Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.
Identifieur interne : 000552 ( Main/Exploration ); précédent : 000551; suivant : 000553Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.
Auteurs : Felipe V. Pereira [Brésil, États-Unis] ; Amanda Campelo L. Melo [Brésil] ; Jun Siong Low [États-Unis] ; Íris Arantes De Castro [Brésil] ; Tárcio T. Braga [Brésil] ; Danilo C. Almeida [Brésil] ; Ana Gabriela U. Batista De Lima [Brésil] ; Meire I. Hiyane [Brésil] ; Matheus Correa-Costa [Brésil] ; Vinicius Andrade-Oliveira [Brésil] ; Clarice S T. Origassa [Brésil] ; Rosana M. Pereira [Brésil] ; Susan M. Kaech [États-Unis] ; Elaine G. Rodrigues [Brésil] ; Niels Olsen S. Câmara [Brésil]Source :
- Oncotarget [ 1949-2553 ] ; 2018.
Abstract
The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. In vitro, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin in vivo was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4+Foxp3+IL-10+ T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1+CD11b+ and RORγ+ IL17+CD4+ cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1-/- mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.
DOI: 10.18632/oncotarget.25380
PubMed: 29899823
PubMed Central: PMC5995253
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Pereira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Melo, Amanda Campelo L" sort="Melo, Amanda Campelo L" uniqKey="Melo A" first="Amanda Campelo L" last="Melo">Amanda Campelo L. 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Braga</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Almeida, Danilo C" sort="Almeida, Danilo C" uniqKey="Almeida D" first="Danilo C" last="Almeida">Danilo C. Almeida</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Batista De Lima, Ana Gabriela U" sort="Batista De Lima, Ana Gabriela U" uniqKey="Batista De Lima A" first="Ana Gabriela U" last="Batista De Lima">Ana Gabriela U. Batista De Lima</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region></placeName></affiliation></author><author><name sortKey="Hiyane, Meire I" sort="Hiyane, Meire I" uniqKey="Hiyane M" first="Meire I" last="Hiyane">Meire I. Hiyane</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Correa Costa, Matheus" sort="Correa Costa, Matheus" uniqKey="Correa Costa M" first="Matheus" last="Correa-Costa">Matheus Correa-Costa</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Andrade Oliveira, Vinicius" sort="Andrade Oliveira, Vinicius" uniqKey="Andrade Oliveira V" first="Vinicius" last="Andrade-Oliveira">Vinicius Andrade-Oliveira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Origassa, Clarice S T" sort="Origassa, Clarice S T" uniqKey="Origassa C" first="Clarice S T" last="Origassa">Clarice S T. Origassa</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Pereira, Rosana M" sort="Pereira, Rosana M" uniqKey="Pereira R" first="Rosana M" last="Pereira">Rosana M. Pereira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Kaech, Susan M" sort="Kaech, Susan M" uniqKey="Kaech S" first="Susan M" last="Kaech">Susan M. Kaech</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Rodrigues, Elaine G" sort="Rodrigues, Elaine G" uniqKey="Rodrigues E" first="Elaine G" last="Rodrigues">Elaine G. Rodrigues</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region></placeName></affiliation></author><author><name sortKey="Camara, Niels Olsen S" sort="Camara, Niels Olsen S" uniqKey="Camara N" first="Niels Olsen S" last="Câmara">Niels Olsen S. Câmara</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29899823</idno><idno type="pmid">29899823</idno><idno type="doi">10.18632/oncotarget.25380</idno><idno type="pmc">PMC5995253</idno><idno type="wicri:Area/Main/Corpus">000529</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000529</idno><idno type="wicri:Area/Main/Curation">000529</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000529</idno><idno type="wicri:Area/Main/Exploration">000529</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.</title><author><name sortKey="Pereira, Felipe V" sort="Pereira, Felipe V" uniqKey="Pereira F" first="Felipe V" last="Pereira">Felipe V. Pereira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Melo, Amanda Campelo L" sort="Melo, Amanda Campelo L" uniqKey="Melo A" first="Amanda Campelo L" last="Melo">Amanda Campelo L. Melo</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Low, Jun Siong" sort="Low, Jun Siong" uniqKey="Low J" first="Jun Siong" last="Low">Jun Siong Low</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="De Castro, Iris Arantes" sort="De Castro, Iris Arantes" uniqKey="De Castro I" first="Íris Arantes" last="De Castro">Íris Arantes De Castro</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Braga, Tarcio T" sort="Braga, Tarcio T" uniqKey="Braga T" first="Tárcio T" last="Braga">Tárcio T. Braga</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Almeida, Danilo C" sort="Almeida, Danilo C" uniqKey="Almeida D" first="Danilo C" last="Almeida">Danilo C. Almeida</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Batista De Lima, Ana Gabriela U" sort="Batista De Lima, Ana Gabriela U" uniqKey="Batista De Lima A" first="Ana Gabriela U" last="Batista De Lima">Ana Gabriela U. Batista De Lima</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region></placeName></affiliation></author><author><name sortKey="Hiyane, Meire I" sort="Hiyane, Meire I" uniqKey="Hiyane M" first="Meire I" last="Hiyane">Meire I. Hiyane</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Correa Costa, Matheus" sort="Correa Costa, Matheus" uniqKey="Correa Costa M" first="Matheus" last="Correa-Costa">Matheus Correa-Costa</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Andrade Oliveira, Vinicius" sort="Andrade Oliveira, Vinicius" uniqKey="Andrade Oliveira V" first="Vinicius" last="Andrade-Oliveira">Vinicius Andrade-Oliveira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Origassa, Clarice S T" sort="Origassa, Clarice S T" uniqKey="Origassa C" first="Clarice S T" last="Origassa">Clarice S T. Origassa</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Pereira, Rosana M" sort="Pereira, Rosana M" uniqKey="Pereira R" first="Rosana M" last="Pereira">Rosana M. Pereira</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Kaech, Susan M" sort="Kaech, Susan M" uniqKey="Kaech S" first="Susan M" last="Kaech">Susan M. Kaech</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Rodrigues, Elaine G" sort="Rodrigues, Elaine G" uniqKey="Rodrigues E" first="Elaine G" last="Rodrigues">Elaine G. Rodrigues</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region></placeName></affiliation></author><author><name sortKey="Camara, Niels Olsen S" sort="Camara, Niels Olsen S" uniqKey="Camara N" first="Niels Olsen S" last="Câmara">Niels Olsen S. Câmara</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP</wicri:regionArea><placeName><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. <i>In vitro</i>, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin <i>in vivo</i> was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4<sup>+</sup>Foxp3<sup>+</sup>IL-10<sup>+</sup> T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1<sup>+</sup>CD11b<sup>+</sup> and RORγ<sup>+</sup> IL17<sup>+</sup>CD4<sup>+</sup> cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1<sup>-/-</sup> mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">29899823</PMID><DateRevised><Year>2019</Year><Month>11</Month><Day>20</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>9</Volume><Issue>40</Issue><PubDate><Year>2018</Year><Month>May</Month><Day>25</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.</ArticleTitle><Pagination><MedlinePgn>25808-25825</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.25380</ELocationID><Abstract><AbstractText>The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. <i>In vitro</i>, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin <i>in vivo</i> was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4<sup>+</sup>Foxp3<sup>+</sup>IL-10<sup>+</sup> T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1<sup>+</sup>CD11b<sup>+</sup> and RORγ<sup>+</sup> IL17<sup>+</sup>CD4<sup>+</sup> cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1<sup>-/-</sup> mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pereira</LastName><ForeName>Felipe V</ForeName><Initials>FV</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Melo</LastName><ForeName>Amanda Campelo L</ForeName><Initials>ACL</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Low</LastName><ForeName>Jun Siong</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>de Castro</LastName><ForeName>Íris Arantes</ForeName><Initials>ÍA</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Braga</LastName><ForeName>Tárcio T</ForeName><Initials>TT</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Almeida</LastName><ForeName>Danilo C</ForeName><Initials>DC</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Batista de Lima</LastName><ForeName>Ana Gabriela U</ForeName><Initials>AGU</Initials><AffiliationInfo><Affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hiyane</LastName><ForeName>Meire I</ForeName><Initials>MI</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Correa-Costa</LastName><ForeName>Matheus</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Andrade-Oliveira</LastName><ForeName>Vinicius</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Origassa</LastName><ForeName>Clarice S T</ForeName><Initials>CST</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pereira</LastName><ForeName>Rosana M</ForeName><Initials>RM</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kaech</LastName><ForeName>Susan M</ForeName><Initials>SM</Initials><AffiliationInfo><Affiliation>Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodrigues</LastName><ForeName>Elaine G</ForeName><Initials>EG</Initials><AffiliationInfo><Affiliation>Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-UNIFESP), 04023-062 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Câmara</LastName><ForeName>Niels Olsen S</ForeName><Initials>NOS</Initials><AffiliationInfo><Affiliation>Laboratory of Transplantation Immunobiology, Department of Immunology, University of São Paulo, Institute of Biomedical Sciences, 05508-900 São Paulo, SP, Brazil.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>05</Month><Day>25</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Oncotarget</MedlineTA><NlmUniqueID>101532965</NlmUniqueID><ISSNLinking>1949-2553</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">T cells</Keyword><Keyword MajorTopicYN="N">cell death</Keyword><Keyword MajorTopicYN="N">metformin</Keyword><Keyword MajorTopicYN="N">sitagliptin</Keyword><Keyword MajorTopicYN="N">tumor immunity</Keyword></KeywordList><CoiStatement>CONFLICTS OF INTEREST The authors declare no conflicts of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>03</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2018</Year><Month>04</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>6</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>6</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>6</Month><Day>15</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId 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