Lactate secreted by cervical cancer cells modulates macrophage phenotype.
| Title: | Lactate secreted by cervical cancer cells modulates macrophage phenotype. |
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| Authors: | Stone SC; Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.; Rossetti RAM; Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.; Alvarez KLF; Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.; Carvalho JP; Department of Oncologic Gynecology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.; Margarido PFR; Division of Obstetrics and Gynecology, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.; Baracat EC; Department of Oncologic Gynecology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.; Division of Obstetrics and Gynecology, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.; Department of Gynecology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Tacla M; Department of Gynecology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Boccardo E; Department of Microbiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.; Yokochi K; Division of Obstetrics and Gynecology, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.; Lorenzi NP; Division of Obstetrics and Gynecology, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.; Department of Gynecology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Lepique AP; Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil. |
| Source: | Journal of leukocyte biology [J Leukoc Biol] 2019 May; Vol. 105 (5), pp. 1041-1054. Date of Electronic Publication: 2019 Feb 27. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Oxford University Press Country of Publication: England NLM ID: 8405628 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1938-3673 (Electronic) Linking ISSN: 07415400 NLM ISO Abbreviation: J Leukoc Biol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2023- : Oxford : Oxford University Press; Original Publication: New York : Alan R. Liss, c1984- |
| MeSH Terms: | Adenocarcinoma/*metabolism ; Carcinoma, Squamous Cell/*metabolism ; Lactic Acid/*metabolism ; Macrophages/*metabolism ; Monocytes/*metabolism ; Uterine Cervical Neoplasms/*metabolism; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Enzyme Inhibitors/pharmacology ; Glycolysis/drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Interleukin-10/genetics ; Interleukin-10/metabolism ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Interleukin-6/genetics ; Interleukin-6/metabolism ; L-Lactate Dehydrogenase/antagonists & inhibitors ; L-Lactate Dehydrogenase/genetics ; L-Lactate Dehydrogenase/metabolism ; Macrophages/drug effects ; Macrophages/pathology ; Monocytes/drug effects ; Monocytes/pathology ; Oxidative Phosphorylation/drug effects ; Spheroids, Cellular/drug effects ; Spheroids, Cellular/metabolism ; Spheroids, Cellular/pathology ; Transcription Factor RelA/genetics ; Transcription Factor RelA/metabolism ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/pathology ; Adult ; Aged ; Aged, 80 and over ; Cell Line, Tumor ; Coculture Techniques ; Female ; Gene Expression Regulation ; Humans ; Middle Aged ; Neoplasm Grading ; Phenotype |
| Abstract: | 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, Mϕs, and dendritic cells. We and others have previously shown that Mϕs 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 Mϕ 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 Mϕs, promoting secretion of IL-1β, IL-10, IL-6, and up-regulation of hypoxia induced factor-1α expression, and down-regulation of p65-NFκB phosphorylation in Mϕs. We also showed that Mϕs 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 Mϕs, promoting a suppressive phenotype.; (©2019 Society for Leukocyte Biology.) |
| Contributed Indexing: | Keywords: cervical cancer; human papillomavirus; lactate; monocarboxylate transporters; tumor microenvironment |
| Substance Nomenclature: | 0 (Enzyme Inhibitors); 0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (IL10 protein, human); 0 (IL1B protein, human); 0 (IL6 protein, human); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Transcription Factor RelA); 130068-27-8 (Interleukin-10); 33X04XA5AT (Lactic Acid); EC 1.1.1.27 (L-Lactate Dehydrogenase) |
| Entry Date(s): | Date Created: 20190228 Date Completed: 20200505 Latest Revision: 20200505 |
| Update Code: | 20260130 |
| DOI: | 10.1002/JLB.3A0718-274RR |
| PMID: | 30811636 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't