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Role of ADAMTS-1 in local and systemic invasion of fibrosarcoma cells

Grant number: 12/24108-2
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): May 01, 2013
Effective date (End): December 31, 2017
Field of knowledge:Biological Sciences - Biology
Principal researcher:Vanessa Morais Freitas
Grantee:Heydi Noriega Guerra
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:10/07699-1 - Protease ADAMTS1 influencing breast cancer behavior and microenvironment , AP.JP


Soft tissue sarcomas are malignant tumors of mesenchymal origin. Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by the presence of immature proliferating fibroblasts. For tumor cell disseminate in the body it must perform several important steps, including invasion of surrounding tissues, intravasation into the blood vessel, survival circulation, extravasation from the blood stream, and proliferation. It has become increasingly recognized that the growth and malignancy of a tumor is largely dictated by the surrounding microenvironment, i.e. tumor stroma. On tumor microenvironment, the extracellular matrix (ECM) is not limited to being a barrier against tumor invasion. The ECM is a reservoir of cell binding proteins and growth factors that affect tumor cell behavior. It is also substantially modified by proteases produced by tumor cells or stroma cells. The secreted proteases ADAMTS-1, member of the ADAMTS family (a disintegrin and metalloproteinase with thrombospondin motifs), possesses three thrombospondin type I motifs at its carboxyl terminus, and metalloproteinase domain in the amino terminus. The interaction between these domains and the growth factors makes ADAMTS-1 candidate to modulate the tumor microenvironment. This study aimed to evaluate the role of ADAMTS-1 within the tumor microenvironment of fibrosarcoma. We addressed to analyze whether this protease is able to interfere with the of growth factors effects, both in the local and systemic invasion of fibrosarcoma in vivo, using zebrafish embryo model. Initially, through in vitro experiments will examine the interactions between growth factors and ADAMTS-1 with the Surface Plasmon Resonance (SPR) System. Functional assays using cell culture will evaluate the effects of this possible interaction in the tumor microenvironment. Moreover, we will evaluate whether the presence of ADAMTS-1 interferes with different signaling pathways, which activated by growth factors. We use zebrafish embryos (Danio rerio) as a model in vivo. Tumor cells would notice with GFP-containing molecules or fluorescent dyes. After modulating ADAMTS-1 expression in tumor cells, will be injected into the embryos. Through time-lapse technique we will observe dynamics of tumor-stroma interactions. Interactions between tumor cells and blood vessels will observe by immunofluorescence. We believe that our data will provide information to increase the chances of successful treatment of this neoplasm in the clinic. (AU)

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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)
NORIEGA-GUERRA, HEYDI; CRUZ, MARIO C.; RIBEIRO, PRISCILLA R. L.; STRNADEL, JAN; WAN, HUAWEI; KLEMKE, RICHARD L.; JAEGER, RUY G.; FREITAS, VANESSA M.. ADAMTS-1 disrupts HGF/c-MET signaling and HGF-stimulated cellular processes in fibrosarcoma. Experimental Cell Research, v. 363, n. 2, p. 271-282, . (10/07699-1, 15/02498-1, 12/24108-2)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
GUERRA, Heydi Noriega. Importance of ADAMTS-1 protease in local and systemic invasion of fibrosarcoma.. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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