related cancer. Chronic inflammation and following tissue damage may activate progenitor cells under reactive oxygen/nitrogen species-rich environment. We previously reported the formation of oxidative/nitrative stress-mediated mutagenic DNA lesions, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine, in columnar epithelial cells of BE tissues and cancer cells of BEA tissues. We investigated the mechanisms of BEA development in relation to oxidative/nitrative DNA damage and stem cell hypothesis. We examined 8-nitroguanine and 8-oxodG formation and the expression of stem cell marker (CD133) in biopsy specimens of patients with BE and BEA by immunohistochemical analysis in comparison with those of normal subjects. CD133 was detected at apical surface of columnar epithelial cells of BE and BEA tissues, and the cytoplasm and cell membrane of cancer cells in BEA tissues. DNA lesions and CD133 were colocalized in columnar epithelial cells and cancer cells. Their relative staining intensities in these tissues were significantly higher than those in normal subjects. Our results suggest that BE columnar epithelial cells with CD133 expression in apical surface undergo inflammation-mediated DNA damage, and mutated cells acquire the property of cancer stem cells with cytoplasmic CD133 expression.
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Li K, Dan Z, Nie YQ. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment. World J Gastroenterol 2014; 20:5420-5426. [PMID: 24833872 PMCID: PMC4017057 DOI: 10.3748/wjg.v20.i18.5420] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gastric cancer. They may be derived from gastric stem cells in gastric tissues, or bone marrow mesenchymal stem cells. As with other stem cells, GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance, which are resistant to chemotherapy and thus form the basis of drug resistance. Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs, diagnosis and grading of gastric cancer, and research on GCSC-targeted therapy for gastric cancer. Therefore, discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment.
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Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2014; 17:97-106. [PMID: 23558457 PMCID: PMC3889295 DOI: 10.1007/s10120-013-0255-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 03/15/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND CD133 is one of the most important stem cell markers in solid cancers. Some recent reports have described a possible relationship between CD133 and hypoxia-inducing factor-1-alpha (HIF-1α). The aim of this study was to clarify the clinical role of CD133 expression in gastric cancer and to investigate the correlation between CD133 expression and HIF-1α expression. METHODS We studied 189 gastric cancer patients who underwent gastrectomy at Kurume University Hospital. CD133 and HIF-1α expression was examined using immunohistochemical staining. Fifty-six cases were CD133 positive, and they were divided into two expression types: luminal expression of the gland and cytoplasmic expression. We investigated the relationship among CD133 expression types, clinicopathological variables, prognosis, and HIF-1α expression. RESULTS When comparing clinicopathological variables, expression of CD133 in the cytoplasm was related to metastasis and tumor progression. However, this relationship was not observed with luminal expression of the gland type. The survival rate in patients with cytoplasmic CD133 expression was significantly worse than that in the CD133-negative group. This relationship was observed in the survival rate of the adjuvant chemotherapy group and the curative resection group. Multivariate analysis revealed that the expression of CD133 in the cytoplasm was an independent prognostic factor in gastric cancer. Regarding the correlation between CD133 expression and HIF-1α expression, the HIF-1α positive rate was lower in patients with CD133 luminal expression of the gland type and higher in patients with cytoplasmic expression of CD133. CONCLUSION Gastric cancer cells with CD133 expression in the cytoplasm were cells with high potential for malignancy, and this phenotype was associated with cancer progression, chemotherapy resistance, recurrence, and poor prognosis. Cytoplasmic expression of CD133 may be a useful prognostic marker in gastric cancer. Significant correlation was observed between HIF-1α expression and the immunohistochemical staining pattern of CD133.
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Affiliation(s)
- Kousuke Hashimoto
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Keishiro Aoyagi
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Taro Isobe
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Kikuo Kouhuji
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Kazuo Shirouzu
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
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Chen S, Hou JH, Feng XY, Zhang XS, Zhou ZW, Yun JP, Chen YB, Cai MY. Clinicopathologic significance of putative stem cell marker, CD44 and CD133, in human gastric carcinoma. J Surg Oncol 2013; 107:799-806. [PMID: 23609373 DOI: 10.1002/jso.23337] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 03/06/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES CD44 and CD133 have been reported as putative stem cell markers. However, the clinicopathologic significance of CD44 and CD133 expression in patients with gastric carcinoma (GC) has not been clearly elucidated. METHODS Immunohistochemistry (IHC) was performed to investigate the CD44 and CD133 expression in gastric carcinomas and normal mucosal tissues. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots, and Cox proportional hazards regression model were used to analyze the data. RESULTS The highly expressed CD44 and CD133 were observed in 27/152 (17.7%) and 64/152 (42.1%) of GCs and in 4/60 (6.7%) and 15/60 (25.0%) normal gastric mucosal tissues, respectively (P < 0.05, Fisher's exact test). High expression of CD44 was significantly correlated with tumor poorer differentiation, presence of distant metastasis, advanced TNM stage, and tumor relapse; and high expression of CD133 was positively associated with tumor invasion depth, presence of distant metastasis and advanced TNM stage. More importantly, high-expressed CD44 and CD133 were both associated with shorter survival as evidenced by univariate and multivariate analysis. CONCLUSIONS Our study introduces high expression of CD44 and CD133 as adverse independent prognostic factors in GC patients. The combined CD44 and CD133 expression may become a useful tool for identifying patients with different clinical outcomes.
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Affiliation(s)
- Shi Chen
- The State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
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25
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Singh SR. Gastric cancer stem cells: a novel therapeutic target. Cancer Lett 2013; 338:110-9. [PMID: 23583679 DOI: 10.1016/j.canlet.2013.03.035] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 03/25/2013] [Accepted: 03/30/2013] [Indexed: 12/14/2022]
Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer.
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Affiliation(s)
- Shree Ram Singh
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
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Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2013. [PMID: 23558457 DOI: 10.1007/s10120-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND CD133 is one of the most important stem cell markers in solid cancers. Some recent reports have described a possible relationship between CD133 and hypoxia-inducing factor-1-alpha (HIF-1α). The aim of this study was to clarify the clinical role of CD133 expression in gastric cancer and to investigate the correlation between CD133 expression and HIF-1α expression. METHODS We studied 189 gastric cancer patients who underwent gastrectomy at Kurume University Hospital. CD133 and HIF-1α expression was examined using immunohistochemical staining. Fifty-six cases were CD133 positive, and they were divided into two expression types: luminal expression of the gland and cytoplasmic expression. We investigated the relationship among CD133 expression types, clinicopathological variables, prognosis, and HIF-1α expression. RESULTS When comparing clinicopathological variables, expression of CD133 in the cytoplasm was related to metastasis and tumor progression. However, this relationship was not observed with luminal expression of the gland type. The survival rate in patients with cytoplasmic CD133 expression was significantly worse than that in the CD133-negative group. This relationship was observed in the survival rate of the adjuvant chemotherapy group and the curative resection group. Multivariate analysis revealed that the expression of CD133 in the cytoplasm was an independent prognostic factor in gastric cancer. Regarding the correlation between CD133 expression and HIF-1α expression, the HIF-1α positive rate was lower in patients with CD133 luminal expression of the gland type and higher in patients with cytoplasmic expression of CD133. CONCLUSION Gastric cancer cells with CD133 expression in the cytoplasm were cells with high potential for malignancy, and this phenotype was associated with cancer progression, chemotherapy resistance, recurrence, and poor prognosis. Cytoplasmic expression of CD133 may be a useful prognostic marker in gastric cancer. Significant correlation was observed between HIF-1α expression and the immunohistochemical staining pattern of CD133.
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Affiliation(s)
- Kousuke Hashimoto
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
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Voon DCC, Wang H, Koo JKW, Nguyen TAP, Hor YT, Chu YS, Ito K, Fukamachi H, Chan SL, Thiery JP, Ito Y. Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. Stem Cells 2013; 30:2088-99. [PMID: 22899304 DOI: 10.1002/stem.1183] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The transcription factor RUNX3 functions as a tumor suppressor in the gastrointestinal epithelium, where its loss is an early event in carcinogenesis. While RUNX3 acts concurrently as a mediator of TGF-β signaling and an antagonist of Wnt, the cellular changes that follow its loss and their contribution to tumorigenicity are not fully understood. Here, we report that the loss of Runx3 in gastric epithelial cells results in spontaneous epithelial-mesenchymal transition (EMT). This produces a tumorigenic stem cell-like subpopulation, which remarkably expresses the gastric stem cell marker Lgr5. This phenomenon is due to the compounding effects of the dysregulation of the TGF-β and Wnt pathways. Specifically, Runx3(-/-) p53(-/-) gastric epithelial cells were unexpectedly sensitized for TGF-β-induced EMT, during which the resultant induction of Lgr5 was enhanced by an aberrantly activated Wnt pathway. These data demonstrate a protective role for RUNX3 in safeguarding gastric epithelial cells against aberrant growth factor signaling and the resultant cellular plasticity and stemness.
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Affiliation(s)
- Dominic Chih-Cheng Voon
- The Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Singapore
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Tabu K, Bizen N, Taga T, Tanaka S. Gene Regulation of Prominin-1 (CD133) in Normal and Cancerous Tissues. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 777:73-85. [PMID: 23161076 DOI: 10.1007/978-1-4614-5894-4_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A pentaspan membrane glycoprotein prominin-1 (frequently called CD133 in human) is widely used as a surface marker to identify and isolate normal stem/progenitor cells from various organs, although it is also expressed in some types of differentiated cells. Since CD133 was identified as a universal marker to isolate cancer stem cells (CSCs) in tumors derived from multiple tissues, much attention has been directed toward the relationship between its gene regulation and identity of CSCs (i.e., cancer stemness). Prominin-1 (PROM1) gene possesses five alternative promoters yielding multiple first exons within the 5'-untranslated region (UTR) and also splicing variants affecting the open reading frame (ORF) sequence, implicating the complicated gene regulation in a context-dependent manner. This chapter aims to organize the accumulated findings on prominin-1 with a focus on its altered expression and regulation in normal and cancerous cells and to discuss potential regulatory networks underlying cancer stemness.
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Affiliation(s)
- Kouichi Tabu
- Department of Stem cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan,
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Ding SZ, Zheng PY. Helicobacter pylori infection induced gastric cancer; advance in gastric stem cell research and the remaining challenges. Gut Pathog 2012; 4:18. [PMID: 23217022 PMCID: PMC3536631 DOI: 10.1186/1757-4749-4-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 11/29/2012] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection is the major cause of gastric cancer, which remains an important health care challenge. Recent investigation in gastric stem cell or progenitor cell biology has uncovered valuable information in understanding the gastric gland renewal and maintenance of homeostasis, they also provide clues for further defining the mechanisms by which gastric cancer may originate and progress. Lgr5, Villin-promoter, TFF2-mRNA and Mist have recently been identified as gastric stem/progenitor cell markers; their identification enriched our understanding on the gastric stem cell pathobiology during chronic inflammation and metaplasia. In addition, advance in gastric cancer stem cell markers such as CD44, CD90, CD133, Musashi-1 reveal novel information on tumor cell behavior and disease progression implicated for therapeutics. However, two critical questions remain to be of considerable challenges for future exploration; one is how H. pylori or chronic inflammation affects gastric stem cell or their progenitors, which give rise to mucus-, acid-, pepsinogen-, and hormone-secreting cell lineages. Another one is how bacterial infection or inflammation induces oncogenic transformation and propagates into tumors. Focus on the interactions of H. pylori with gastric stem/progenitor cells and their microenvironment will be instrumental to decipher the initiation and origin of gastric cancer. Future studies in these areas will be critical to uncover molecular mechanisms of chronic inflammation-mediated oncogenic transformation and provide options for cancer prevention and intervention. We review recent progress and discuss future research directions in these important research fields.
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Affiliation(s)
- Song-Ze Ding
- Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, 450000, China.
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Lee HH, Seo KJ, An CH, Kim JS, Jeon HM. CD133 expression is correlated with chemoresistance and early recurrence of gastric cancer. J Surg Oncol 2012; 106:999-1004. [PMID: 22674531 DOI: 10.1002/jso.23178] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Accepted: 05/14/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND CD133 has been suggested to be a cancer stem cell (CSC) marker in various types of cancers. The present study assessed the relationship between CD133 expression and clinicopathological features of gastric cancer. In addition, the prognostic value of CD133 for gastric cancer was evaluated. METHODS In total, 100 advanced gastric cancer patients who received curative gastrectomy and adjuvant chemotherapy were included. CD133 expression was determined by immunohistochemistry and clinicopathological results, including survival, were analyzed. RESULTS CD133 was expressed in 23% of advanced gastric cancer patients (23/100). CD133 expression was significantly associated with serosal exposure (P = 0.036), venous invasion (P = 0.047), well and moderate differentiation (P = 0.002), and intestinal-type Lauren classification (P = 0.001). CD133-positive patients had a significantly worse 5-year disease-free (28.1% vs. 65.8%, P = 0.002) and overall (47.5% vs. 74.0%, P = 0.037) survival rate than those who were CD133-negative. A multivariate analysis suggested that CD133 expression significantly affected the 5-year disease-free and overall survival. CONCLUSIONS CD133 may play an important role in chemoresistance and recurrence, thus representing a promising predictive marker for the prognosis of gastric cancer.
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Affiliation(s)
- Han Hong Lee
- Division of Gastrointestinal Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
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