Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chou, F-P; Chen, Y-W; Zhao, XF; Xu-Monette, ZY; Young, KH; Gartenhaus, RB; Wang, J-K; Kataoka, H; Zuo, AH; Barndt, RJ; Johnson, M; Lin, C-Y

Published Date

  • October 2013

Published In

Volume / Issue

  • 183 / 4

Start / End Page

  • 1306 - 1317

PubMed ID

  • 24070417

Pubmed Central ID

  • 24070417

Electronic International Standard Serial Number (EISSN)

  • 1525-2191

International Standard Serial Number (ISSN)

  • 0002-9440

Digital Object Identifier (DOI)

  • 10.1016/j.ajpath.2013.06.024

Language

  • eng