A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase
Autor(a) principal: | |
---|---|
Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/11921 |
Resumo: | The harmonic functioning of cells involves an orchestrated synchronization of signaling that maintains the balance between proliferation and cell death in healthy tissues. Eventually, gene mutations can occur and the accumulation of these alterations culminate in uncontrolled cellular divisions and consequently in the formation of malignant neoplasias. Breast cancer is the most frequent among women, with metastasis being the major cause of death. The triple negative subtype of breast cancer is one of the most aggressive tumors and there is no specific therapy for its treatment. Bone is the most common site for breast cancer metastasis and the existence of membrane receptors such as integrins on tumor cells assist in this addressing. In this study, divided into two chapters, we evaluated the role of α2β1 integrin in the metastasis of breast cancer. In the first chapter, we used alternagin-C, a protein that binds to α2β1 integrin and from the venom of Bothrops alternatus snake, and the transient silencing of the α2 subunit to verify the role of this receptor in mammary metastasis. The results demonstrated that alternagin-C decreased in 50% tumor cell adhesion to type I collagen and increased more than three times the expression of the metastasis suppressor 1 (MTSS1). In the second chapter, we used three in vivo models (Mammary Fat Pad-MFP, intracardiac-IC and intratibial-IT) of breast bone metastasis with human tumor cells in athymic nude mice. All three models were treated with the α2β1 integrin inhibitor, TCI-15, or superexpressing the α2 subunit in tumor cells that were injected into the animals with the aim of evaluate the role of α2β1 integrin specifically in breast tumor bone metastasis. With these models, we observed that α2β1 integrin plays a significant role in primary tumor growth (MFP model), but there were no significant results in later stages of bone metastasis (IC and IT models). In addition, we verified a biphasic expression of α2β1 integrin during the metastasis cascade, with lower expression in the metastatic cells compared to expression in the parental breast tumor cells. We also demonstrated that the metastatic cells express high levels of PTHrP (parathyroid hormone related protein), Gli2, and TGFβRII, which have been shown to contribute to bone destruction. These data suggest an inverse relation between α2 integrin expression and a bone destructive phenotype. Furthermore, TGF-β treatment decreased α2β1 integrin levels in metastatic cells, suggesting that TGF-β may influence the selection of tumor cells to bone through this integrin regulation. Taken together, these results demonstrated that α2β1 integrin is involved with different roles in metastasis cascade of breast cancer to bone. Thus, this study contributed to identify a possible molecular target for the treatment and prevention of triple negative breast cancer metastasis. |
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Moritz, Milene Nóbrega de OliveiraAraújo, Heloísa Sobreiro Selistre dehttp://lattes.cnpq.br/4065824911933203http://lattes.cnpq.br/637623216305591371b05250-848c-432e-a0c9-3b4220c90fd62019-10-07T13:07:58Z2019-10-07T13:07:58Z2019-08-23MORITZ, Milene Nóbrega de Oliveira. A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase. 2019. Tese (Doutorado em Genética Evolutiva e Biologia Molecular) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11921.https://repositorio.ufscar.br/handle/ufscar/11921The harmonic functioning of cells involves an orchestrated synchronization of signaling that maintains the balance between proliferation and cell death in healthy tissues. Eventually, gene mutations can occur and the accumulation of these alterations culminate in uncontrolled cellular divisions and consequently in the formation of malignant neoplasias. Breast cancer is the most frequent among women, with metastasis being the major cause of death. The triple negative subtype of breast cancer is one of the most aggressive tumors and there is no specific therapy for its treatment. Bone is the most common site for breast cancer metastasis and the existence of membrane receptors such as integrins on tumor cells assist in this addressing. In this study, divided into two chapters, we evaluated the role of α2β1 integrin in the metastasis of breast cancer. In the first chapter, we used alternagin-C, a protein that binds to α2β1 integrin and from the venom of Bothrops alternatus snake, and the transient silencing of the α2 subunit to verify the role of this receptor in mammary metastasis. The results demonstrated that alternagin-C decreased in 50% tumor cell adhesion to type I collagen and increased more than three times the expression of the metastasis suppressor 1 (MTSS1). In the second chapter, we used three in vivo models (Mammary Fat Pad-MFP, intracardiac-IC and intratibial-IT) of breast bone metastasis with human tumor cells in athymic nude mice. All three models were treated with the α2β1 integrin inhibitor, TCI-15, or superexpressing the α2 subunit in tumor cells that were injected into the animals with the aim of evaluate the role of α2β1 integrin specifically in breast tumor bone metastasis. With these models, we observed that α2β1 integrin plays a significant role in primary tumor growth (MFP model), but there were no significant results in later stages of bone metastasis (IC and IT models). In addition, we verified a biphasic expression of α2β1 integrin during the metastasis cascade, with lower expression in the metastatic cells compared to expression in the parental breast tumor cells. We also demonstrated that the metastatic cells express high levels of PTHrP (parathyroid hormone related protein), Gli2, and TGFβRII, which have been shown to contribute to bone destruction. These data suggest an inverse relation between α2 integrin expression and a bone destructive phenotype. Furthermore, TGF-β treatment decreased α2β1 integrin levels in metastatic cells, suggesting that TGF-β may influence the selection of tumor cells to bone through this integrin regulation. Taken together, these results demonstrated that α2β1 integrin is involved with different roles in metastasis cascade of breast cancer to bone. Thus, this study contributed to identify a possible molecular target for the treatment and prevention of triple negative breast cancer metastasis.O funcionamento harmônico das células envolve uma sincronia orquestrada de sinalização que mantém o equilíbrio entre proliferação e morte celular nos tecidos saudáveis. Eventualmente, mutações em genes podem ocorrer e o acúmulo dessas alterações culminar em divisões celulares descontroladas e, consequentemente, na formação de neoplasias malignas. O câncer de mama é o mais frequente entre as mulheres, sendo a metástase a maior causa de morte entre as pacientes. O subtipo triplo negativo de câncer de mama é um dos tumores mais agressivos e ainda não existe terapia específica para seu tratamento. O tecido ósseo é o destino mais comum para a metástase de câncer de mama e a existência de receptores de membrana, como as integrinas, nas células tumorais auxiliam nesse endereçamento. Neste estudo, dividido em dois capítulos, avaliamos o papel da integrina α2β1 na metástase do câncer de mama. Na primeira etapa, utilizamos a alternagina-C, uma proteína ligante da integrina α2β1 proveniente do veneno da serpente Bothrops alternatus e o silenciamento transiente da subunidade α2 a fim de verificar o papel desse receptor na metástase de origem mamária. Os resultados demonstraram que a alternagina-C reduziu em 50% a adesão das células tumorais ao colágeno tipo I e aumentou mais de três vezes a expressão do supressor de metástase 1 (MTSS1). Na segunda etapa deste estudo, utilizamos três modelos in vivo (Mammary Fat Pad-MFP, intracardíaco-IC e intratibial-IT) de metástase óssea de câncer de mama com células tumorais humanas em camundongos nudes atímicos. Os três modelos foram tratados com o inibidor da integrina α2β1, TCI-15, ou injeção de células tumorais superexprepressando a subunidade α2 com o objetivo de avaliar o papel da integrina α2β1 especificamente na metástase óssea de tumor de mama. Com esses modelos verificamos que a integrina α2β1 possui papel relevante no crescimento do tumor primário (modelo MFP), porém não houve resultados significativos nas fases mais tardias da metástase óssea (modelos IC e IT). Além disso, observamos uma expressão bifásica da integrina α2β1, sendo menor a expressão dessa integrina nas células metastáticas para osso comparado à expressão nas células tumorais de mama parentais. Para as células metastáticas, também demonstramos uma alta expressão dos genes PTHrP (parathyroid hormone related protein), Gli2 e TGFβRII, os quais contribuem com a destruição óssea. Estes dados sugerem uma relação inversa entre a expressão da integrina α2 e um fenótipo destrutivo ósseo. O tratamento com TGF-β diminuiu a quantidade da integrina α2β1 nas células metastáticas, indicando que o TGF-β pode influenciar a seleção de células tumorais para o osso através da regulação dessa integrina. Em conjunto, esses resultados demonstraram que a integrina α2β1 está envolvida com diferentes funções ao longo da cascata metastática de câncer de mama para o osso. Dessa forma, esse estudo contribuiu para a identificação de um possível alvo molecular para tratamento e prevenção de metástase de câncer de mama triplo negativo.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP 14/17651-7CAPES: Código do Financiamento 001porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Genética Evolutiva e Biologia Molecular - PPGGEvUFSCarAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessCâncer de mamaMetástase ósseaMicroambiente tumoralIntegrinaAlternagina-CBreast CancerSkeletal metastasisTumor microenvironmentIntegrinAlternagin-CCIENCIAS BIOLOGICAS::BIOQUIMICA::BIOLOGIA MOLECULARCIENCIAS BIOLOGICASCIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICAA integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástaseThe a2b1 integrin in mammary tumor progression: role in tumor microenvironment and metastasisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis600b61211db-d955-45b7-886e-a0cefb89980freponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTese versão completa.pdfTese versão completa.pdfapplication/pdf6231932https://repositorio.ufscar.br/bitstream/ufscar/11921/2/Tese%20vers%c3%a3o%20completa.pdfe0a4d369e5bce2b66f56bad8650b32d0MD52Carta comprovante.pdfCarta comprovante.pdfapplication/pdf475989https://repositorio.ufscar.br/bitstream/ufscar/11921/4/Carta%20comprovante.pdf93a8ecc79c019f24a69cbb9b0cc864c3MD54CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufscar.br/bitstream/ufscar/11921/5/license_rdfe39d27027a6cc9cb039ad269a5db8e34MD55TEXTTese versão completa.pdf.txtTese versão completa.pdf.txtExtracted texttext/plain189512https://repositorio.ufscar.br/bitstream/ufscar/11921/6/Tese%20vers%c3%a3o%20completa.pdf.txt0ad33aed2ef1612a5742c0106abc8e69MD56Carta comprovante.pdf.txtCarta comprovante.pdf.txtExtracted texttext/plain1https://repositorio.ufscar.br/bitstream/ufscar/11921/8/Carta%20comprovante.pdf.txt68b329da9893e34099c7d8ad5cb9c940MD58THUMBNAILTese versão completa.pdf.jpgTese versão completa.pdf.jpgIM Thumbnailimage/jpeg7116https://repositorio.ufscar.br/bitstream/ufscar/11921/7/Tese%20vers%c3%a3o%20completa.pdf.jpg273fc444484eb9d4e2b420ed6c9c1170MD57Carta comprovante.pdf.jpgCarta comprovante.pdf.jpgIM Thumbnailimage/jpeg11908https://repositorio.ufscar.br/bitstream/ufscar/11921/9/Carta%20comprovante.pdf.jpg1de729b2781cdcb2452d1dae89d4ecc6MD59ufscar/119212023-09-18 18:32:11.715oai:repositorio.ufscar.br:ufscar/11921Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:32:11Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
dc.title.alternative.eng.fl_str_mv |
The a2b1 integrin in mammary tumor progression: role in tumor microenvironment and metastasis |
title |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
spellingShingle |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase Moritz, Milene Nóbrega de Oliveira Câncer de mama Metástase óssea Microambiente tumoral Integrina Alternagina-C Breast Cancer Skeletal metastasis Tumor microenvironment Integrin Alternagin-C CIENCIAS BIOLOGICAS::BIOQUIMICA::BIOLOGIA MOLECULAR CIENCIAS BIOLOGICAS CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA |
title_short |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
title_full |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
title_fullStr |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
title_full_unstemmed |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
title_sort |
A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase |
author |
Moritz, Milene Nóbrega de Oliveira |
author_facet |
Moritz, Milene Nóbrega de Oliveira |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/6376232163055913 |
dc.contributor.author.fl_str_mv |
Moritz, Milene Nóbrega de Oliveira |
dc.contributor.advisor1.fl_str_mv |
Araújo, Heloísa Sobreiro Selistre de |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/4065824911933203 |
dc.contributor.authorID.fl_str_mv |
71b05250-848c-432e-a0c9-3b4220c90fd6 |
contributor_str_mv |
Araújo, Heloísa Sobreiro Selistre de |
dc.subject.por.fl_str_mv |
Câncer de mama Metástase óssea Microambiente tumoral Integrina Alternagina-C |
topic |
Câncer de mama Metástase óssea Microambiente tumoral Integrina Alternagina-C Breast Cancer Skeletal metastasis Tumor microenvironment Integrin Alternagin-C CIENCIAS BIOLOGICAS::BIOQUIMICA::BIOLOGIA MOLECULAR CIENCIAS BIOLOGICAS CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA |
dc.subject.eng.fl_str_mv |
Breast Cancer Skeletal metastasis Tumor microenvironment Integrin Alternagin-C |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOQUIMICA::BIOLOGIA MOLECULAR CIENCIAS BIOLOGICAS CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA |
description |
The harmonic functioning of cells involves an orchestrated synchronization of signaling that maintains the balance between proliferation and cell death in healthy tissues. Eventually, gene mutations can occur and the accumulation of these alterations culminate in uncontrolled cellular divisions and consequently in the formation of malignant neoplasias. Breast cancer is the most frequent among women, with metastasis being the major cause of death. The triple negative subtype of breast cancer is one of the most aggressive tumors and there is no specific therapy for its treatment. Bone is the most common site for breast cancer metastasis and the existence of membrane receptors such as integrins on tumor cells assist in this addressing. In this study, divided into two chapters, we evaluated the role of α2β1 integrin in the metastasis of breast cancer. In the first chapter, we used alternagin-C, a protein that binds to α2β1 integrin and from the venom of Bothrops alternatus snake, and the transient silencing of the α2 subunit to verify the role of this receptor in mammary metastasis. The results demonstrated that alternagin-C decreased in 50% tumor cell adhesion to type I collagen and increased more than three times the expression of the metastasis suppressor 1 (MTSS1). In the second chapter, we used three in vivo models (Mammary Fat Pad-MFP, intracardiac-IC and intratibial-IT) of breast bone metastasis with human tumor cells in athymic nude mice. All three models were treated with the α2β1 integrin inhibitor, TCI-15, or superexpressing the α2 subunit in tumor cells that were injected into the animals with the aim of evaluate the role of α2β1 integrin specifically in breast tumor bone metastasis. With these models, we observed that α2β1 integrin plays a significant role in primary tumor growth (MFP model), but there were no significant results in later stages of bone metastasis (IC and IT models). In addition, we verified a biphasic expression of α2β1 integrin during the metastasis cascade, with lower expression in the metastatic cells compared to expression in the parental breast tumor cells. We also demonstrated that the metastatic cells express high levels of PTHrP (parathyroid hormone related protein), Gli2, and TGFβRII, which have been shown to contribute to bone destruction. These data suggest an inverse relation between α2 integrin expression and a bone destructive phenotype. Furthermore, TGF-β treatment decreased α2β1 integrin levels in metastatic cells, suggesting that TGF-β may influence the selection of tumor cells to bone through this integrin regulation. Taken together, these results demonstrated that α2β1 integrin is involved with different roles in metastasis cascade of breast cancer to bone. Thus, this study contributed to identify a possible molecular target for the treatment and prevention of triple negative breast cancer metastasis. |
publishDate |
2019 |
dc.date.accessioned.fl_str_mv |
2019-10-07T13:07:58Z |
dc.date.available.fl_str_mv |
2019-10-07T13:07:58Z |
dc.date.issued.fl_str_mv |
2019-08-23 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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dc.identifier.citation.fl_str_mv |
MORITZ, Milene Nóbrega de Oliveira. A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase. 2019. Tese (Doutorado em Genética Evolutiva e Biologia Molecular) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11921. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/11921 |
identifier_str_mv |
MORITZ, Milene Nóbrega de Oliveira. A integrina a2b1 na progressão tumoral mamária: papel no microambiente tumoral e na metástase. 2019. Tese (Doutorado em Genética Evolutiva e Biologia Molecular) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11921. |
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https://repositorio.ufscar.br/handle/ufscar/11921 |
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Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ |
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openAccess |
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Universidade Federal de São Carlos Câmpus São Carlos |
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Programa de Pós-Graduação em Genética Evolutiva e Biologia Molecular - PPGGEv |
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UFSCar |
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Universidade Federal de São Carlos Câmpus São Carlos |
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