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

• Published in: The American journal of pathology Vol. 183; no. 4; pp. 1306 - 1317
• Main Authors: Chou, Feng-Pai, Chen, Ya-Wen, Zhao, Xianfeng F, Xu-Monette, Zijun Y, Young, Ken H, Gartenhaus, Ronald B, Wang, Jehng-Kang, Kataoka, Hiroaki, Zuo, Annie H, Barndt, Robert J, Johnson, Michael, Lin, Chen-Yong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2013; American Society for Investigative Pathology
• Subjects: Animals; B-Lymphocytes - enzymology; B-Lymphocytes - pathology; Cell Line, Tumor; Cell Proliferation; Female; Hepatocyte Growth Factor - metabolism; Humans; Lymph Nodes - enzymology; Lymph Nodes - pathology; Lymphoma, B-Cell - enzymology; Lymphoma, B-Cell - pathology; Mice; Mice, SCID; Pathology; Proteinase Inhibitory Proteins, Secretory - metabolism; Proteolysis; Regular; Serine Endopeptidases - metabolism; Urokinase-Type Plasminogen Activator - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2013.06.024

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.