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The alfa2beta1 integrin in breast tumor progression: the role in tumor microenvironment and metastasis

Grant number: 14/17651-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2014
Effective date (End): August 31, 2019
Field of knowledge:Biological Sciences - Biochemistry
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Heloisa Sobreiro Selistre de Araújo
Grantee:Milene Nóbrega de Oliveira Moritz
Home Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated research grant:13/00798-2 - The extracellular matrix in aging, exercise and in the tumor microenvironment, AP.TEM
Associated scholarship(s):17/23094-1 - The role of integrin 221 in breast cancer metastasis to bone, BE.EP.DR

Abstract

The ability of cells to adhere to each other and to the extracellular matrix is of essential importance for the cellular distribution in the body and the formation of tissues and organs. Among the different classes of adhesion molecules, integrins stand out because they act as signaling molecules to mechanical signals. Besides these adhesion molecules are involved in normal cellular functions, also participate in pathological processes such as the migration of immune cells from the blood to the tissues in inflammatory responses and the release of metastatic cells from the primary tumor and the attachment to secondary organs. One of the most common tumors in women is breast cancer that is often characterized by skeletal metastases. One possibility that could explain the selectivity to the bone is that tumor cells express surface molecules that facilitate their attachment to proteins present in the extracellular matrix of bone, mainly collagen. Recent studies have shown a relationship between the alfa2beta1 integrin, a receptor for collagen and the development of metastases. In this context, to understand the mechanisms by which this integrin promotes tumor may provide an important target for pharmacological intervention in the prevention of metastases. Previous studies have shown that the disintegrin alternagin-C (C-ALT) inhibited cell adhesion to type I collagen in various tumor and non-tumor cell lines by interaction with integrin alfa2beta1. This disintegrin also modulated the expression of genes related to angiogenesis, extracellular matrix disintegration and metastases, being, however, needed more studies to elucidate its molecular mechanism of action. Thus, we propose to investigate the role of the alfa2beta1 integrin targeting the inhibition of mammary tumor progression using the silencing of the alfa2 subunit and the C-ALT, a competitive inhibitor of ±2²1 integrin. The major hypothesis is that integrin alfa2beta1 is relevant for the development of bone metastases and their interaction with extracellular matrix aids in the promotion of bone metastasis. To investigate this hypothesis adhesion tests (static and under flow) to collagen I and to externalized matrix by osteoblasts and cell migration of tumor cells and not tumor breast cells (MDA-MB-231 and MCF10A) silenced or inhibited will be performed. Gene expression array platform focused on real-time PCR, protein expression by western blotting and enzyme activity by zymography will be evaluated too. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE OLIVEIRA MORITZ, MILENE NOBREGA; SANTOS EUSTAQUIO, LIVIA MARA; MICOCCI, KELLI CRISTINA; CAETANO NUNES, ANA CAROLINA; DOS SANTOS, PATTY KARINA; VIEIRA, TAMIRES DE CASTRO; SELISTRE-DE-ARAUJO, HELOISA SOBREIRO. Alternagin-C binding to a(2)beta(1) integrin controls matrix metalloprotease-9 and matrix metalloprotease-2 in breast tumor cells and endothelial cells. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 24, APR 25 2018. Web of Science Citations: 3.
MILENE NÓBREGA DE OLIVEIRA MORITZ; LÍVIA MARA SANTOS EUSTÁQUIO; KELLI CRISTINA MICOCCI; ANA CAROLINA CAETANO NUNES; PATTY KARINA DOS SANTOS; TAMIRES DE CASTRO VIEIRA; HELOÍSA SOBREIRO SELISTRE-DE-ARAUJO. Alternagin-C binding to α2β1 integrin controls matrix metalloprotease-9 and matrix metalloprotease-2 in breast tumor cells and endothelial cells. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 24, p. -, 2018.

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