Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas.
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.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Feng-Pai
FP
Chou
Ya-Wen
YW
Chen
Xianfeng F
XF
Zhao
Zijun Y
ZY
Xu-Monette
Ken H
KH
Young
Ronald B
RB
Gartenhaus
Jehng-Kang
JK
Wang
Hiroaki
H
Kataoka
Annie H
AH
Zuo
Robert J
RJ
Barndt
Michael
M
Johnson
Chen-Yong
CY
Lin
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008198:Lymph Nodes / Q000201:enzymology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D017228:Hepatocyte Growth Factor; D012697:Serine Endopeptidases; C485595:matriptase; D014568:Urokinase-Type Plasminogen Activator