Imbalanced Matriptase Pericellular Proteolysis Contributes to the Pathogenesis of Malignant B-Cell Lymphomas

Abstract

Membrane-associated serine protease matriptase is widely expressed by epithelial/carcinoma cells in which its proteolytic activity is tightly controlled by the Kunitz-type protease inhibitor, hepatocyte growth factor activator inhibitor (HAI-1). We demonstrate that, although matriptase is not expressed in lymphoid hyperplasia, roughly half of the non-Hodgkin B-cell lymphomas analyzed express significant amounts of matriptase. Furthermore, a significant proportion of these tumors express matriptase in the absence of HAI-1. Aggressive Burkitt lymphoma was more likely than indolent follicular lymphoma to express matriptase alone (86% versus 36%). In the absence of significant HAI-1 expression, the lymphoma cells activate and shed active matriptase when the cells are stimulated with mildly acidic buffer or the hypoxia-mimicking agent, CoCl2. The shed active matriptase can initiate pericellular proteolytic cascades by activating urokinase-type plasminogen activator on the cell surface of monocytes, and it can activate prohepatocyte growth factor. In addition, matriptase knockdown suppressed proliferation and colony-forming ability of neoplastic B cells in culture and growth as tumor xenografts in mice. Furthermore, exogenous expression of HAI-1 significantly suppressed proliferation of neoplastic B cells. These studies suggest that dysregulated pericellular proteolysis as a result of unregulated matriptase expression with limited HAI-1 may contribute to the pathological characteristics of several human B-cell lymphomas through modulation of the tumor microenvironment and enhanced tumor growth.

Structure-based discovery of small molecule hepsin and HGFA protease inhibitors: Evaluation of potency and selectivity derived from distinct binding pockets

“…This proteolytic processing is essential for ligand-dependent activation of c-MET and RON kinases in cancer. Increased activity of hepsin, matriptase, and/or HGFA 6 , resulting from either expression or upregulation of these proteases 7 and/or downregulation 8 of their endogenous serine protease inhibitors (serpins), HAI-1, HAI-2 , and protein C inhibitor (PCI) 9 , has been demonstrated in almost every tumor type driven by c-MET and/or RON pathway signaling 10 . This increased protease function has been clearly associated with increased metastatic cancer phenotypes and direct inhibition 11 of this protease activity has been demonstrated to reduce this metastatic potential in multiple tumor types.…”

Type II transmembrane serine proteases as potential targets for cancer therapy

“… References: 1 Zoratti et al, 2015; 2 Welman et al, 2012; 3 Kang et al, 2003; 4 Lee et al, 2005; 5 Kosa et al, 2011; 6 Förbs et al, 2005; 7 Vogel et al, 2006; 8 Nakamura et al, 2009; 9 Cheng et al, 2006; 10 Zeng et al, 2005; 11 Szabo et al, 2011; 12 Cheng et al, 2014; 13 Baba et al, 2012; 14 Jin et al, 2006; 15 Gao et al, 2012; 16 Tsai et al, 2006; 17 Chou et al, 2013; 18 Hoang et al, 2004; 19 Ye et al, 2014; 20 Uhland et al, 2009; 21 Riddick et al, 2005; 22 Tsai et al, 2014; 23 Wu et al, 2010; 24 Tripathi et al, 2011; 25 Sanders et al, 2006; 26 List et al, 2005; 27 Sales et al, 2014; 28 Sales et al, 2015; 29 Bocheva et al, 2009; 30 Netzel-Arnett et al, 2006; 31 Alef et al, 2008; 32 List et al, 2002; 33 List et al, 2009; 34 Buzza et al, 2010; 35 Netzel-Arnett et al, 2...…”

Engineering a potent inhibitor of matriptase from the natural hepatocyte growth factor activator inhibitor type-1 (HAI-1) protein

“…1B). As such, the ratio of HAI-1 expression to matriptase expression correlates with cancer aggression and patient prognosis, and has been established as a key biomarker (2,5,7,10,31,32).…”

“…1B). As such, the ratio of HAI-1 expression to matriptase expression correlates with cancer aggression and patient prognosis, and has been established as a key biomarker (2,5,7,10,31,32).Inhibition of matriptase-driven cancer progression has been proposed as an attractive strategy for cancer therapy. In one study, induced cell surface expression of HAI-1 within the tumor environment of an orthotopic adenopancreatic cancer model resulted in reduced tumor size and eliminated metastatic nodule formation (2).…”