Anti-EMMPRIN monoclonal antibody as a novel agent for therapy of head and neck cancer

Clin Cancer Res. 2009 Jun 15;15(12):4058-65. doi: 10.1158/1078-0432.CCR-09-0212. Epub 2009 Jun 9.

Abstract

Purpose: Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer. These features make it a potential therapeutic target for monoclonal antibody (mAb)-based therapy. Because molecular therapy is considered more effective when delivered with conventional cytotoxic agents, anti-EMMPRIN therapy was assessed alone and in combination with external beam radiation.

Experimental design: Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells.

Results: Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN-expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb-treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1beta (IL-1beta), IL-6, and IL-8 cytokine production, in vitro and in vivo.

Conclusions: These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Basigin / immunology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / drug effects
  • Cytokines / metabolism*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy
  • Humans
  • Immunologic Factors / therapeutic use*
  • Mice
  • Mice, SCID
  • RNA, Small Interfering / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • BSG protein, human
  • Cytokines
  • Immunologic Factors
  • RNA, Small Interfering
  • Basigin