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Andries M. Bergman - One of the best experts on this subject based on the ideXlab platform.
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The Adaptive Immune System promotes initiation of prostate carcinogenesis in a human c-Myc transgenic mouse model.
Oncotarget, 2017Co-Authors: Monique H.m Melis, Karin E De Visser, Ekaterina Nevedomskaya, Johan Van Burgsteden, Bianca Cioni, Hester J.t. Van Zeeburg, Ji-ying Song, John Zevenhoven, Lukas J.a.c. Hawinkels, Andries M. BergmanAbstract:// Monique H.M. Melis 1 , Ekaterina Nevedomskaya 1 , Johan van Burgsteden 1 , Bianca Cioni 1 , Hester J.T. van Zeeburg 1 , Ji-Ying Song 2 , John Zevenhoven 1 , Lukas J.A.C Hawinkels 3 , Karin E. de Visser 4 and Andries M. Bergman 1, 5 1 Division of Molecular Genetics, Netherlands Cancer Institute, The Netherlands 2 Division of Experimental Animal Pathology, Netherlands Cancer Institute, The Netherlands 3 Division of Gastroenterology-Hepatology and Molecular Cell biology, Leiden university medical center, (LUMC), Netherlands 4 Division of Immunology, Netherlands Cancer Institute, The Netherlands 5 Division of Medical Oncology, Netherlands Cancer Institute, The Netherlands Correspondence to: Andries M. Bergman, email: a.bergman@nki.nl Keywords: prostate cancer, GEMM, Adaptive Immune System Received: April 07, 2017 Accepted: August 26, 2017 Published: September 28, 2017 ABSTRACT Increasing evidence from epidemiological and pathological studies suggests a role of the Immune System in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the Adaptive Immune System are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of Immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the Adaptive Immune System in prostate cancer development. Our findings indicate that the endogenous Adaptive Immune System does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies.
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Abstract 1080: The Adaptive Immune System promotes spontaneous prostate carcinogenesis in a transgenic mouse model
Tumor Biology, 2014Co-Authors: Monique H.m Melis, Johan Van Burgsteden, Hester J.t. Van Zeeburg, Ji-ying Song, John Zevenhoven, Ke De Visser, Andries M. BergmanAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Increasing evidence from epidemiological and pathological studies indicates a role of the Immune System in initiation and progression of multiple cancers, including prostate cancer. Throughout carcinogenesis of the prostate, Immune cells are found in the microenvironment. Overexpression of MYC or loss of PTEN are frequent genetic lesions in human prostate cancer. It has been shown that these genetic lesions induce chemokine expression and attraction of Immune cells. In previous studies the Adaptive System has shown to play a pivotal role in disease progression, however the role of the Adaptive Immune System in prostate carcinogenesis has been inadequately studied. In this study we address the role of the Adaptive Immune System in the development of prostate cancer in two independent spontaneous prostate cancer mouse models; the FVB/HiMYC mouse model in which prostate cancer formation is driven by transgenic expression of human MYC under control of the ARR2/probasin promoter, and the PB-Cre;PTENF/F mouse model in which prostate cancer formation is initiated by loss of PTEN expression. Both mouse models develop Prostatic Intraepithelial Neoplasia (PIN) from the age of 4 weeks on. FVB/HiMYC mice develop adenocarcinoma of the prostate from the age of 24 weeks and PB-Cre;PTENF/F mice from the age of 12 weeks on. To address the functional significance of lymphocytes in prostate cancer development, FVB/HiMYC and PB-Cre;PTENF/F were crossed to lymphocyte deficient RAG-1-/- mice. Analysis of the PTEN model is ongoing, however in the HiMYC model a small but significant delay (p
Martin F. Flajnik - One of the best experts on this subject based on the ideXlab platform.
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A cold-blooded view of Adaptive immunity
Nature Reviews Immunology, 2018Co-Authors: Martin F. FlajnikAbstract:The Adaptive Immune System arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the Adaptive Immune System has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an Adaptive Immune System in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the Adaptive Immune System. Adaptive immunity arose 500 million years ago in cold-blooded vertebrates. Here, Martin Flajnik discusses how recent discoveries in fish, amphibians and reptiles have improved our understanding of the origins and functions of Adaptive Immune Systems.
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A cold-blooded view of Adaptive immunity.
Nature Reviews Immunology, 2018Co-Authors: Martin F. FlajnikAbstract:The Adaptive Immune System arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the Adaptive Immune System has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an Adaptive Immune System in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the Adaptive Immune System.
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origin and evolution of the Adaptive Immune System genetic events and selective pressures
Nature Reviews Genetics, 2010Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:The Adaptive Immune System (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence System consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS.
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Origin and evolution of the Adaptive Immune System: genetic events and selective pressures
Nature Reviews Genetics, 2010Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:How did the intricate Adaptive Immune System of mammals arise? New clues have recently emerged from studies of the Immune Systems of non-mammalian vertebrates. Here, these findings are integrated with current knowledge of macroevolutionary events and selective pressures. The Adaptive Immune System (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence System consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS. The Adaptive Immune System as defined in humans — which includes antigen receptors generated by recombination-activating gene (RAG)-mediated rearrangement and diversified by members of the AID-APOBEC family; the major histocompatibility (MHC); extensive chemokine and cytokine networks; and secondary lymphoid tissues — arose early in the evolution of jawed vertebrates (in placoderms). The RAG transposon is believed to have invaded an immunoglobulin superfamily exon in early jawed vertebrates. It is thought to have provided a new mechanism for generating antigen receptor diversity and led to the emergence of Adaptive immunity. Some features of Adaptive immunity are evolutionarily conserved across species and other features show great plasticity, the latter driven by pathogens. Two rounds of whole-genome duplication produced many paralogues (ohnologues) that are essential for the Adaptive Immune System of jawed vertebrates. Jawless vertebrates have developed an Adaptive Immune System that employs variable lymphocyte receptors instead of T cell and B cell receptors. Two types of variable lymphocyte receptors — VLRA and VLRB — are expressed on T- and B-like lymphoid cells, respectively, which suggests that the origin of cell-mediated and humoral immunity predates the origin of jawed vertebrates.
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Comparative genomics of the MHC: glimpses into the evolution of the Adaptive Immune System.
Immunity, 2001Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:Abstract MHC gene organization (size, complexity, gene order) differs markedly among different species, and yet all nonmammalian vertebrates examined to date have a true "class I region" with tight linkage of genes encoding the class I presenting and processing molecules. Three paralogous regions of the human genome contain sets of linked genes homologous to various loci in the MHC class I, class II, and/or class III regions, providing insight into the organization of the "proto MHC" before the emergence of the Adaptive Immune System in the jawed vertebrates.
Masanori Kasahara - One of the best experts on this subject based on the ideXlab platform.
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The Immune System of jawless vertebrates: insights into the prototype of the Adaptive Immune System
Immunogenetics, 2021Co-Authors: Yoichi Sutoh, Masanori KasaharaAbstract:Jawless vertebrates diverged from an ancestor of jawed vertebrates approximately 550 million years ago. They mount Adaptive Immune responses to repetitive antigenic challenges, despite lacking major histocompatibility complex molecules, immunoglobulins, T cell receptors, and recombination-activating genes. Instead of B cell and T cell receptors, agnathan lymphocytes express unique antigen receptors named variable lymphocyte receptors (VLRs), which generate diversity through a gene conversion-like mechanism. Although gnathostome antigen receptors and VLRs are structurally unrelated, jawed and jawless vertebrates share essential features of lymphocyte-based Adaptive immunity, including the expression of a single type of receptor on each lymphocyte, clonal expansion of antigen-stimulated lymphocytes, and the dichotomy of cellular and humoral immunity, indicating that the backbone of the Adaptive Immune System was established in a common ancestor of all vertebrates. Furthermore, recent evidence indicates that, unlike previously thought, agnathans have a unique classical pathway of complement activation where VLRB molecules act as antibodies instead of immunoglobulins. It seems likely that the last common ancestor of all vertebrates had an Adaptive Immune System resembling that of jawless vertebrates, suggesting that, as opposed to jawed vertebrates, agnathans have retained the prototype of vertebrate Adaptive immunity.
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origin and evolution of the Adaptive Immune System genetic events and selective pressures
Nature Reviews Genetics, 2010Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:The Adaptive Immune System (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence System consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS.
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Origin and evolution of the Adaptive Immune System: genetic events and selective pressures
Nature Reviews Genetics, 2010Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:How did the intricate Adaptive Immune System of mammals arise? New clues have recently emerged from studies of the Immune Systems of non-mammalian vertebrates. Here, these findings are integrated with current knowledge of macroevolutionary events and selective pressures. The Adaptive Immune System (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence System consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS. The Adaptive Immune System as defined in humans — which includes antigen receptors generated by recombination-activating gene (RAG)-mediated rearrangement and diversified by members of the AID-APOBEC family; the major histocompatibility (MHC); extensive chemokine and cytokine networks; and secondary lymphoid tissues — arose early in the evolution of jawed vertebrates (in placoderms). The RAG transposon is believed to have invaded an immunoglobulin superfamily exon in early jawed vertebrates. It is thought to have provided a new mechanism for generating antigen receptor diversity and led to the emergence of Adaptive immunity. Some features of Adaptive immunity are evolutionarily conserved across species and other features show great plasticity, the latter driven by pathogens. Two rounds of whole-genome duplication produced many paralogues (ohnologues) that are essential for the Adaptive Immune System of jawed vertebrates. Jawless vertebrates have developed an Adaptive Immune System that employs variable lymphocyte receptors instead of T cell and B cell receptors. Two types of variable lymphocyte receptors — VLRA and VLRB — are expressed on T- and B-like lymphoid cells, respectively, which suggests that the origin of cell-mediated and humoral immunity predates the origin of jawed vertebrates.
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Comparative genomics of the MHC: glimpses into the evolution of the Adaptive Immune System.
Immunity, 2001Co-Authors: Martin F. Flajnik, Masanori KasaharaAbstract:Abstract MHC gene organization (size, complexity, gene order) differs markedly among different species, and yet all nonmammalian vertebrates examined to date have a true "class I region" with tight linkage of genes encoding the class I presenting and processing molecules. Three paralogous regions of the human genome contain sets of linked genes homologous to various loci in the MHC class I, class II, and/or class III regions, providing insight into the organization of the "proto MHC" before the emergence of the Adaptive Immune System in the jawed vertebrates.
Monique H.m Melis - One of the best experts on this subject based on the ideXlab platform.
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The Adaptive Immune System promotes initiation of prostate carcinogenesis in a human c-Myc transgenic mouse model.
Oncotarget, 2017Co-Authors: Monique H.m Melis, Karin E De Visser, Ekaterina Nevedomskaya, Johan Van Burgsteden, Bianca Cioni, Hester J.t. Van Zeeburg, Ji-ying Song, John Zevenhoven, Lukas J.a.c. Hawinkels, Andries M. BergmanAbstract:// Monique H.M. Melis 1 , Ekaterina Nevedomskaya 1 , Johan van Burgsteden 1 , Bianca Cioni 1 , Hester J.T. van Zeeburg 1 , Ji-Ying Song 2 , John Zevenhoven 1 , Lukas J.A.C Hawinkels 3 , Karin E. de Visser 4 and Andries M. Bergman 1, 5 1 Division of Molecular Genetics, Netherlands Cancer Institute, The Netherlands 2 Division of Experimental Animal Pathology, Netherlands Cancer Institute, The Netherlands 3 Division of Gastroenterology-Hepatology and Molecular Cell biology, Leiden university medical center, (LUMC), Netherlands 4 Division of Immunology, Netherlands Cancer Institute, The Netherlands 5 Division of Medical Oncology, Netherlands Cancer Institute, The Netherlands Correspondence to: Andries M. Bergman, email: a.bergman@nki.nl Keywords: prostate cancer, GEMM, Adaptive Immune System Received: April 07, 2017 Accepted: August 26, 2017 Published: September 28, 2017 ABSTRACT Increasing evidence from epidemiological and pathological studies suggests a role of the Immune System in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the Adaptive Immune System are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of Immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the Adaptive Immune System in prostate cancer development. Our findings indicate that the endogenous Adaptive Immune System does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies.
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Abstract 1080: The Adaptive Immune System promotes spontaneous prostate carcinogenesis in a transgenic mouse model
Tumor Biology, 2014Co-Authors: Monique H.m Melis, Johan Van Burgsteden, Hester J.t. Van Zeeburg, Ji-ying Song, John Zevenhoven, Ke De Visser, Andries M. BergmanAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Increasing evidence from epidemiological and pathological studies indicates a role of the Immune System in initiation and progression of multiple cancers, including prostate cancer. Throughout carcinogenesis of the prostate, Immune cells are found in the microenvironment. Overexpression of MYC or loss of PTEN are frequent genetic lesions in human prostate cancer. It has been shown that these genetic lesions induce chemokine expression and attraction of Immune cells. In previous studies the Adaptive System has shown to play a pivotal role in disease progression, however the role of the Adaptive Immune System in prostate carcinogenesis has been inadequately studied. In this study we address the role of the Adaptive Immune System in the development of prostate cancer in two independent spontaneous prostate cancer mouse models; the FVB/HiMYC mouse model in which prostate cancer formation is driven by transgenic expression of human MYC under control of the ARR2/probasin promoter, and the PB-Cre;PTENF/F mouse model in which prostate cancer formation is initiated by loss of PTEN expression. Both mouse models develop Prostatic Intraepithelial Neoplasia (PIN) from the age of 4 weeks on. FVB/HiMYC mice develop adenocarcinoma of the prostate from the age of 24 weeks and PB-Cre;PTENF/F mice from the age of 12 weeks on. To address the functional significance of lymphocytes in prostate cancer development, FVB/HiMYC and PB-Cre;PTENF/F were crossed to lymphocyte deficient RAG-1-/- mice. Analysis of the PTEN model is ongoing, however in the HiMYC model a small but significant delay (p
Kelly Kersten - One of the best experts on this subject based on the ideXlab platform.
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Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the Adaptive Immune System
Oncoimmunology, 2020Co-Authors: Sjoerd Klarenbeek, Chris W Doornebal, Sjors M. Kas, Nicola Bonzanni, Jinhyuk Bhin, Tanya M. Braumuller, Ingrid Van Der Heijden, Mark Opdam, Philip C. Schouten, Kelly KerstenAbstract:Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) Immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the Adaptive Immune System. The therapeutic efficacy of mTOR inhibition was reduced in Rag1-/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naive immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the Adaptive Immune System.
