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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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Chico MA, Mesas C, Doello K, Quiñonero F, Perazzoli G, Ortiz R, Prados J, Melguizo C. Cancer Stem Cells in Sarcomas: In Vitro Isolation and Role as Prognostic Markers: A Systematic Review. Cancers (Basel) 2023; 15:cancers15092449. [PMID: 37173919 PMCID: PMC10177331 DOI: 10.3390/cancers15092449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/19/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Sarcomas are a diverse group of neoplasms with an incidence rate of 15% of childhood cancers. They exhibit a high tendency to develop early metastases and are often resistant to available treatments, resulting in poor prognosis and survival. In this context, cancer stem cells (CSCs) have been implicated in recurrence, metastasis, and drug resistance, making the search for diagnostic and prognostic biomarkers of the disease crucial. The objective of this systematic review was to analyze the expression of CSC biomarkers both after isolation from in vitro cell lines and from the complete cell population of patient tumor samples. A total of 228 publications from January 2011 to June 2021 was retrieved from different databases, of which 35 articles were included for analysis. The studies demonstrated significant heterogeneity in both the markers detected and the CSC isolation techniques used. ALDH was identified as a common marker in various types of sarcomas. In conclusion, the identification of CSC markers in sarcomas may facilitate the development of personalized medicine and improve treatment outcomes.
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Affiliation(s)
- Maria Angeles Chico
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Cristina Mesas
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Kevin Doello
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Francisco Quiñonero
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Department of Medicine, Faculty of Health Sciences, University of Almería, 04120 Granada, Spain
| | - Raul Ortiz
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Jose Prados
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Consolacion Melguizo
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
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Singh S, Bhardwaj M, Sen A, Nambiyar K, Ahuja A. Cancer Stem Cell Markers - CD133 and CD44 - in Paediatric Solid Tumours: A Study of Immunophenotypic Expression and Correlation with Clinicopathological Parameters. Indian J Surg Oncol 2023; 14:113-121. [PMID: 36891437 PMCID: PMC9986167 DOI: 10.1007/s13193-022-01626-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 08/18/2022] [Indexed: 11/28/2022] Open
Abstract
Paediatric solid tumours account for about 30% of all the paediatric malignancies. They differ from adult tumours in various aspects like incidence, etiopathogenesis, biology, response rate and outcome. Immunohistochemical markers such as CD133, CD44, CD24, CD90, CD34, CD117, CD20 and ALDH 1 (aldehyde dehydrogenase-1) have been proposed to detect cancer stem cells in tumours. CD133 is a marker of tumour initiating cells in many human cancers and therefore, it may be possible to develop future therapies by targeting cancer stem cells via this marker. CD44 is a transmembrane glycoprotein also known as homing cell adhesion molecule. It is a multifunctional cell-adhesion molecule and plays an important role in cell-cell interaction, lymphocyte homing, tumour progression and metastasis. In the present study, we assessed the expression of CD133 and CD44 in paediatric solid tumours and correlated their expression with clinico-pathological parameters in paediatric solid tumours. This study was a cross-sectional observational study conducted in the department of pathology at a tertiary care centre. All the histologically diagnosed paediatric solid tumours for a period of one year and four months were retrieved from the archives. The cases were reviewed and included in the study after obtaining informed consent. Immunohistochemistry using the monoclonal antibodies for CD133 and CD44 was performed in the representative tissue sections of all the cases. Immuno-scores were assessed, and the results were compared using Pearson's chi-square test. The present study included 50 cases of paediatric solid tumours. The majority (34%) of the patients were in the age group of less than 5 years, with male preponderance (M:F = 2.3:1). The tumours included were Wilms tumour, yolk sac tumour, rhabdomyosarcoma, lymphoma, neuroblastoma, hepatoblastoma, gastrointestinal stromal tumour (GIST), medulloblastomas, pilocytic astrocytomas, ependymomas and glioblastoma. On immunohistochemical analysis, high expression of CD133 and CD44 was found. A significant association between the expression of CD133 and various tumour groups was observed (p = 0.004). However, CD44 showed variable expression in different tumour groups. Both CD133 and CD44 identified cancer stem cell in paediatric solid tumours. A further validation is warranted to investigate their potential role in therapy and prognosis.
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Affiliation(s)
- Shashikant Singh
- Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Minakshi Bhardwaj
- Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Amita Sen
- Department of Paediatric Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Kaniyappan Nambiyar
- Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Arvind Ahuja
- Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
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Banerjee S, Yoon H, Ting S, Tang CM, Yebra M, Wenzel AT, Yeerna H, Mesirov JP, Wechsler-Reya RJ, Tamayo P, Sicklick JK. KIT low Cells Mediate Imatinib Resistance in Gastrointestinal Stromal Tumor. Mol Cancer Ther 2021; 20:2035-2048. [PMID: 34376580 PMCID: PMC8492542 DOI: 10.1158/1535-7163.mct-20-0973] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 04/06/2021] [Accepted: 06/30/2021] [Indexed: 11/16/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34+KIThigh progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell-associated transcription factors (OCT4 and NANOG) and concomitant enrichment of the CD34+KITlow cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our in vitro findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets in vitro and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34+KITlow cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy.
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Affiliation(s)
- Sudeep Banerjee
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, California
- Department of Surgery, University of California, Los Angeles, California
- Moores Cancer Center, University of California, San Diego, California
| | - Hyunho Yoon
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, California
- Moores Cancer Center, University of California, San Diego, California
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Stephanie Ting
- Moores Cancer Center, University of California, San Diego, California
- Department of Medicine, Division of Medical Genetics, University of California, San Diego, California
| | - Chih-Min Tang
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, California
- Moores Cancer Center, University of California, San Diego, California
| | - Mayra Yebra
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, California
- Moores Cancer Center, University of California, San Diego, California
| | - Alexander T Wenzel
- Moores Cancer Center, University of California, San Diego, California
- Department of Medicine, Division of Medical Genetics, University of California, San Diego, California
| | - Huwate Yeerna
- Moores Cancer Center, University of California, San Diego, California
- Department of Medicine, Division of Medical Genetics, University of California, San Diego, California
| | - Jill P Mesirov
- Moores Cancer Center, University of California, San Diego, California
- Department of Medicine, Division of Medical Genetics, University of California, San Diego, California
| | | | - Pablo Tamayo
- Moores Cancer Center, University of California, San Diego, California
- Department of Medicine, Division of Medical Genetics, University of California, San Diego, California
- UCSD Center for Novel Therapeutics, La Jolla, California
| | - Jason K Sicklick
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, California.
- Moores Cancer Center, University of California, San Diego, California
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Hayashi Y, Nguyen VTT. A narrative review of imatinib-resistant gastrointestinal stromal tumors. GASTROINTESTINAL STROMAL TUMOR 2021; 4. [PMID: 35814621 PMCID: PMC9268655 DOI: 10.21037/gist-21-10] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objective: Review the studies that investigate the mechanisms underlying imatinib-resistant gastrointestinal stromal tumors (GIST). Background: GIST are the most common mesenchymal tumors of the gastrointestinal (GI) tract and the most common sarcoma in humans. GIST are thought to be arise from interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells in the GI tract, as well as “fibroblast”-like cells, which are another type of interstitial cells of the gut wall and also known as telocyte or platelet-derived growth factor-alpha (PDGFRA)-positive cells. The majority of GIST harbor gain-of-function mutations in either KIT or PDGFRA, and these gain-of-function mutations are mutually exclusive and most often heterozygous. GIST are responsive to the KIT/PDGFRA tyrosine kinase inhibitor (TKI), imatinib, the standard first-line drug for advanced and metastatic GIST. However, imatinib alone does not eradicate GIST despite an initial clinical benefit, and more than 90% of GIST harbor imatinib-resistance. Although second and third-generation TKIs have been developed and are currently in clinical use, they are not curative for refractory and metastatic GIST due to the emergence of clones with drug-resistant mutations. Eradication of drug-resistant GIST will cure patients with refractory GIST. Several mechanisms may contribute to refractory GIST. These mechanisms are secondary mutations in KIT and/or PDGFRA, alternative activation of tyrosine kinases, stem cells for GIST and cellular quiescence, a reversible nonproliferating state in which cells retain the ability to reenter cell proliferation. Methods: We review our current optimal treatment approach for managing patients with advanced and refractory GIST. Conclusions: This review explores the novel and potential therapeutic approaches to combat drug-resistant GIST.
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Affiliation(s)
- Yujiro Hayashi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.,Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Vy Truong Thuy Nguyen
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.,Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
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Adityan S, Tran M, Bhavsar C, Wu SY. Nano-therapeutics for modulating the tumour microenvironment: Design, development, and clinical translation. J Control Release 2020; 327:512-532. [DOI: 10.1016/j.jconrel.2020.08.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/08/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022]
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Bai C, Liu X, Xu J, Qiu C, Wang R, Zheng J. Expression profiles of stemness genes in gastrointestinal stromal tumor. Hum Pathol 2018; 76:76-84. [PMID: 29486292 DOI: 10.1016/j.humpath.2018.02.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is believed to originate from intestinal cells of Cajal or their stem cell precursors, and expresses stemness-related markers, such as CD117, CD34, DOG1 and nestin. To further characterize phenotypic features of GISTs, we examined expression profiles of a panel of stemness genes in GISTs, by analyzing existing gene expression profiling datasets. Our results showed that mRNA levels of B-lymphoma moloney murine leukaemia virus insertion region-1 (BMI1), kruppel-like factor 4 (KLF4), sal-like protein 4 (SALL4) and telomerase reverse transcriptase (TERT) were significantly unregulated in GISTs. Subsequently, protein expression of BMI1 and TERT was identified in GIST specimens by immunohistochemistry. Especially, we found that high expression of nuclear BMI1 was associated with large tumor size (P = .0239), high mitotic count (P < .01), high Ki-67 index (P = .0357), advanced National Institute of Health (NIH) criteria (P = .0025) and advanced World Health Organization (WHO) classification (P < .01) in GISTs. Functional and pathway enrichment analysis showed that most of BMI1's coexpressed genes were involved in tumor growth-related process, such as regulation of cell cycle and proliferation. Furthermore, we confirmed RAS oncogene family (RAB18) and limb development membrane protein 1 (LMBR1) genes as novel targets for BMI1 in GIST cells. These results provide valuable information for the expression profiles of stemness genes in GISTs, and identified nuclear BMI1 as an important marker of GIST cell proliferation and progression.
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Affiliation(s)
- Chenguang Bai
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China
| | - Xiaohong Liu
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China
| | - Jingjing Xu
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China
| | - Cen Qiu
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China
| | - Runqiu Wang
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Second Milltary Medical University, Shanghai, 200433, China.
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Kövecsi A, Gurzu S, Szentirmay Z, Kovacs Z, Bara TJ, Jung I. Paradoxical expression pattern of the epithelial mesenchymal transition-related biomarkers CD44, SLUG, N-cadherin and VSIG1/Glycoprotein A34 in gastrointestinal stromal tumors. World J Gastrointest Oncol 2017; 9:436-443. [PMID: 29204252 PMCID: PMC5700385 DOI: 10.4251/wjgo.v9.i11.436] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/31/2017] [Accepted: 09/05/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the immunohistochemical (IHC) expression of five biomarkers, commonly involved in epithelial mesenchymal/mesenchymal epithelial transition (EMT/MET), in gastrointestinal stromal tumors (GISTs). METHODS In 80 consecutive GISTs the IHC examinations were performed using the EMT-related antibodies E-cadherin, N-cadherin, SLUG, V-set and immunoglobulin domain containing 1 (VSIG1) and CD44. RESULTS The positivity rate was 88.75% for SLUG, 83.75% for VSIG1, 36.25% for CD44 and 10% for N-cadherin. No correlation was noted between the examined markers and clinicopathological parameters. Nuclear positivity for SLUG and VSIG1 was observed in all cases with distant metastasis. The extra-gastrointestinal stromal tumors (e-GISTs) expressed nuclear positivity for VSIG1 and SLUG, with infrequent positivity for N-cadherin and CD44. The low overall survival was mainly dependent on VSIG1 negativity (P = 0.01) and nuclear positivity for SLUG and/or CD44. CONCLUSION GIST aggressivity may be induced by nuclear up-regulation of SLUG and loss or cytoplasm-to-nuclear translocation of VSIG1. SLUG and VSIG1 may act as activated nuclear transcription factors. The CD44, but not N-cadherin, might also have an independent prognostic value in these tumors. The role of the EMT/MET-related transcription factors in the evolution of GISTs, should be revisited with a larger dataset. This is the first study exploring the IHC pattern of VSIG1 in GISTs.
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Affiliation(s)
- Attila Kövecsi
- Department of Pathology, University of Medicine and Pharmacy, Tirgu Mures 540139, Romania
| | - Simona Gurzu
- Department of Pathology, University of Medicine and Pharmacy, Tirgu Mures 540139, Romania
- Research Center, University of Medicine and Pharmacy, Timi oara 3000041, Romania
| | - Zoltan Szentirmay
- Department of Pathology, National Institute of Oncology, Budapest 1525, Hungary
| | - Zsolt Kovacs
- Department of Pathology, University of Medicine and Pharmacy, Tirgu Mures 540139, Romania
- Department of Biochemistry, University of Medicine and Pharmacy, Timi oara 3000041, Romania
| | - Tivadar Jr Bara
- Department of Surgery, University of Medicine and Pharmacy, Timi oara 3000041, Romania
| | - Ioan Jung
- Department of Pathology, University of Medicine and Pharmacy, Tirgu Mures 540139, Romania
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Geddert H, Braun A, Kayser C, Dimmler A, Faller G, Agaimy A, Haller F, Moskalev EA. Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors. Am J Clin Pathol 2017; 147:515-524. [PMID: 28398518 DOI: 10.1093/ajcp/aqx028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES This study ascertained the regulation of the stem cell marker CD133 and its potential applicability for prognostication of gastrointestinal stromal tumors (GISTs). METHODS A total of 95 resected GISTs were included in the study. CD133 protein expression was assessed immunohistochemically on tissue microarrays. Methylation percentage was quantified by pyrosequencing. Gene expression in cell lines GIST48b and GIST882 upon treatment with DNA demethylation agent 5-aza-2'-deoxycytidine was analyzed by quantitative polymerase chain reaction. RESULTS The expression of hypermethylated CD133 could be reactivated in the GIST cell line upon hypomethylation with the drug. Similarly, in patient material, CD133 methylation percentage correlated inversely with the protein expression and reflected tumor size with hypermethylation in small (<2 cm) tumors and virtually no methylation in large (>10 cm) GISTs. The gene's methylation percentage and expression level were clearly specific to anatomic sites and distinct driver mutations. KIT -mutant gastric GISTs exhibited significantly lower methylation degrees and concomitant high CD133 protein abundance compared with KIT -mutant GISTs from the small intestine. CD133 hypermethylation was documented in PDGFRA -mutant gastric GISTs along with low CD133 expression compared with KIT -mutant gastric GISTs. High CD133 expression was a prognosticator of shorter disease-free survival in all patients. In a subgroup of KIT -mutant gastric GISTs, low CD133 methylation degree was correlated with a shorter disease-free survival. CONCLUSIONS Our results strongly suggest epigenetic regulation of CD133 expression by promoter methylation in GISTs. Pending further validation studies, high abundance of the protein can serve as a marker for malignant GISTs.
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Affiliation(s)
- Helene Geddert
- Institute for Pathology, St Vincentius Hospital, Karlsruhe, Germany
| | - Alexander Braun
- Institute for Pathology, Albert Ludwigs University, Freiburg, Germany
| | - Claudia Kayser
- Institute for Pathology, Albert Ludwigs University, Freiburg, Germany
| | - Arno Dimmler
- Institute for Pathology, St Vincentius Hospital, Karlsruhe, Germany
| | - Gerhard Faller
- Institute for Pathology, St Vincentius Hospital, Karlsruhe, Germany
| | - Abbas Agaimy
- Institute for Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Florian Haller
- Institute for Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Evgeny A Moskalev
- Institute for Pathology, Friedrich Alexander University, Erlangen, Germany
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Wang L, Hao J, Zhang Y, Yang Z, Cao Y, Lu W, Shu Y, Jiang L, Hu Y, Lv W, Liu Y, Dong P. Orai1 mediates tumor-promoting store-operated Ca 2+ entry in human gastrointestinal stromal tumors via c-KIT and the extracellular signal-regulated kinase pathway. Tumour Biol 2017; 39:1010428317691426. [PMID: 28231736 DOI: 10.1177/1010428317691426] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal stromal tumors originate from interstitial cells of Cajal, the pacemaker cells of the gut. Ca2+ regulates the pacemaker activity of interstitial cells of Cajal. Store-operated Ca2+ entry mediates the majority of Ca2+ entry in most cancer cells and may be a factor in regulating intracellular Ca2+ in interstitial cells of Cajal and gastrointestinal stromal tumors. Therefore, a blockade of this mechanism may affect the progression of gastrointestinal stromal tumors. Orai1 is the pore subunit of store-operated Ca2+ channels. Here, we reported that Orai1 was overexpressed in gastrointestinal stromal tumor tissues and was positively correlated with a high-risk grade in gastrointestinal stromal tumor patients. Furthermore, upon Orai1 silencing, the functional store-operated Ca2+ entry in gastrointestinal stromal tumor cells was decreased, indicating that the function of store-operated Ca2+ entry was mediated by Orai1. Inhibition of Orai1-mediated store-operated Ca2+ entry by Orai1 silencing or store-operated Ca2+ entry blockers (SKF-96365 and 2-aminoethyl diphenylborate) induced obvious cell proliferation suppression, cell-cycle distribution, and apoptosis stimulation in GIST-T1 cells. Conversely, Orai1 overexpression increased store-operated Ca2+ entry and cell proliferation in GIST882 cells. In addition, we found that activation of c-KIT and the extracellular signal-regulated kinase pathway participated in the oncogenic functions of Orai1-mediated store-operated Ca2+ entry in gastrointestinal stromal tumor cells. These results revealed that Orai1-mediated store-operated Ca2+ entry is critical for gastrointestinal stromal tumor cell proliferation via c-KIT and ERK signaling pathway activation. Orai1-mediated store-operated Ca2+ entry plays an oncogenic role and may be a novel prognostic factor and therapeutic target for patients with gastrointestinal stromal tumors.
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Affiliation(s)
- Lei Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaqi Hao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziyi Yang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Cao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Lu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yijun Shu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjie Lv
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Dong
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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11
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Pantaleo MA, Ravegnini G, Astolfi A, Simeon V, Nannini M, Saponara M, Urbini M, Gatto L, Indio V, Sammarini G, Santini D, Ferracin M, Negrini M, Hrelia P, Biasco G, Angelini S. Integrating miRNA and gene expression profiling analysis revealed regulatory networks in gastrointestinal stromal tumors. Epigenomics 2016; 8:1347-1366. [PMID: 27625077 DOI: 10.2217/epi-2016-0030] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIM Currently, little is known about differences in miRNA expression between KIT/PDGFRA mutant and KIT/PDGFRA wild-type (WT)-SDH deficient gastrointestinal stromal tumors (GIST). This prompted us to perform an integrated multiple expression profile of miRNA and mRNA, constructing an original miRNA-mRNA regulatory network in KIT/PDGFRA WT-SDH deficient GIST patients. PATIENTS & METHODS Analyses were carried out on KIT/PDGFRA mutant versus KIT/PDGFRA WT-SDH deficient GIST. Genome-wide miRNA and gene-expression analysis were performed using Agilent Human miRNA microarray and Affimetrix array, respectively. RESULTS Three potential regulatory networks (IGF1R → miR-139-5p/miR-455/let-7b, cyclin-dependent kinase 6 (CDK6) → miR-139-5p/let-7b and CD44 → miR-330-3p) were identified. CONCLUSION The miR-139-5p, 455-5p and let-7b signature, in particular, may represent an important therapeutic target in KIT/PDGFRA WT-SDH deficient GIST, usually characterized by IGF1R overexpression.
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Affiliation(s)
- Maria Abbondanza Pantaleo
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.,Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Annalisa Astolfi
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy
| | - Vittorio Simeon
- Laboratory of Pre-Clinical & Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
| | - Margherita Nannini
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Maristella Saponara
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Milena Urbini
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Lidia Gatto
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Valentina Indio
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Giulia Sammarini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Donatella Santini
- Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Manuela Ferracin
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Massimo Negrini
- Department of Morphology, Surgery & Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Patrizia Hrelia
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Guido Biasco
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.,Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
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12
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ETV1 mRNA is specifically expressed in gastrointestinal stromal tumors. Virchows Arch 2015; 467:393-403. [PMID: 26243012 DOI: 10.1007/s00428-015-1813-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 06/17/2015] [Accepted: 07/14/2015] [Indexed: 12/15/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) develop from interstitial cells of Cajal (ICCs) mainly by activating mutations in the KIT or PDGFRA genes. Immunohistochemical analysis for KIT, DOG1, and PKC-θ is used for the diagnosis of GIST. Recently, ETV1 has been shown to be a lineage survival factor for ICCs and required for tumorigenesis of GIST. We investigated the diagnostic value of ETV1expression in GIST. On fresh-frozen tissue samples, RT-PCR analysis showed that ETV1 as well as KIT, DOG1, and PKC-θ are highly expressed in GISTs. On tissue microarrays containing 407 GISTs and 120 non-GIST mesenchymal tumors of GI tract, we performed RNA in situ hybridization (ISH) for ETV1 together with immunohistochemical analysis for KIT, DOG1, PKC-θ, CD133, and CD44. Overall, 387 (95 %) of GISTs were positive for ETV1, while KIT and DOG1 were positive in 381 (94 %) and 392 (96 %) cases, respectively, showing nearly identical overall sensitivity of ETV1, KIT, and DOG1 for GISTs. In addition, ETV1 expression was positively correlated with that of KIT. Notably, ETV1 was positive in 15 of 26 (58 %) KIT-negative GISTs and even positive in 2 cases of GIST negative for KIT and DOG1, whereas only 6 (5 %) non-GIST mesenchymal GI tumors expressed ETV1. We conclude that ETV1 is specifically expressed in the majority of GISTs, even in some KIT-negative cases, suggesting that ETV1 may be useful as ancillary marker in diagnostically difficult select cases of GIST.
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13
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Canter RJ, Ames E, Mac S, Grossenbacher SK, Chen M, Li CS, Borys D, Smith RC, Tellez J, Sayers TJ, Monjazeb AM, Murphy WJ. Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma. BMC Cancer 2014; 14:756. [PMID: 25301268 PMCID: PMC4200119 DOI: 10.1186/1471-2407-14-756] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/02/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Increasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic). METHODS We exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate. RESULTS After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05). CONCLUSIONS Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.
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Affiliation(s)
- Robert J Canter
- Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, 4501 X Street, Sacramento, CA 95817, USA.
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14
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Mouallif M, Albert A, Zeddou M, Ennaji MM, Delvenne P, Guenin S. Expression profile of undifferentiated cell transcription factor 1 in normal and cancerous human epithelia. Int J Exp Pathol 2014; 95:251-9. [PMID: 24738751 DOI: 10.1111/iep.12077] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 02/15/2014] [Indexed: 02/02/2023] Open
Abstract
Undifferentiated cell Transcription Factor 1 (UTF1) is a chromatin-bound protein involved in stem cell differentiation. It was initially reported to be restricted to stem cells or germinal tissues. However, recent work suggests that UTF1 is also expressed in somatic cells and that its expression may increase during carcinogenesis. To further clarify the expression profile of UTF1, we evaluated UTF1 expression levels immunohistochemically in eight normal human epithelia (from breast, prostate, endometrium, bladder, colon, oesophagus, lung and kidney) and their corresponding tumours as well as in several epithelial cell lines. We showed UTF1 staining in normal and tumour epithelial tissues, but with varying intensities according to the tissue location. In vitro analyses also revealed that UTF1 is expressed in somatic epithelial cell lines even in the absence of Oct4A and Sox2, its two main known regulators. The comparison of UTF1 levels in normal and tumoral tissues revealed significant overexpression in endometrial and prostatic adenocarcinomas, whereas lower intensity of the staining was observed in renal and colic tumours, suggesting a potential tissue-specific function of UTF1. Altogether, these results highlight a potential dual role for UTF1, acting either as an oncogene or as a tumour suppressor depending on the tissue. These findings also question its role as a specific marker for stem cells.
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Affiliation(s)
- Mustapha Mouallif
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium; Laboratory of Virology and Hygiene & Microbiology, University Hassan II-Mohammedia, Mohammedia, Morocco
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15
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Linch M, Claus J, Benson C. Update on imatinib for gastrointestinal stromal tumors: duration of treatment. Onco Targets Ther 2013; 6:1011-23. [PMID: 23935374 PMCID: PMC3735340 DOI: 10.2147/ott.s31260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future.
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Affiliation(s)
- Mark Linch
- Sarcoma Unit, Royal Marsden Hospital, United Kingdom ; Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, London, United Kingdom
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16
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Deng Y, Hassan MM, Mo J, Lin EH. Peripheral blood mononuclear CD133 mRNA levels correlates with response to treatment in patients with gastrointestinal stromal tumors. PLoS One 2013; 8:e55520. [PMID: 23408993 PMCID: PMC3567095 DOI: 10.1371/journal.pone.0055520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 12/24/2012] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND CD133 is a marker that identifies/enriches cancer stem cell implicated in tumor initiation. We hypothesize that changes in the CD133 mRNA expression levels and vascular endothelial growth factor (VEGF) may correlate tumor response in GIST. METHODOLOGY/PRINCIPAL FINDINGS After informed consent, we obtained peripheral blood samples from 24 evaluable patients with gastrointestinal stromal tumors (GIST). There were 7 -paired samples before and after treatment, We measured CD133 mRNA levels by real time RT-PCR method and vascular endothelial growth factor (VEGF) levels by ELISA. All measurements were done in duplicates in two separate experiments. The treatment resulted in significant reduction of CD133 mRNA expression (p = 0.048) as well as the level of VEGF (p = 0.003). The mean CD133 mRNA levels for GIST patients was 615. We found no correlation between the CD133 mRNA levels and VEGF levels. (p = 0.826). Logistic regression analysis suggested a relationship between elevated CD133 mRNA levels and fitted probability of eventual progressive disease (PD) and mixed response at 37% for CD133 mRNA of 2.25, and the probability of eventual PD/MR is 84% for a CD133 of 2072 (p = 0.08). CONCLUSIONS/SIGNIFICANCE CD133 mRNA expression levels in GIST patients measured by real time RT-PCR assay appeared to correlate with tumor response to surgery or imatinib and may be used to predict tumor progression. Additional prospective studies are warranted.
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Affiliation(s)
- Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yatsen University, Guangzhou, China
- * E-mail: (YD); (EHL)
| | - Manal M. Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Jianwen Mo
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yatsen University, Guangzhou, China
| | - Edward H. Lin
- Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America
- * E-mail: (YD); (EHL)
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Abstract
Gastrointestinal stromal tumor has received a lot of attention over the last 10 years due to its unique biologic behavior, clinicopathological features, molecular mechanisms, and treatment implications. GIST is the most common mesenchymal neoplasm in the gastrointestinal tract and has emerged from a poorly understood and treatment resistant neoplasm to a well-defined tumor entity since the discovery of particular molecular abnormalities, KIT and PDGFRA gene mutations. The understanding of GIST biology at the molecular level promised the development of novel treatment modalities. Diagnosis of GIST depends on the integrity of histology, immunohistochemistry and molecular analysis. The risk assessment of the tumor behavior relies heavily on pathological evaluation and significantly impacts clinical management. In this review, historic review, epidemiology, pathogenesis and genetics, diagnosis, role of molecular analysis, prognostic factor and treatment strategies have been discussed.
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De Filippis L, Binda E. Concise review: self-renewal in the central nervous system: neural stem cells from embryo to adult. Stem Cells Transl Med 2012. [PMID: 23197809 DOI: 10.5966/sctm.2011-0045] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The recent discovery of neural stem cells (NSCs) in the adult mammalian brain has fostered a plethora of translational and preclinical studies to investigate future therapeutic approaches for the cure of neurodegenerative diseases. These studies are finally at the clinical stage, and some of them are already under way. The definition of a bona fide stem cell has long been the object of much debate focused on the establishment of standard and univocal criteria to distinguish between stem and progenitor cells. It is commonly accepted that NSCs have to fulfill two basic requirements, the capacity for long-term self-renewal and the potential for differentiation, which account for their physiological role, namely central nervous system tissue homeostasis. Strategies such as immortalization or reprogramming of somatic cells to the embryonic-like stage of pluripotency indicate the relevance of extensive self-renewal ability of NSCs either in vitro or in vivo. Moreover, the discovery of stem-like tumor cells in brain tumors, such as gliomas, accompanied by the isolation of these cells through the same paradigm used for related healthy cells, has provided further evidence of the key role that self-renewal plays in the development and progression of neurodegenerative diseases and cancer. In this review we provide an overview of the current understanding of the self-renewal capacity of nontransformed human NSCs, with or without immortalization or reprogramming, and of stem-like tumor cells, referring to both research and therapeutic studies.
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Affiliation(s)
- Lidia De Filippis
- Department of Biotechnology and Biosciences, University of Milan-Bicocca, Italy.
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