Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms.
Identifieur interne : 004103 ( Main/Exploration ); précédent : 004102; suivant : 004104Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms.
Auteurs : P. Tripathi [États-Unis] ; Y. Wang [États-Unis] ; M. Coussens [États-Unis] ; K R Manda [États-Unis] ; A M Casey [États-Unis] ; C. Lin [États-Unis] ; E. Poyo [États-Unis] ; J D Pfeifer [États-Unis] ; N. Basappa [États-Unis] ; C M Bates [États-Unis] ; L. Ma [États-Unis] ; H. Zhang [États-Unis] ; M. Pan [États-Unis] ; L. Ding [États-Unis] ; F. Chen [États-Unis]Source :
- Oncogene [ 1476-5594 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Carcinogenèse, Carcinome épidermoïde (anatomopathologie), Cellules souches (cytologie), Facteurs de transcription NFATC (génétique), Facteurs de transcription NFATC (métabolisme), Femelle, Humains, Inflammation, Microenvironnement tumoral, Modèles animaux de maladie humaine, Régulation de l'expression des gènes tumoraux, Souris, Souris nude, Souris transgéniques, Transduction du signal, Transplantation tumorale, Tumeurs cutanées (métabolisme), Tumeurs de l'ovaire (anatomopathologie), Tumeurs de l'ovaire (métabolisme).
- MESH :
- anatomopathologie : Carcinome épidermoïde, Tumeurs de l'ovaire.
- cytologie : Cellules souches.
- génétique : Facteurs de transcription NFATC.
- métabolisme : Facteurs de transcription NFATC, Tumeurs cutanées, Tumeurs de l'ovaire.
- Animaux, Carcinogenèse, Femelle, Humains, Inflammation, Microenvironnement tumoral, Modèles animaux de maladie humaine, Régulation de l'expression des gènes tumoraux, Souris, Souris nude, Souris transgéniques, Transduction du signal, Transplantation tumorale.
English descriptors
- KwdEn :
- Animals, Carcinogenesis, Carcinoma, Squamous Cell (pathology), Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Inflammation, Mice, Mice, Nude, Mice, Transgenic, NFATC Transcription Factors (genetics), NFATC Transcription Factors (metabolism), Neoplasm Transplantation, Ovarian Neoplasms (metabolism), Ovarian Neoplasms (pathology), Signal Transduction, Skin Neoplasms (metabolism), Stem Cells (cytology), Tumor Microenvironment.
- MESH :
- chemical , genetics : NFATC Transcription Factors.
- chemical , metabolism : NFATC Transcription Factors.
- cytology : Stem Cells.
- metabolism : Ovarian Neoplasms, Skin Neoplasms.
- pathology : Carcinoma, Squamous Cell, Ovarian Neoplasms.
- Animals, Carcinogenesis, Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Inflammation, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Transplantation, Signal Transduction, Tumor Microenvironment.
Abstract
NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.
DOI: 10.1038/onc.2013.132
PubMed: 23624921
Affiliations:
- États-Unis
- Californie, Maryland, Massachusetts, Missouri (État), Pennsylvanie
- College Park (Maryland), Saint-Louis (Missouri)
- Université du Maryland, École de médecine (Université Washington de Saint-Louis)
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Le document en format XML
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Lin</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Poyo, E" sort="Poyo, E" uniqKey="Poyo E" first="E" last="Poyo">E. 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Tripathi</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Wang, Y" sort="Wang, Y" uniqKey="Wang Y" first="Y" last="Wang">Y. Wang</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Coussens, M" sort="Coussens, M" uniqKey="Coussens M" first="M" last="Coussens">M. Coussens</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Manda, K R" sort="Manda, K R" uniqKey="Manda K" first="K R" last="Manda">K R Manda</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Casey, A M" sort="Casey, A M" uniqKey="Casey A" first="A M" last="Casey">A M Casey</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Lin, C" sort="Lin, C" uniqKey="Lin C" first="C" last="Lin">C. Lin</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Poyo, E" sort="Poyo, E" uniqKey="Poyo E" first="E" last="Poyo">E. Poyo</name><affiliation wicri:level="4"><nlm:affiliation>Department of Bioengineering, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Bioengineering, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Pfeifer, J D" sort="Pfeifer, J D" uniqKey="Pfeifer J" first="J D" last="Pfeifer">J D Pfeifer</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Basappa, N" sort="Basappa, N" uniqKey="Basappa N" first="N" last="Basappa">N. Basappa</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biology, University of Maryland, Baltimore, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, University of Maryland, Baltimore, MD</wicri:regionArea><placeName><region type="state">Maryland</region><settlement type="city">College Park (Maryland)</settlement></placeName><orgName type="university">Université du Maryland</orgName></affiliation></author><author><name sortKey="Bates, C M" sort="Bates, C M" uniqKey="Bates C" first="C M" last="Bates">C M Bates</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Ma, L" sort="Ma, L" uniqKey="Ma L" first="L" last="Ma">L. Ma</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Zhang, H" sort="Zhang, H" uniqKey="Zhang H" first="H" last="Zhang">H. Zhang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Pan, M" sort="Pan, M" uniqKey="Pan M" first="M" last="Pan">M. Pan</name><affiliation wicri:level="2"><nlm:affiliation>Division of Oncology, Kaiser Permanente Medical Center, Santa Clara, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Oncology, Kaiser Permanente Medical Center, Santa Clara, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Ding, L" sort="Ding, L" uniqKey="Ding L" first="L" last="Ding">L. Ding</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, The Genome Institute, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Chen, F" sort="Chen, F" uniqKey="Chen F" first="F" last="Chen">F. Chen</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO</wicri:regionArea><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author></analytic><series><title level="j">Oncogene</title><idno type="eISSN">1476-5594</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Carcinogenesis</term><term>Carcinoma, Squamous Cell (pathology)</term><term>Disease Models, Animal</term><term>Female</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Inflammation</term><term>Mice</term><term>Mice, Nude</term><term>Mice, Transgenic</term><term>NFATC Transcription Factors (genetics)</term><term>NFATC Transcription Factors (metabolism)</term><term>Neoplasm Transplantation</term><term>Ovarian Neoplasms (metabolism)</term><term>Ovarian Neoplasms (pathology)</term><term>Signal Transduction</term><term>Skin Neoplasms (metabolism)</term><term>Stem Cells (cytology)</term><term>Tumor Microenvironment</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Carcinogenèse</term><term>Carcinome épidermoïde (anatomopathologie)</term><term>Cellules souches (cytologie)</term><term>Facteurs de transcription NFATC (génétique)</term><term>Facteurs de transcription NFATC (métabolisme)</term><term>Femelle</term><term>Humains</term><term>Inflammation</term><term>Microenvironnement tumoral</term><term>Modèles animaux de maladie humaine</term><term>Régulation de l'expression des gènes tumoraux</term><term>Souris</term><term>Souris nude</term><term>Souris transgéniques</term><term>Transduction du signal</term><term>Transplantation tumorale</term><term>Tumeurs cutanées (métabolisme)</term><term>Tumeurs de l'ovaire (anatomopathologie)</term><term>Tumeurs de l'ovaire (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>NFATC Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>NFATC Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Tumeurs de l'ovaire</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Cellules souches</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Stem Cells</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteurs de transcription NFATC</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Ovarian Neoplasms</term><term>Skin Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteurs de transcription NFATC</term><term>Tumeurs cutanées</term><term>Tumeurs de l'ovaire</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Ovarian Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Carcinogenesis</term><term>Disease Models, Animal</term><term>Female</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Inflammation</term><term>Mice</term><term>Mice, Nude</term><term>Mice, Transgenic</term><term>Neoplasm Transplantation</term><term>Signal Transduction</term><term>Tumor Microenvironment</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Carcinogenèse</term><term>Femelle</term><term>Humains</term><term>Inflammation</term><term>Microenvironnement tumoral</term><term>Modèles animaux de maladie humaine</term><term>Régulation de l'expression des gènes tumoraux</term><term>Souris</term><term>Souris nude</term><term>Souris transgéniques</term><term>Transduction du signal</term><term>Transplantation tumorale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Maryland</li><li>Massachusetts</li><li>Missouri (État)</li><li>Pennsylvanie</li></region><settlement><li>College Park (Maryland)</li><li>Saint-Louis (Missouri)</li></settlement><orgName><li>Université du Maryland</li><li>École de médecine (Université Washington de Saint-Louis)</li></orgName></list><tree><country name="États-Unis"><region name="Missouri (État)"><name sortKey="Tripathi, P" sort="Tripathi, P" uniqKey="Tripathi P" first="P" last="Tripathi">P. Tripathi</name></region><name sortKey="Basappa, N" sort="Basappa, N" uniqKey="Basappa N" first="N" last="Basappa">N. Basappa</name><name sortKey="Bates, C M" sort="Bates, C M" uniqKey="Bates C" first="C M" last="Bates">C M Bates</name><name sortKey="Casey, A M" sort="Casey, A M" uniqKey="Casey A" first="A M" last="Casey">A M Casey</name><name sortKey="Chen, F" sort="Chen, F" uniqKey="Chen F" first="F" last="Chen">F. Chen</name><name sortKey="Coussens, M" sort="Coussens, M" uniqKey="Coussens M" first="M" last="Coussens">M. Coussens</name><name sortKey="Ding, L" sort="Ding, L" uniqKey="Ding L" first="L" last="Ding">L. Ding</name><name sortKey="Lin, C" sort="Lin, C" uniqKey="Lin C" first="C" last="Lin">C. Lin</name><name sortKey="Ma, L" sort="Ma, L" uniqKey="Ma L" first="L" last="Ma">L. Ma</name><name sortKey="Manda, K R" sort="Manda, K R" uniqKey="Manda K" first="K R" last="Manda">K R Manda</name><name sortKey="Pan, M" sort="Pan, M" uniqKey="Pan M" first="M" last="Pan">M. Pan</name><name sortKey="Pfeifer, J D" sort="Pfeifer, J D" uniqKey="Pfeifer J" first="J D" last="Pfeifer">J D Pfeifer</name><name sortKey="Poyo, E" sort="Poyo, E" uniqKey="Poyo E" first="E" last="Poyo">E. Poyo</name><name sortKey="Wang, Y" sort="Wang, Y" uniqKey="Wang Y" first="Y" last="Wang">Y. Wang</name><name sortKey="Zhang, H" sort="Zhang, H" uniqKey="Zhang H" first="H" last="Zhang">H. Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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