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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2018.tde-18092018-142306
Document
Author
Full name
Renata Ariza Marques Rossetti
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Lepique, Ana Paula (President)
Armelin, Hugo Aguirre
Campa, Ana
Mauro, Eliana Faquim de Lima
Seelaender, Marilia Cerqueira Leite
Title in Portuguese
Estudo do estado de ativação de vias de sinalização no microambiente tumoral e leucócitos circulantes em pacientes com tumor do colo do útero.
Keywords in Portuguese
Akt
Câncer cervical
Linfócitos B
NFκB
Papilomavírus humano
STAT3
Vias de sinalização
Abstract in Portuguese
Infecção pelo HPV é o principal fator de risco para câncer cervical. Os tumores apresentam microambiente complexo, células tumorais e inflamatórias integram sinais modulando a atividade de vias de sinalização. Caracterizamos o estado de ativação de três vias de sinalização importantes para a progressão tumoral. Com o aumento do grau da lesão, observamos: aumento da expressão de NFκB e Akt fosforiladas no microambiente tumoral; redução de NFκB fosforilada e aumento de STAT3 e Akt fosforiladas em leucócitos circulantes. Em modelos experimentais, a via de NFκB também encontra-se inibida, principalmente em células apresentadoras de antígenos. Para testar se a modulação de vias de sinalização poderiam alterar as respostas a tumores, tratamos linfócitos B de pacientes com agonista de CD40, ativador de NFκB, e observamos aumento do potencial de apresentação antigênica. Nossos resultados mostram o panorama do estado de ativação de importantes vias de sinalização para a progressão tumoral e trazem a possibilidade de uma ferramenta imunomoduladora.
Title in English
Signaling pathways characterization in tumor microenvironment and peripheral blood mononuclear cells in cervical cancer patients.
Keywords in English
Akt
B lymphocytes
Cervical cancer
Human papillomavirus
NFκB
Signaling pathways
STAT3
Abstract in English
Cervical cancers have HPV infection as a main factor. HPV tumors recruit leucocytes and change their phenotype as an evasion mechanism. We tried to understand how the tumor influences the immune cells behavior, analyzing signaling pathways important to tumor progression in cervical biopsy and PBMC from patients with high-grade lesions and cancer. We find an increase in NFκB activation in immune cells from tumor microenvironment, but a decrease in PBMC. We could not find any difference in STAT3 signaling pathway in the tumor microenvironment, however, there was an activation increase in PBMC. Both tumor microenvironment immune cells and PBMC had an increase in Akt signaling pathway. To identify a possible strategy to reverse the tumor influence, we stimulated B lymphocytes from patients with sCD40L, achieving an increase in the numbers of CD80+CD86+ cells. Our results demonstrate a tumor effect over the immune cells, with an important systemic effect. However, the approach used to stimulate B lymphocytes from patients present us with a possible immunotherapy.
 
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Release Date
2020-09-17
Publishing Date
2018-09-18
 
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