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


METHODS
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.
Dean
Nichole R
NR
Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Newman
J Robert
JR
Helman
Emily E
EE
Zhang
Wenyue
W
Safavy
Seena
S
Weeks
D M
DM
Cunningham
Mark
M
Snyder
Linda A
LA
Tang
Yi
Y
Yan
Li
L
McNally
Lacey R
LR
Buchsbaum
Donald J
DJ
Rosenthal
Eben L
EL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D051926:Basigin / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C497886:BSG protein, human; D016207:Cytokines; D007155:Immunologic Factors; D034741:RNA, Small Interfering; D051926:Basigin