Imaging a functional tumorigenic biomarker in the transformed epithelium

Aaron M. LeBeau, Minhee Lee, Stephanie T. Murphy, Byron C. Hann, Robert S. Warren, Romelyn Delos Santos, John Kurhanewicz, Samir M. Hanash, Henry F. VanBrocklin, Charles S. Craik

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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, 111In-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.

Original languageEnglish (US)
Pages (from-to)93-98
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

Keywords

  • Cancer biomarker
  • Molecular imaging

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