Estudio de la expresión del sistema fibrinolítico y del sistema de las metaloproteasas en el cáncer de mama.
The plasminogen activation system and matrix metalloproteinases (MMPs) play a key role in the degradation of basement membrane and extracellular matrix in tissue remodeling, cancer cell invasion and metastasis.
It is generally believed that uPA initiates a proteinase cascade at the cell surface that contributes to tumor invasion, metastasis and angiogenesis. uPA is inhibited by plasminogen activator inhibitor type-1 (PAI-1) and it can also be inhibited by PAI type-3 (PAI-3).
On the other hand, MMPs are involved in several pathological processes, including tumor invasion, in which degradation of the extracellular matrix is a key event. MMP-3 is a stromelysin implicated in invasion and metastasis processes. MMP-3 activity is regulated by tissue inhibitors of metalloproteinases type-1 (TIMP-1).
The quantitative real-time RT-PCR technique allowed us to obtain a highly sensitive, specific, and reproducible mRNAs quantification of uPA, PAI-1, PAI-3, MMP-3 and TIMP-1.
PAI-1, uPA and TIMP-1 mRNA and antigen levels and PAI-1 and uPA functional levels increased with tumor severity, and in node-positive patients than those who were node-negative. However, no significant variations were observed for PAI-3 and MMP-3 for all the groups studied.
PAI-3 antigen levels were significantly higher in early relapse-free patients than in patients who suffered a relapse. However, PAI-1 and MMP-3 antigen levels were significantly higher in patients who suffered an early relapse than in those who did not .
uPA immunoreactivity was localized mainly in stromal and endothelial cells and with lower intensity in cancer cells. PAI-1 immunostaining was stronger in cancer cells and in endothelial cells, than in stromal cells surrounding cancer cells. PAI-3 antigen was localized in the stromal cells surrounding nested cancer cells, but it was not observed in cancer cells or in endothelial cells.
uPA and PAI-1 mRNA was localized mainly in stromal cells, indicating that uPA and PAI-1 are mainly synthesized by stromal cells, secreted and captured by cancer cells.
We have found, for the first time, that PAI-3 is expressed in breast cancer tissue. Our data indicated that uPA, PAI-1, MMP-3 and TIMP-1 are implicated in invasion and metastasis in breast cancer. However, PAI-3 seems to inhibit these processes.
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Advisor:Estellés Cortés, Amparo; Vázquez Albadalejo, Carlos; España Furió, Francisco
School:Universitat de València
Source Type:Master's Thesis
Keywords:bioquímica i biologia molecular
Date of Publication:04/02/2004