title: Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.
abstract: Most patients with ovarian cancer are diagnosed late in progression and often experience tumor recurrence and relapses due to drug resistance. Surface expression of matrix metalloprotease (MMP)-14 on ovarian cancer cells stimulates a tumor-stromal signaling pathway that promotes angiogenesis and tumor growth. In a cohort of 92 patients, we found that MMP-14 was increased in the serum of women with malignant ovarian tumors. Therefore, we investigated the preclinical efficacy of a MMP-14 monoclonal antibody that could inhibit the migratory and invasive properties of aggressive ovarian cancer cells in vitro. MMP-14 antibody disrupted ovarian tumor-stromal communication and was equivalent to Avastin in suppressing blood vessel growth in mice harboring Matrigel plugs. These effects on angiogenesis correlated with downregulation of several important angiogenic factors. Furthermore, mice with ovarian cancer tumors treated with anti-MMP-14 monotherapy showed a marked and sustained regression in tumor growth with decreased angiogenesis compared with immunoglobulin G (IgG)-treated controls. In a model of advanced peritoneal ovarian cancer, MMP-14-dependent invasion and metastasis was effectively inhibited by intraperitoneal administration of monoclonal MMP-14 antibody. Together, these studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer.
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors: Rajani
authors: R
authors: Kaimal
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.|Department of Medicine, Tufts Medical Center, Boston, MA 02111.
authors: Raid
authors: R
authors: Aljumaily
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors: Sarah L
authors: SL
authors: Tressel
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors: Rutika V
authors: RV
authors: Pradhan
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.|Department of Medicine, Tufts Medical Center, Boston, MA 02111.|Departments of Biochemistry and Genetics, Tufts University Medical School Boston, MA 02111.
authors: Lidija
authors: L
authors: Covic
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.|Department of Medicine, Tufts Medical Center, Boston, MA 02111.|Departments of Biochemistry and Genetics, Tufts University Medical School Boston, MA 02111.
authors: Athan
authors: A
authors: Kuliopulos
authors: Department of Hematology and Oncology, Lahey Clinic Medical Center, Burlington, MA-02111.
authors: Corrine
authors: C
authors: Zarwan
authors: Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA-02111.
authors: Young B
authors: YB
authors: Kim
authors: Department of Pathology, Tufts Medical center and Mt Auburn Hospital, Boston, MA-02111.
authors: Sheida
authors: S
authors: Sharifi
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111.|Department of Medicine, Tufts Medical Center, Boston, MA 02111.
authors: Anika
authors: A
authors: Agarwal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000097:blood; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D000077143:Docetaxel; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D061965:Matrix Metalloproteinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D053511:Matrix Metalloproteinase 14