Lactate secreted by cervical cancer cells modulates macrophage phenotype

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art_STONE_Lactate_secreted_by_cervical_cancer_cells_modulates_macrophage_2019.PDF (1.21 MB)
Citações na Scopus
51
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
STONE, Simone Cardozo
ROSSETTI, Renata Ariza Marques
ALVAREZ, Karla Lucia Fernandez
BOCCARDO, Enrique
Citação
JOURNAL OF LEUKOCYTE BIOLOGY, v.105, n.5, p.1041-1054, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Cervical cancer continues to be a public health problem in developing countries. Previous studies have shown that cervical cancer cells display markers of aerobic glycolysis, indicating that these tumors are likely to secrete lactate. Mostly, lactate is recognized as a molecule capable of suppressing immune responses, through inhibition of T cells, M phi s, and dendritic cells. We and others have previously shown that M phi s are frequent cells infiltrating cervical cancers with the ability to inhibit antitumor immune responses and promote tumor growth through angiogenesis. Here, we have tested the hypothesis that lactate, secreted by cervical cancer cells, can modulate M phi phenotype. First, we showed higher lactate plasma concentrations in patients with increasing cervical lesion grades, with maximum concentration in the plasma of cancer patients, which supported our hypothesis. We then inhibited lactate production in tumor cell spheroids established from cervical cancer derived cell lines, using the lactate dehydrogenase inhibitor, oxamate, prior to co-culture with monocytes. Lactate mediated part of the crosstalk between tumor cells and M phi s, promoting secretion of IL-1, IL-10, IL-6, and up-regulation of hypoxia induced factor-1 expression, and down-regulation of p65-NFB phosphorylation in M phi s. We also showed that M phi s from co-cultures treated with oxamate were better inducers of T cell activation. Of note, experiments performed with inhibition of the monocarboxylate transporters rendered similar results. Our data confirms the hypothesis that lactate, secreted by cervical tumor cells, influences the phenotype of tumor M phi s, promoting a suppressive phenotype.
Palavras-chave
cervical cancer, lactate, human papillomavirus, tumor microenvironment, monocarboxylate transporters
URI
https://observatorio.fm.usp.br/handle/OPI/31757
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MOG
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - ODS/03