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Modulation of Tumor Cell Growth In Vivo by Extracellular Matrix Metalloprotease Inducer
J. Robert Newman, MD;
Isaac A. Bohannon, MD;
Wenyue Zhang, MS;
Joni B. Skipper, MD;
William E. Grizzle, MD;
Eben L. Rosenthal, MD
Arch Otolaryngol Head Neck Surg. 2008;134(11):1218-1224.
Objective To investigate if loss of extracellular matrix metalloprotease inducer (EMMPRIN) will inhibit the growth of head and neck squamous cell carcinoma (HNSCC) tumor cell lines in vivo. Tumor cell–derived EMMPRIN is highly overexpressed in HNSCC and is thought to be induced by surrounding fibroblasts to stimulate matrix metalloproteases, which modulate tumor cell invasion, growth, and angiogenesis.
Design In vivo study using FaDu tumor xenografts.
Setting Academic research facility.
Subjects Severe combined immunodeficiency (SCID) mice.
Interventions The HNSCC cell line FaDu was transfected with EMMPRIN (FaDu/E), control vector (FaDu), or plasmid-expressing small-interfering RNA against EMMPRIN (FaDu/siE). Tumor cells combined with fibroblast cells were xenografted onto the flank of SCID mice. Tumors were measured biweekly over 4 weeks, at which time the mice were killed, and tumor samples were analyzed for proliferation (Ki-67 immunohistochemical analysis), vascularization (factor VIII staining), and apoptosis (TUNEL [terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick end labeling] assay).
Main Outcome Measure Growth of head and neck cancer cell lines genetically engineered to express variable levels of EMMPRIN.
Results Tumor growth positively correlated and animal survival negatively correlated with increasing EMMPRIN expression. FaDu/E tumor growth was significantly larger at 4 weeks compared with FaDu tumors (P = .006). Similarly, the control vector–transfected FaDu tumors were significantly larger than FaDu/siE (P < .001). Immunohistochemical analysis demonstrated increased Ki-67 in EMMPRIN-transfected cells, without a significant change in the rate of apoptosis between groups. Vascular density and tumor formation rate also increased significantly with EMMPRIN expression.
Conclusion This study suggests that anti-EMMPRIN–targeted therapy may prove to be a novel treatment option in HNSCC.
Author Affiliations: Division of Otolaryngology–Head and Neck Surgery, Department of Surgery (Drs Newman, Bohannon, Skipper, and Rosenthal and Mr Zhang), and Department of Pathology (Dr Grizzle), University of Alabama at Birmingham.
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