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      Oral submucous fibrosis stimulates invasion and epithelial‐mesenchymal transition in oral squamous cell carcinoma by activating MMP‐2 and IGF‐IR


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          Oral submucous fibrosis (OSF) involves a high risk of malignant transformation and has been implicated in oral cancer. Limited studies have been conducted on the role of OSF in relation to the invasive capabilities and epithelial‐mesenchymal transition (EMT) in oral cancer. Herein, we investigated the effects of OSF on the microenvironment of human oral cancer cells. The results showed that the conditioned medium (CM) of fibrotic buccal mucosal fibroblasts (fBMFs) strongly induced the invasion of oral cancer cells and increased the activities of matrix metalloproteinase‐2. OSF significantly induced the EMT in oral cancer cells and downregulated epithelial markers, such as E‐cadherin, but significantly elevated vimentin, fibronectin, N‐cadherin, RhoA, Rac‐1 and FAK. Insulin‐like growth factor‐1 (IGF‐1) was elevated in OSF. The protein levels of the IGF‐1R were upregulated specifically in fBMF CM treatment for oral cancer cells, and the IGFR gene was confirmed by The Cancer Genome Atlas patient transcriptome data. The Kaplan‐Meier curve analysis revealed that patients with oral squamous cell carcinoma and high IGFR expression levels had poorer 5‐year survival than those with low IGFR expression ( p = 0.004). The fBMF‐stimulated EMT cell model may recapture some of the molecular changes during EMT progression in clinical patients with oral cancer.

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          The biology and function of fibroblasts in cancer.

           Raghu Kalluri (2016)
          Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.
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            Every step of the way: integrins in cancer progression and metastasis

            Cell adhesion to the extracellular matrix is fundamental to tissue integrity and human health. Integrins are the main cellular adhesion receptors that through multifaceted roles as signalling molecules, mechanotransducers and key components of the cell migration machinery are implicated in nearly every step of cancer progression from primary tumour development to metastasis. Altered integrin expression is frequently detected in tumours, where integrins have roles in supporting oncogenic growth factor receptor (GFR) signalling and GFR-dependent cancer cell migration and invasion. In addition, integrins determine colonization of metastatic sites and facilitate anchorage-independent survival of circulating tumour cells. Investigations describing integrin engagement with a growing number of versatile cell surface molecules, including channels, receptors and secreted proteins, continue to lead to the identification of novel tumour-promoting pathways. Integrin-mediated sensing, stiffening and remodelling of the tumour stroma are key steps in cancer progression supporting invasion, acquisition of cancer stem cell characteristics and drug resistance. Given the complexity of integrins and their adaptable and sometimes antagonistic roles in cancer cells and the tumour microenvironment, therapeutic targeting of these receptors has been a challenge. However, novel approaches to target integrins and antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as potential ways forward.
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              The two faces of transforming growth factor beta in carcinogenesis.


                Author and article information

                J Cell Mol Med
                J Cell Mol Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                15 September 2021
                October 2021
                : 25
                : 20 ( doiID: 10.1111/jcmm.v25.20 )
                : 9814-9825
                [ 1 ] Clinical Laboratory Chung Shan Medical University Hospital Taichung Taiwan
                [ 2 ] Institute of Medicine Chung Shan Medical University Taichung Taiwan
                [ 3 ] Institute of Oral Sciences Chung Shan Medical University Taichung Taiwan
                [ 4 ] Department of Dentistry Chung Shan Medical University Hospital Taichung Taiwan
                [ 5 ] Department of Medical Research Chung Shan Medical University Hospital Taichung Taiwan
                [ 6 ] School of Dentistry Chung Shan Medical University Taichung Taiwan
                Author notes
                [* ] Correspondence

                Yu‐Chao Chang, School of Dentistry, Chung Shan Medical School, Taichung, Taiwan.

                Email: cyc@ 123456csmu.edu.tw

                © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 0, Pages: 12, Words: 8352
                Funded by: Ministry of Science and Technology, Taiwan , doi 10.13039/501100004663;
                Award ID: MOST 105‐2632‐B‐040‐001
                Award ID: MOST 103‐2632‐B‐040‐001
                Award ID: MOST 104‐2632‐B‐040‐001
                Original Article
                Original Articles
                Custom metadata
                October 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:12.10.2021


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