Tumor Detection by Imaging Proteolytic Activity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-02, Vol.70 (4), p.1505-1512
• Main Authors: DARRAGH, Molly R, SCHNEIDER, Eric L, JIANLONG LOU, PHOJANAKONG, Paul J, FARADY, Christopher J, MARKS, James D, HANN, Byron C, CRAIK, Charles S
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibody Specificity; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - immunology; Biomarkers, Tumor - metabolism; Diagnostic Imaging - methods; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Female; Fluorescent Antibody Technique - methods; HT29 Cells; Humans; Medical sciences; Mice; Mice, Nude; Neoplasms - diagnosis; Neoplasms - metabolism; Pharmacology. Drug treatments; Protein Processing, Post-Translational - drug effects; Serine Endopeptidases - immunology; Serine Endopeptidases - metabolism; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1640

The cell surface protease membrane-type serine protease-1 (MT-SP1), also known as matriptase, is often upregulated in epithelial cancers. We hypothesized that dysregulation of MT-SP1 with regard to its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1), a situation that increases proteolytic activity, might be exploited for imaging purposes to differentiate malignant from normal tissue. In this study, we show that MT-SP1 is active on cancer cells and that its activity may be targeted in vivo for tumor detection. A proteolytic activity assay with several MT-SP1-positive human cancer cell lines showed that MT-SP1 antibodies that inhibit recombinant enzyme activity in vitro also bind and inhibit the full-length enzyme expressed on cells. In contrast, in the same assay, MT-SP1-negative cancer cell lines were inactive. Fluorescence microscopy confirmed the cell surface localization of labeled antibodies bound to MT-SP1-positive cells. To evaluate in vivo targeting capability, 0.7 to 2 nmoles of fluorescently labeled antibodies were administered to mice bearing tumors that were positive or negative for MT-SP1. Antibodies localized to MT-SP1-positive tumors (n = 3), permitting visualization of MT-SP1 activity, whereas MT-SP1-negative tumors (n = 2) were not visualized. Our findings define MT-SP1 activity as a useful biomarker to visualize epithelial cancers using a noninvasive antibody-based method.