title: Extracelluar matrix metalloproteinase as a novel target for pancreatic cancer therapy.
abstract: The objective of this study was to evaluate extracellular matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, whereas MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, whereas the other groups served as the control. In the residual tumor model, tumor growth of anti-EMMPRIN-treated group was successfully arrested for 21 days (15 ± 4 mm(3)), which was significantly lower than that of the EMMPRIN knockdown group (80 ± 15 mm(3); P=0.001) or the control group (240 ± 41 mm(3); P<0.001). In the established tumor model, anti-EMMPRIN therapy lowered tumor volume increase by approximately 40% compared with the control, regardless of the dose amount. Ki67-expressed cell density of group 5 was 939 ± 150 mm(-2), which was significantly lower than that of group 4 (1709 ± 145 mm(-2); P=0.006). Microvessel density of group 5 (30 ± 6 mm(-2)) was also significantly lower than that of group 4 (53 ± 5 mm(-2); P=0.014), whereas the microvessel size of group 5 (191 ± 22 μm(2)) was significantly larger than that of group 4 (113 ± 26 μm(2); P=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer and support its clinical translation.
authors: Department of Radiology, University of Alabama at Birmingham, USA. hyunki@uab.edu
authors: Hyunki
authors: H
authors: Kim
authors: Guihua
authors: G
authors: Zhai
authors: Zhiyong
authors: Z
authors: Liu
authors: Sharon
authors: S
authors: Samuel
authors: Nemil
authors: N
authors: Shah
authors: Emily E
authors: EE
authors: Helman
authors: Joseph A
authors: JA
authors: Knowles
authors: Cecil R
authors: CR
authors: Stockard
authors: Naomi S
authors: NS
authors: Fineberg
authors: William E
authors: WE
authors: Grizzle
authors: Tong
authors: T
authors: Zhou
authors: Kurt R
authors: KR
authors: Zinn
authors: Eben L
authors: EL
authors: Rosenthal
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use*; D051926:Basigin / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011863:Radioimmunoassay; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000888:Antibodies, Anti-Idiotypic; D058846:Antibodies, Monoclonal, Murine-Derived; C497886:BSG protein, human; D019394:Ki-67 Antigen; D051926:Basigin; D020782:Matrix Metalloproteinases