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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population

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Farina Silveira, Caio Raony [1] ; Cipelli, Marcella [1] ; Manzine, Carolina [1] ; Rabelo-Santos, Silvia Helena [2] ; Zeferino, Luiz Carlos [3] ; Rodriguez, Gretel Rodriguez [1] ; de Assis, Josiane Betim [1] ; Hebster, Suellen [4] ; Bernadinelli, Isabel [5] ; Laginha, Fabio [5] ; Boccardo, Enrique [4] ; Villa, Luisa Lina [6, 7] ; Termini, Lara [7] ; Lepique, Ana Paula [1]
Total Authors: 14
Affiliation:
[1] Univ Sao Paulo, Dept Imunol, Inst Ciencias Biomed, Sao Paulo - Brazil
[2] Univ Fed Goias, Inst Patol Trop & Saude Publ, Fac Farma, Goiania, Go - Brazil
[3] Univ Estadual Campinas, Dept Ginecol & Obstet, Campinas, SP - Brazil
[4] Univ Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Sao Paulo - Brazil
[5] Hosp Perola Byington, Sao Paulo - Brazil
[6] Inst Canc Estado Sao Paulo, Sao Paulo - Brazil
[7] Univ Sao Paulo, Dept Radiol & Oncol, Fac Med, Sao Paulo - Brazil
Total Affiliations: 7
Document type: Journal article
Source: PLoS One; v. 14, n. 3 MAR 6 2019.
Web of Science Citations: 1
Abstract

Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified a-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed a-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo, SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth. (AU)

FAPESP's process: 14/19326-6 - Tumor microenvironment, inflammation and immunomodulation: therapeutic possibilities and prognostic markers
Grantee:Ana Paula Lepique
Support Opportunities: Regular Research Grants
FAPESP's process: 08/57889-1 - Institute of Science and Technology to study Diseases Associated with Papillomavirus
Grantee:Luisa Lina Villa
Support Opportunities: Research Projects - Thematic Grants