ID: 310 The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals.

Vogel, Lotte K.; Sæbø, Mona; Skjelbred, Camilla Furu; Abell, Katherine; Pedersen, E.M.; Vogel, U.; Kure, Elin H.

doi:10.1111/j.1538-7836.2006.00310.x

Cited by 23 publications

(31 citation statements)

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“…Analysis of mRNA expression in healthy and diseased colon tissue found that a matriptase/HAI-1 mRNA ratio >1 is clinically significant. These data mirrored an earlier study that found the dysregulation of the matriptase/HAI-1 mRNA ratio occurred early in colon cancer tumorigenesis and was higher in adenomas and carcinomas (33). qPCR does not distinguish between zymogen and active matriptase, but immunofluorescence with A11-AF488 in tissue microarays confirmed that active matriptase was present in malignant colon cancer tissue, but absent in normal tissue where HAI-1 mRNA levels are elevated.…”

Section: Discussionsupporting

confidence: 75%

Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Proteases responsible for the increased peritumoral proteolysis associated with cancer represent functional biomarkers for monitoring tumorigenesis. One attractive extracellular biomarker is the transmembrane serine protease matriptase. Found on the surface of epithelial cells, the activity of matriptase is regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). Quantitative mass spectrometry allowed us to show that, in selected cancers, HAI-1 expression decreases, leading to active matriptase. A preclinical probe specific for the measurement of emergent active matriptase was developed. Using an active-site-specific, recombinant human antibody for matriptase, we found that the selective targeting of active matriptase can be used to visualize the tumorigenic epithelium. Live-cell fluorescence imaging validated the selectivity of the antibody in vitro by showing that the probe localized only to cancer cell lines with active matriptase on the surface. Immunofluorescence with the antibody documented significant levels of active matriptase in 68% of primary and metastatic colon cancer sections from tissue microarrays. Labeling of the active form of matriptase in vivo was measured in human colon cancer xenografts and in a patient-derived xenograft model using near-infrared and single-photon emission computed tomography imaging. Tumor uptake of the radiolabeled antibody, 111 In-A11, by active matriptase was high in xenografts (28% injected dose per gram) and was blocked in vivo by the addition of a matriptase-specific variant of ecotin. These findings suggest, through a HAI-1-dependent mechanism, that emergent active matriptase is a functional biomarker of the transformed epithelium and that its proteolytic activity can be exploited to noninvasively evaluate tumorigenesis in vivo.cancer biomarker | molecular imaging

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Section: Discussionsupporting

confidence: 75%

Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Yeast cell surface binding assays and library screening conditions. Induced EBY100 yeast cells were counted (OD600 of 1 = 10 7 cells/ml), 1x10 5 cells/sample were washed with 1 mL matriptase assay buffer, and then mixed with soluble matriptase (final concentration 0 to 1 nM, serial dilution) and matriptase assay buffer (final concentration 200 μL to 100 mL). Ligand depleting conditions were addressed using methods previously described, and estimated by assuming each yeast displayed 50,000 copies of inhibitor per cell (57,58).…”

Section: Discussionmentioning

confidence: 99%

“…5x10 5 cancer cells were resuspended in cold 1xPBS with 1 mg/mL bovine serum albumin (0.1% BPBS) (50 μL to 10mL final volume), containing soluble inhibitor (50 pM to 1 μM serial dilution) or a 1:100 dilution soluble human matriptase antibody (Fisher Scientific). Cell solutions were incubated at 4 o C for at least 3 hours (for single point binding assays) or overnight (for binding curve assays).…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Mitchell

Kannan

Hunter

et al. 2018

Journal of Biological Chemistry

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Abstract:Dysregulated matriptase activity has been established as a key contributor to cancer progression through its activation of growth factors including the hepatocyte growth factor (HGF). Despite its critical role and prevalence in many human cancers, limitations to developing an effective matriptase inhibitor include weak binding affinity, poor selectivity, and short circulating half-life. We applied rational and combinatorial approaches to engineer a potent inhibitor based on the hepatocyte growth factor activator inhibitor type 1 (HAI-1), a natural matriptase inhibitor. The first Kunitz domain (KD1) of HAI-1 has been well established as a minimal matriptase binding and inhibition domain, while the second Kunitz domain (KD2) is inactive and involved in negative regulation. Here, we replaced the inactive KD2 domain of HAI-1 with an engineered chimeric variant of KD2/KD1 domains, and fused the resulting construct to an antibody Fc domain to increase valency and circulating serum half-life. The final protein variant contains 4 stoichiometric binding sites that we showed were needed to effectively inhibit matriptase with a Ki =70 ± 5 pM, an increase of 120-fold compared to the natural HAI-1 inhibitor, to our knowledge making it one of the most potent matriptase inhibitors identified to date. Furthermore, the engineered inhibitor demonstrates a protease selectivity profile similar to wild-type KD1 but distinct from HAI-1. It also inhibits activation of the natural pro-HGF substrate and matriptase expressed on cancer cells with at least an order of magnitude greater efficacy than KD1. ________________________________________ High expression and dysregulated activity of the type II, membrane-anchored serine protease matriptase in the local tumor environment has been shown to correlate with poor patient prognosis in many human cancers including breast, colorectal, pancreatic, cervical, and prostate cancers (1-10). This dysregulation is partly driven by the high proteolytic processing and turnover of pro-hepatocyte growth factor (Pro-HGF) (9, 11) to a form of HGF that activates its cognate receptor, c-Met (12) (Fig. 1A). Matriptase is also known to activate other proteases and growth factors including urokinase plasminogen activator (uPA) (11), pro-macrophage stimulating protein (Pro-MSP) (13), and platelet derived growth factor-D (PDGF-D) (14), all of which play key roles in cancer growth and metastasis. Furthermore, matriptase has been identified as a critical driver of other diseases, including iron overload disease (15) and osteoarthritis (16), and has been shown to activate the human airway influenza virus (H1N1) (17) and human immunodeficiency virus (HIV) (18 (19)(20)(21)(22)(23). The activity of matriptase is regulated in healthy tissue by the serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1) (Fig. 1A). HAI-1 is primarily expressed on the surface of epithelial cells and naturally blocks the substrate-activating properties of matriptase (24)(25)(26), as well as other struc...

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Genetic upregulation of matriptase‐2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation

Sanders

Parr

Martin

et al. 2008

Journal Cellular Physiology

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The cellular function and the role of matriptase-2 in cancer progression are poorly understood. This study assesses the importance of this protease in prostate cancer cell lines. Two prostate cancer cell lines, PC-3 and DU-145, previously displaying minimal expression of matriptase-2, were forced to over-express matriptase-2 using a human mammalian expression construct. Over-expression of matriptase-2 significantly reduced the invasive capacity and significantly slowed the migration rates of PC-3 and DU-145 cells in vitro. Similarly, PC-3 cells containing the matriptase-2 expression plasmid were dramatically less able to survive, grow and develop into noticeable tumours, compared to control PC-3 cells containing an empty plasmid alone, following subcutaneous inoculation into CD1 nude mice. This trend was observed throughout the experiment, becoming apparent after the initial reading on day 7 (P = 0.0002) and continuing to the experimental end point at day 27 (P = 0.0002). Enhanced matriptase-2 levels were also seen to correlate with increased fluorescent staining of the paxillin and FAK adhesion molecules, where a greater extent of these molecules were localised to the focal adhesion complexes. This data suggests a suppressive role for matriptase-2 in the invasion and migration of prostate cancer cells in vitro and also in their development and growth in vivo, highlighting the potential of this molecule to interfere with key stages of metastasis. Furthermore, the data presented implies a possible connection between matriptase-2 and the paxillin and FAK adhesion molecules which may ultimately contribute to the reduced migration rates seen in this study.

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ID: 310 The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals.

Cited by 23 publications

References 0 publications

Imaging a functional tumorigenic biomarker in the transformed epithelium

Imaging a functional tumorigenic biomarker in the transformed epithelium

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

Genetic upregulation of matriptase‐2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation

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