The role of thrombospondin-1 on the regulation of the plasminogen plasmin system and tumor cell invasion

Daniel Albo

doi:10.17918/00008914

Thrombospondin-1 (TSP-1) is a large glycoprotein that localizes to the extracellular matrix in several different tumors. There is a growing body of data demonstrating that TSP-1 plays a critical role in tumor progression and invasion. TSP-1 has been shown to promote tumor cell adhesion, migration, invasion and angiogenesis, crucial steps in the process of metastasis. Metastasis is a complex multistep process that involves the controlled degradation of the extracellular matrix by tumor-associated proteases. While pericellular proteolysis is crucial for tumor cell invasion to occur, excessive degradation of the tumor associated-matrix can destroy the matrix scaffold that tumor cells need in order to migrate and invade. Therefore, it is currently believed that a balance between proteolytic enzymes and their inhibitors must exist in order to localize the proteolytic activity preferentially to the tumor cell surface. This would allow tumor cells to efficiently invade and metastasize. One of the main proteases involved in malignancy is the plasminogen/plasmin system. The proteolytic conversion of plasminogen to plasmin is catalyzed by the urokinase-type plasminogen activator (uPA) and inhibited by the plasminogen activator inhibitor type 1 (PAI-1). Once generated, plasmin is an enzyme with a broad substrate specificity with the capacity to cleave most of the extracellular matrix components. Additionally, by activating inactive precursors of other proteolytic enzymes such as matrix metalloproteinases, plasmin is believed to control an enzymatic proteolytic cascade. Furthermore, plasmin activates inactive precursors of growth factors stored in latent form in the extracellular matrix such as transforming growth factor beta 1 (TGF-[beta]1). These growth factors may then enhance plasmin generation by upregulating uPA and its receptor, uPAR, therefore generating an amplification loop that further enhances pericellular proteolysis. Localization of proteolytic activity to the tumor cell surface by receptors such as uPAR allows for a more efficient and localized plasmin generation and, therefore, may further enhance pericellular proteolysis and tumor cell invasion. The objective of this thesis work was to determine the effect of TSP-1 in the regulation of the plasminogen plasmin system. Furthermore, we sought to determine what role the plasminogen/plasmin system may play in TSP-1-mediated tumor cell invasion. Our working hypothesis was that TSP-I, through regulation of the plasminogen/plasmin system, promoted a controlled proteolysis of tumor-associated matrix and, therefore, promoted tumor cell invasion. The long term goal of our research efforts is to develop new diagnostic and therapeutic tools that would hopefully allow us to diagnose tumors earlier and treat them more efficiently, while minimizing the side effects to the patient. Translating our bench work to the patient's bedside is the ultimate goal of our work.

The role of thrombospondin-1 on the regulation of the plasminogen plasmin system and tumor cell invasion

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The role of thrombospondin-1 on the regulation of the plasminogen plasmin system and tumor cell invasion

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