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Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon

World Journal of Gastroenterology 2012年第7期18卷 601-608页

作者： ferenc sipos Orsolya Galamb Cell Analysis Laboratory 2nd Department of Internal MedicineSemmelweis University1088 BudapestHungary Molecular Medicine Research Unit Hungarian Academy of Sciences1051 BudapestHungary

Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.

关键词： Epithelial-to-mesenchymal transition Mesen-chymal-to-epithelial transition Colorectal cancer Fibrosis Mucosal healing

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Disagreements in the therapeutic use of mesenchymal stem cellderived secretome

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World Journal of Stem Cells 2022年第6期14卷 365-371页

作者： ferenc sipos Györgyi Műzes Department of Internal Medicine and Hematology Semmelweis UniversityBudapest 1088Hungary

In a recent article,the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells(MSCs),as well as a discussion on the potential mechanisms of action of MSC-based *** describe the morphology,biogenesis,and current isolation techniques of exosomes,one of the most important fractions of the MSC-derived *** also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney,liver,cardiovascular,neurological,and musculoskeletal diseases,as well as cutaneous wound *** the fact that MSCs are regarded as an important pillar of regenerative medicine,their regenerative potential has been demonstrated to be limited in a number of pathological *** negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived *** the other hand,MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development,including *** can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging ***,enzymes secreted into and activated within exosomes can result in tumor cells acquiring new *** a result,therapeutic applications of MSC-derived secretomes must be approached with extreme caution.

关键词： Mesenchymal stem cells Secretome Exosomes Regeneration Therapy Cancer

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Issues and opportunities of stem cell therapy in autoimmune diseases

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World Journal of Stem Cells 2019年第4期11卷 212-221页

作者： Gy?rgyi M?zes ferenc sipos Immunology Team 2nd Department of Internal MedicineSemmelweis University

The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.

关键词： Stem cell therapy Autoimmune Autoinflammatory Immunomodulation Disease modification

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Controversies in therapeutic application of mesenchymal stem cell-derived secretome

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BIOCELL 2022年第4期46卷 903-906页

作者： ferenc sipos GYÖRGYI MŰZES Department of Internal Medicine and Hematology Semmelweis UniversityBudapest1088Hungary

Though mesenchymal stem cells(MSCs)are considered as an important pillar of regenerative medicine,their regenerative potential has been shown to be limited in several pathological *** adverse properties of MSCbased cell therapy have drawn attention to the therapeutic use of MSC-derived ***,MSC-originated exosomes and microvesicles can also possess a significant impact on disease development,including *** interchanging secretome,MSCs can interact with tumor cells and promote mutual exchange/induction of cellular *** addition,enzymes secreted into and activated within exosomes can result in the acquisition of new tumor cell ***,therapeutic applications of MSC-derived secretome require much caution.

关键词： Mesenchymal stem cells Secretome Exosomes Cancer

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Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases

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World Journal of Gastroenterology 2016年第35期22卷 7938-7950页

作者： ferenc sipos Gábor Firneisz Györgyi Mũzes 2nd Department of Internal Medicine Semmelweis UniversityH-1088 Budapest Hungary

Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several protooncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and microRNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be sele

关键词： c-MYC Therapy Apoptosis Autophagy Colon Inflammation Colorectal cancer

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Intratumoral functional heterogeneity and chemotherapy

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World Journal of Gastroenterology 2014年第10期20卷 2429-2432页

作者： ferenc sipos Miklós Constantinovits Gyrgyi Müzes 2nd Department of Internal Medicine Semmelweis University 1088 Budapest Hungary

Intratumoral heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst malignant cells originated within the same ***,cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of cancer *** a tumor consists of cancer cell clones that display distinct behaviours,changes in clonal proliferative behavior may also contribute to the phenotypic variability of tumor *** is a need to reveal molecular actions driving chemotherapeutic resistance in colon cancer *** general,it is widely hypothesized that therapeutic resistance in colorectal cancer is a consequence of the preferential survival of cancer stem ***,recent data regarding colorectal cancer suggest that resistance to anticancer therapy and post-therapeutic tumor reappearence could be related to variations of clonal *** the interaction of genetic and nongenetic determinants influencing the functional diversity and therapy response of tumors should be a future direction for cancer research.

关键词： Colorectal cancer Clonal dynamics Functional heterogeneity Chemotherapy Xenograft Oxaliplatin

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Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer

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World Journal of Gastroenterology 2017年第46期23卷 8109-8119页

作者： ferenc sipos Hajnal Székely Imre Dániel Kis Zsolt Tulassay Gyorgyi Muzes 2nd Department of Internal Medicine Semmelweis University Faculty of Medicine Semmelweis University Molecular Medicine Research Group Hungarian Academy of Sciences

Metabolic syndrome(Met S), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor(IGF1 R) signaling pathway. The IGF1 R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1 R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from Met S who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1 R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1 R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1 R modulation can initiate additional, sometimes unfavorable biologic effects.

关键词： Insulin-like growth factor IGF1R Autophagy Colitis Colorectal cancer Metabolic syndrome

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Effect of ageing on colonic mucosal regeneration

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World Journal of Gastroenterology 2011年第25期17卷 2981-2986页

作者： ferenc sipos Katalin Leiszter Zsolt Tulassay 2nd Department of Internal Medicine Semmelweis University Molecular Medicine Research Unit Hungarian Academy of Sciences

The physiologic and pathologic cellular and molecular changes occurring with age in the human colon affect both the inflammatory process leading to mucosal injury and the regenerative capacity of the *** the one hand,age-related telomere shortening and inflamm-ageing may lead to the development of colonic inflammation,which results in epithelial *** the other hand,the altered migration and function of regenerative stem cells,the age-related methylation of mucosal healing-associated genes,together with the alterations of growth factor signaling with age,may be involved in delayed mucosal *** connections of these alterations to the process of ageing are not fully *** understanding and customtailored modification of these mechanisms are of great clinical importance with regard to disease prevention and modern therapeutic ***,we aim to summarize the age-related microscopic and molecular changes of the human colon,as well as their role in altered mucosal healing.

关键词： Colon Mucosal repair Ageing Colorectalcancer Telomere shortening DNA methylation

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Contribution of TLR signaling to the pathogenesis of colitisassociated cancer in inflammatory bowel disease

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World Journal of Gastroenterology 2014年第36期20卷 12713-12721页

作者： ferenc sipos István Fri Miklós Constantinovits Zsolt Tulassay Gyrgyi Mzes 2nd Department of Internal Medicine Semmelweis University 1088 Budapest Hungary Molecular Medicine Research Unit Hungarian Academy of Sciences 1088 Budapest Hungary

In the intestine a balance between proinflammatory and repair signals of the immune system is essential for the maintenance of intestinal homeostasis. The innate immunity ensures a primary host response to microbial invasion, which induces an inflammatory process to localize the infection and prevent systemic dissemination of pathogens. The key elements of this process are the germline encoded pattern recognition receptors including Toll-like receptors (TLRs). If pathogens cannot be eliminated, they may elicit chronic inflammation, which may be partly mediated via TLRs. Additionally, chronic inflammation has long been suggested to trigger tissue tumorous transformation. Inflammation, the seventh hallmark of cancer, may affect all phases of tumor development, and evade the immune system. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability. Furthermore, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Colorectal cancers in inflammatory bowel disease patients are considered typical examples of inflammation-related cancers. Although data regarding the role of TLRs in the pathomechanism of cancer-associated colitis are rather conflicting, functionally these molecules can be classified as ”largely antitumorigenic” and ”largely pro-tumorigenic” with the caveat that the underlying signaling pathways are mainly context (i.e., organ-, tissue-, cell-) and ligand-dependent.

关键词： Inflammation Tissue repair Immunoregulation Colitis-associated cancer Toll-like receptor Inflammatory bowel disease Carcinogenesis

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Isolated lymphoid follicles in colon: Switch points between inflammation and colorectal cancer?

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World Journal of Gastroenterology 2011年第13期17卷 1666-1673页

作者： ferenc sipos Gyrgyi Müzes 2nd Department of Internal Medicine Semmelweis University

Gut-associated lymphoid tissue is supposed to play a central role in both the organization of colonic repair mechanisms and colorectal carcinogenesis. In inflammatory conditions, the number, diameter and density of isolated lymphoid follicles (ILFs) increases. They are not only involved in immune surveillance, but their presence is also indispensable in normal mucosal regeneration of the colon. In carcinogenesis, ILFs may play a dual role. On the one hand they may support tumor growth and the metastatic process by vascular endothelial growth factor receptor signaling and producing a specific cytokine and cellular milieu, but on the other hand their presence is sometimes associated with a better prognosis. The relation of ILFs to bone marrow derived stem cells, follicular dendritic cells, subepithelial myofibroblasts or crypt formation, which are all involved in mucosal repair and carcinogenesis, has not been directly studied. Data about the putative organizer role of ILFs is scattered in scientific literature.

关键词： Isolated lymphoid follicle Colon Mucosal repair Colorectal cancer Epithelial stem cell Myofibroblast Follicular dendritic cell Mesenchymal-epithelial transition Epithelial-mesenchymal transition

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