title: Post-Sepsis State Induces Tumor-Associated Macrophage Accumulation through CXCR4/CXCL12 and Favors Tumor Progression in Mice.
abstract: Survivors from sepsis are in an immunosuppressed state that is associated with higher long-term mortality and risk of opportunistic infections. Whether these factors contribute to neoplastic proliferation, however, remains unclear. Tumor-associated macrophages (TAM) can support malignant cell proliferation, survival, and angiogenesis. We addressed the relationship between the post-sepsis state, tumor progression and TAM accumulation, and phenotypic and genetic profile, using a mouse model of sepsis resolution and then B16 melanoma in mice. In addition, we measured the serum concentrations of TNFα, TGFβ, CCL2, and CXCL12 and determined the effect of in vivo CXCR4/CXCL12 inhibition in this context. Mice that survived sepsis showed increased tumor progression both in the short and long term, and survival times were shorter. TAM accumulation, TAM local proliferation, and serum concentrations of TGFβ, CXCL12, and TNFα were increased. Naïve mice inoculated with B16 together with macrophages from post-sepsis mice also had faster tumor progression and shorter survival. Post-sepsis TAMs had less expression of MHC-II and leukocyte activation-related genes. Inhibition of CXCR4/CXCL12 prevented the post-sepsis-induced tumor progression, TAM accumulation, and TAM in situ proliferation. Collectively, our data show that the post-sepsis state was associated with TAM accumulation through CXCR4/CXCL12, which contributed to B16 melanoma progression.
authors.affiliation: Hematology/Oncology Division and Center for Cell-Based Therapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: José M
authors.initials: JM
authors.lastname: Mota
authors.affiliation: Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Caio A
authors.initials: CA
authors.lastname: Leite
authors.affiliation: Laboratory of Gene Transfer, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Lucas E
authors.initials: LE
authors.lastname: Souza
authors.affiliation: Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Paulo H
authors.initials: PH
authors.lastname: Melo
authors.affiliation: Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Nascimento
authors.affiliation: Hematology/Oncology Division and Center for Cell-Based Therapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. OMICS Laboratory, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: de-Deus-Wagatsuma
authors.affiliation: OMICS Laboratory, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Jessica
authors.initials: J
authors.lastname: Temporal
authors.affiliation: Laboratory of Pathology, Department of Pathology, University of Brasilia, Brasília, Brazil.
authors.forename: Florêncio
authors.initials: F
authors.lastname: Figueiredo
authors.affiliation: OMICS Laboratory, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Houtan
authors.initials: H
authors.lastname: Noushmehr
authors.affiliation: Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Hematology/Oncology Division and Center for Cell-Based Therapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. emrego@hcrp.fmrp.usp.br.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rego
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000150:complications / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha