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      Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition

      review-article
      1 , 2 , 3 , 4 , 5 , 6 , 5 , 6 , 5 , 6 , 5 , 6 , 7 , 5 , 6 , 7 , 5 , 6 , 1 , 2 , 5 , 6 , 8 , 5 , 6 , 8 , 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 1 , 28 , 29 , 29 , 30 , 31 , 32 , 24 , 24 , 5 , 6 ,
      Journal of Hematology & Oncology
      BioMed Central
      Cancer, Tumor microenvironment (TME), T-cells, B-cells, tumor-associated macrophages (TAMs) , Natural killer (NK) cells, Myeloid-derived suppressor cells (MDSCs), Tumor-associated neutrophils (TANs), Dendritic cells (DCs), Cancer-associated fibroblasts (CAFs), Extracellular matrix (ECM), Chimeric antigen-receptor (CAR) T-cell therapy, T-cell receptor (TCR) therapy, Metastasis, Epithelial-mesenchymal transition (EMT), Theranostics

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          Abstract

          The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME’s contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME’s implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

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          Most cited references1,175

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

            Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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              Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

              An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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                Author and article information

                Contributors
                apkumar@nus.edu.sg
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                13 January 2025
                13 January 2025
                2025
                : 18
                : 6
                Affiliations
                [1 ]Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, ( https://ror.org/044k9ta02) 90123 Palermo, Italy
                [2 ]Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, ( https://ror.org/03bqk3e80) Singapore, 169610 Singapore
                [3 ]Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117597 Singapore
                [4 ]Department of Medical Physics, Memorial Sloan Kettering Cancer Center, ( https://ror.org/02yrq0923) New York, NY USA
                [5 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117600 Singapore
                [6 ]NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 119228 Singapore
                [7 ]School of Chemical and Life Sciences, Singapore Polytechnic, ( https://ror.org/05pxcn248) Singapore, 139651 Singapore
                [8 ]Cancer Science Institute of Singapore, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117599 Singapore
                [9 ]Immunology Program, Life Sciences Institute, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117456 Singapore
                [10 ]Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 119228 Singapore
                [11 ]School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, ( https://ror.org/05bqach95) Taipei, 10051 Taiwan
                [12 ]Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, 117456 Singapore
                [13 ]First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), ( https://ror.org/01tvm6f46) Campus Lübeck, 23538 Lübeck, Germany
                [14 ]Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, ( https://ror.org/008xxew50) 1081 Amsterdam, The Netherlands
                [15 ]Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017 San Giuliano, Italy
                [16 ]Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, ( https://ror.org/0499dwk57) Buffalo, NY 14263 USA
                [17 ]Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263 USA
                [18 ]Department of Immunology, School of Medicine, University of Pittsburgh, ( https://ror.org/01an3r305) Pittsburgh, PA USA
                [19 ]Department of Oncology, Zhujiang Hospital, Southern Medical University, ( https://ror.org/02mhxa927) Guangzhou, Guangdong China
                [20 ]National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, ( https://ror.org/051dzw862) Herlev, Denmark
                [21 ]Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, ( https://ror.org/013q1eq08) Shanghai, China
                [22 ]Department of Bioengineering, Imperial College London, ( https://ror.org/041kmwe10) London, W12 0BZ UK
                [23 ]Department of Cancer Biology, Mayo Clinic, ( https://ror.org/02qp3tb03) Jacksonville, FL 32224 USA
                [24 ]Dana-Farber Cancer Institute, Harvard Medical School, ( https://ror.org/03vek6s52) Boston, MA USA
                [25 ]Herbert Irving Comprehensive Cancer Center, Columbia University, ( https://ror.org/00hj8s172) New York, NY USA
                [26 ]Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, ( https://ror.org/03xjwb503) Villejuif, France
                [27 ]Faculty of Medicine, University Paris-Saclay, ( https://ror.org/03xjwb503) Kremlin Bicêtre, Paris, France
                [28 ]Department of Pathology, Yale School of Medicine, Yale University, ( https://ror.org/03v76x132) New Haven, CT USA
                [29 ]Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, ( https://ror.org/02r109517) New York, NY USA
                [30 ]Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, ( https://ror.org/05bnh6r87) New York, NY USA
                [31 ]Department of Radiology, Memorial Sloan Kettering Cancer Center, ( https://ror.org/02yrq0923) New York, NY USA
                [32 ]Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, ( https://ror.org/01q496a73) Oxford, OX3 9DS UK
                Article
                1634
                10.1186/s13045-024-01634-6
                11733683
                39806516
                41ab3030-4407-4b64-a75c-5220a5348ed8
                © The Author(s) 2025

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 20 April 2024
                : 11 November 2024
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001459, Ministry of Education - Singapore;
                Award ID: MOE-T2EP30120-0016
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100011744, National University Health System;
                Award ID: NUHSRO/2023/039/RO5+6/Seed-Mar/04
                Award Recipient :
                Categories
                Review
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                © BioMed Central Ltd., part of Springer Nature 2025

                Oncology & Radiotherapy
                cancer,tumor microenvironment (tme),t-cells, b-cells, tumor-associated macrophages (tams),natural killer (nk) cells,myeloid-derived suppressor cells (mdscs),tumor-associated neutrophils (tans),dendritic cells (dcs),cancer-associated fibroblasts (cafs),extracellular matrix (ecm),chimeric antigen-receptor (car) t-cell therapy,t-cell receptor (tcr) therapy,metastasis,epithelial-mesenchymal transition (emt),theranostics

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