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GUERRA, H. N. Importance of ADAMTS-1 protease in local and systemic invasion of fibrosarcoma. 2017. 93 p. PhD Thesis (Cell and Tissue Biology) Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2017. The growth and malignancy of a tumor are dictated by the surrounding microenvironment. The extracellular matrix forms part of the tumor microenvironment, and serves as a reservoir for biologically active factors, such as growth factors and proteases that influence the tumor cell behavior. ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs) is a secreted protease that has the ability to modify the extracellular matrix during physiological and pathological processes. Here, we addressed the role played by ADAMTS-1 regulating HGF and TGF-β1 activities in the high-grade fibrosarcoma cell line (HT1080). For this, we generated HT1080 and HEK293T cells that overexpress ADAMTS-1. BrdU incorporation and Ki67 expression assays demonstrated that ADAMTS-1 overexpression induced a significant decrease of HT1080 cell proliferation, in the presence of HGF. In addition, the HT1080 cells overexpressing ADAMTS-1 presented a migration velocity of 6.120 ± 0.416 μm/hour, which was at least 2 times lower than the control cell migration velocity (13.763 ± 1.421 μm/hour), both in presence of HGF. Likewise, when HT1080 cells were treated with HGF added into the conditioned medium of other cell type (HEK293T) that overexpressed ADAMTS1, we observed a decrease of cell proliferation and migration velocity. Next, we demonstrate that ADAMTS-1 overexpression interrupts c-Met activation upon HGF stimulation. Consequently, the downstream ERK1/2 and FAK signaling pathways are disturbed. On the other hand, ADAMTS-1 overexpression failed to affect TGF-β1 activity associated with HT1080 cell proliferation and migration velocity. Although we observed a decrease of smad2/3 phosphorylation in HT1080 cells overexpressing ADAMTS-1, this partial reduction was not sufficient to alter ERK1/2 and Akt activation, after treatment with TGF-β1. Additionally, through 3D culture in Hanging drop we showed that in presence of HGF, ADAMTS-1 overexpression decreased the fibrosarcospheres diameter (~0.7 mm), as compared to the control (fibrosarcospheres diameter of ~1.3 mm). In vivo studies showed that in presence of HGF, ADAMTS-1 overexpression disrupted the formation of microtumors. These microtumors, including individual cells, presented characteristics of low invasive tumor cells (rounded morphology). Our results suggest that ADAMTS-1 is involved in regulating HGF-related functions on fibrosarcoma cells. This protease may then represent an endogenous mechanism in controlling the bioavailability of different growth factors that have a direct influence on tumor cell behavior.

Importância da protease ADAMTS-1 na invasão local e sistêmica de células do fibrossarcoma.