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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2020.tde-09042021-104341
Document
Author
Full name
Vanessa Almeida Amorin
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2020
Supervisor
Committee
Soares, Edson Garcia (President)
Maciel, Lea Maria Zanini
Saggioro, Fabiano Pinto
Simões, Renata Toscano
Title in Portuguese
Relação entre a expressão proteica de MT1-MMP, MMP-2 e TIMP-2 e a progressão do carcinoma papilífero de tireoide
Keywords in Portuguese
Carcinoma papilífero de tireoide
Fatores clínicos
Imunoistoquímica
Matriz extracelular
Metaloproteinases
Metástase linfonodal
Abstract in Portuguese
O câncer de tireoide é a neoplasia endócrina mais prevalente e sua incidência aumentou nas últimas três décadas em todo o mundo. Sabe-se que o crescimento e a proliferação de células cancerígenas são amplamente influenciados por sua interação mecânica com o microambiente. Assim, as metaloproteinases da matriz (MMPs) interferem fisicamente na matriz extracelular (MEC) circundante para permitir a migração celular e o desenvolvimento do tumor, sendo que o complexo ternário MT1-MMP/ MMP-2/ TIMP-2 tem demonstrado ter grande participação nesse mecanismo. Este estudo teve como objetivo investigar a expressão imunoistoquímica da MT1-MMP, MMP-2 e TIMP-2 no carcinoma papilífero da tireoide (CPT) e correlacionar os achados com os parâmetros clínico-patológicos e com a progressão tumoral. Os pacientes com CPT foram divididos em: CPT sem metástase (CPTS), CPT com metástase (CPTM) e metástase linfonodal cervical (ML). Também foi realizada análise morfométrica dos colágenos tipo I e III em tumores primários de CPT. O CPT apresentou um aumento da expressão de MT1-MMP, MMP-2 e TIMP-2 quando comparadas com o tecido normal. A protease MT1-MMP mostrou-se positiva em 82,6% dos casos de CPTM e em 60% no CPTS, sendo que na ML houve um aumento da expressão moderada e intensa (34,7%). A expressão de MT1-MMP foi correlacionada com o estadio da doença (p= 0,02) e idade (p= 0,01). A MMP-2 mostrou-se positiva em 60% dos casos de CPTM e em 80% no CPTS, com predomínio de marcação leve, porém na ML houve um aumento da marcação moderada e intensa (48%). Todos os casos apresentaram marcação positiva para o TIMP-2 e a marcação predominante foi a intensa nos grupos CPTM e ML, e moderada no grupo CPTS (80%). O colágeno tipo I diminuiu no CPTS e CPTM. A expressão concomitante de MT1-MMP, MMP-2 e TIMP-2 foi vista em 48% dos pacientes com CPTM, 52% no grupo ML e em 40% no grupo CPTS. Embora nem todos os pacientes que evoluíram para a metástase possuíam expressão concomitante dessas proteínas em células malignas, a MT1-MMP foi correlacionada com o alto estadio (III e IV) e idade acima de 45 anos no CPT. Houve uma diminuição do colágeno tipo I no CPT quando comparados com tecido tireoidiano saudável, que é característico do remodelamento da MEC nos estágios iniciais da doença.
Title in English
Relationship between MT1-MMP, MMP-2 and TIMP-2 protein expression and the progression of papillary thyroid carcinoma
Keywords in English
Clinical factors
Extracellular matrix
Immunohistochemistry
Lymph node metastasis
Metalloproteinases
Papillary thyroid carcinoma
Abstract in English
Thyroid cancer is a more prevalent endocrine neoplasia and its increase in the last three decades worldwide. It is known that the growth and proliferation of cancer cells are largely influenced by their mechanical interaction with the microenvironment. Thus, matrix metalloproteinases (MMPs) physically interfere with the surrounding extracellular matrix to allow cell migration and tumor development. The MT1-MMP/ MMP-2/ TIMP-2 ternary complex has been shown to play a major role in this mechanism. This study aimed to investigate the immunohistochemical expression of MT1-MMP, MMP-2 and TIMP-2 in papillary thyroid carcinoma (PTC) and to correlate the findings with clinical pathological parameters and tumor progression. PTC patients were divided into: PTC without metastasis (CPTS), PTC with metastasis (CPTM) and cervical lymph node metastasis (ML). Morphometric analysis of collagen types I and III in primary PTC tumors was also performed. PTC showed an increased expression of MT1-MMP, MMP-2 and TIMP-2 when compared to normal tissue. The MT1-MMP protease was positive in 82.6% of CPTM cases and in 60% without CPTS, whereas in ML there was an increase in moderate and intense expression (34.7%). MT1-MMP expression was correlated with the stage of the disease (p= 0.02) and age (p=0.01). MMP-2 was positive in 60% of CPTM and 80% in CPTS, with a predominance of weak marking, but in ML there was an increase in moderate to intense marking (48%). All cases showed positive expression for TIMP-2 and the predominant marking was intense in the CPTM and ML group, and moderate in the CPTS group (80%). Type I collagen decreased in CPTS and CPTM. Concomitant expression of MT1-MMP, MMP-2 and TIMP-2 was seen in 48% of patients with CPTM, 52% in the ML group and 40% in the CPTS group. Although not all patients who progressed to metastasis had concomitant expression of these proteins in malignant cells, MT1-MMP was correlated with high stage (III and IV) and age over 45 years on CPT. There was a decrease in type I collagen in CPT when compared to healthy thyroid tissue, which is characteristic of ECM remodeling in the early stages of the disease.
 
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Publishing Date
2021-04-16
 
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