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Targeting the MMP-14/MMP-2/integrin ?v?3 axis with multispecific N-TIMP2-based antagonists for cancer therapy.

ABSTRACT: The pathophysiological functions of the signaling molecules matrix metalloproteinase-14 (MMP-14) and integrin ?v?3 in various types of cancer are believed to derive from their collaborative activity in promoting invasion, metastasis, and angiogenesis, as shown in vitro and in vivo The two effectors act in concert in a cell-specific manner through the localization of pro-MMP-2 to the cell surface, where it is processed to intermediate and matured MMP-2. The matured MMP-2 product is localized to the cell surface via its binding to integrin ?v?3 The MMP-14/MMP-2/integrin ?v?3 axis thus constitutes an attractive putative target for therapeutic interventions, but the development of inhibitors that target this axis remains an unfulfilled task. To address the lack of such multitarget inhibitors, we have established a combinatorial approach that is based on flow cytometry screening of a yeast-displayed N-TIMP2 (N-terminal domain variant of tissue inhibitor of metalloproteinase-2) mutant library. On the basis of this screening, we generated protein monomers and a heterodimer that contain monovalent and bivalent binding epitopes to MMP-14 and integrin ?v?3 Among these proteins, the bi-specific heterodimer, which bound strongly to both MMP-14 and integrin ?v?3, exhibited superior ability to inhibit MMP-2 activation and displayed the highest inhibitory activity in cell-based models of a MMP-14-, MMP-2-, and integrin ?v?3-dependent glioblastoma and of endothelial cell invasiveness and endothelial capillary tube formation. These assays enabled us to show the superiority of the combined target effects of the inhibitors and to investigate separately the role each of the three signaling molecules in various malignant processes.

SUBMITTER: Yosef G

PROVIDER: S-EPMC6109916 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Targeting the MMP-14/MMP-2/integrin αvβ3 axis with multispecific N-TIMP2-based antagonists for cancer therapy.

Yosef Gal G Arkadash Valeria V Papo Niv N

The Journal of biological chemistry 20180709 34

The pathophysiological functions of the signaling molecules matrix metalloproteinase-14 (MMP-14) and integrin αvβ3 in various types of cancer are believed to derive from their collaborative activity in promoting invasion, metastasis, and angiogenesis, as shown in vitro and in vivo The two effectors act in concert in a cell-specific manner through the localization of pro-MMP-2 to the cell surface, where it is processed to intermediate and matured MMP-2. The mat ...[more]

PMID: 29986882

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Project description:PurposeThere is a clinical need for agents that target glioma cells for non-invasive and intraoperative imaging to guide therapeutic intervention and improve the prognosis of glioma. Matrix metalloproteinase (MMP)-14 is overexpressed in glioma with negligible expression in normal brain, presenting MMP-14 as an attractive biomarker for imaging glioma. In this study, we designed a peptide probe containing a near-infrared fluorescence (NIRF) dye/quencher pair, a positron emission tomography (PET) radionuclide, and a moiety with high affinity to MMP-14. This novel substrate-binding peptide allows dual modality imaging of glioma only after cleavage by MMP-14 to activate the quenched NIRF signal, enhancing probe specificity and imaging contrast.MethodsMMP-14 expression and activity in human glioma tissues and cells were measured in vitro by immunofluorescence and gel zymography. Cleavage of the novel substrate and substrate-binding peptides by glioma cells in vitro and glioma xenograft tumors in vivo was determined by NIRF imaging. Biodistribution of the radiolabeled MMP-14-binding peptide or substrate-binding peptide was determined in mice bearing orthotopic patient-derived xenograft (PDX) glioma tumors by PET imaging.ResultsGlioma cells with MMP-14 activity showed activation and retention of NIRF signal from the cleaved peptides. Resected mouse brains with PDX glioma tumors showed tumor-to-background NIRF ratios of 7.6-11.1 at 4 h after i.v. injection of the peptides. PET/CT images showed localization of activity in orthotopic PDX tumors after i.v. injection of 68Ga-binding peptide or 64Cu-substrate-binding peptide; uptake of the radiolabeled peptides in tumors was significantly reduced (p < 0.05) by blocking with the non-labeled-binding peptide. PET and NIRF signals correlated linearly in the orthotopic PDX tumors. Immunohistochemistry showed co-localization of MMP-14 expression and NIRF signal in the resected tumors.ConclusionsThe novel MMP-14 substrate-binding peptide enabled PET/NIRF imaging of glioma models in mice, warranting future image-guided resection studies with the probe in preclinical glioma models.

Dataset Information

Targeting the MMP-14/MMP-2/integrin ?v?3 axis with multispecific N-TIMP2-based antagonists for cancer therapy.

Publications

Targeting the MMP-14/MMP-2/integrin α<sub>v</sub>β<sub>3</sub> axis with multispecific N-TIMP2-based antagonists for cancer therapy.

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