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A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models.
Ling, Binbing; Watt, Kathleen; Banerjee, Sunandan; Newsted, Daniel; Truesdell, Peter; Adams, Jarrett; Sidhu, Sachdev S; Craig, Andrew W B.
Afiliación
  • Ling B; Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
  • Watt K; Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
  • Banerjee S; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Newsted D; Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
  • Truesdell P; Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
  • Adams J; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Sidhu SS; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Craig AWB; Department of Biomedical and Molecular Sciences, Queen's University, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, ON, Canada.
Oncotarget ; 8(35): 58372-58385, 2017 Aug 29.
Article en En | MEDLINE | ID: mdl-28938563
ABSTRACT
Matrix metalloproteinase-14 (MMP-14) is a clinically relevant target in metastatic cancers due to its role in tumor progression and metastasis. Since active MMP-14 is localized on the cell surface, it is amenable to antibody-mediated blockade in cancer, and here we describe our efforts to develop novel inhibitory anti-MMP-14 antibodies. A phage-displayed synthetic humanized Fab library was screened against the extracellular domain of MMP-14 and a panel of MMP14-specific Fabs were identified. A lead antibody that inhibits the catalytic domain of MMP-14 (Fab 3369) was identified and treatment of MDA-MB-231 breast cancer cells with Fab 3369 led to significant loss of extracellular matrix degradation and cell invasion abilities. In mammary orthotopic tumor xenograft assays, MMP-14 blockade by IgG 3369 limited tumor growth and metastasis. Analysis of tumor tissue sections revealed that MMP-14 blockade limited tumor neoangiogenesis and hypoxia. Similar effects of MMP-14 blockade in syngeneic 4T1 mammary tumors were observed, along with increased detection of cytotoxic immune cell markers. In conclusion, we show that immunotherapies targeting MMP-14 can limit immune suppression, tumor progression, and metastasis in triple-negative breast cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Oncotarget Año: 2017 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Oncotarget Año: 2017 Tipo del documento: Article País de afiliación: Canadá