Extracelluar matrix metalloproteinase as a novel target for pancreatic cancer therapy

• DOI: 10.1097/cad.0b013e328349311e
• Publication Date: 2011-07-06T08:51:21Z
• Authors: Hyunki Kim; Guihua Zhai; Zhiyong Liu; Sharon Samuel; Nemil Shah; Emily E. Helman; Joseph A. Knowles; Cecil R. Stockard; Naomi S. Fineberg; William E. Grizzle; Tong Zhou; Kurt R. Zinn; Eben L. Rosenthal
• Keywords: Mice, Inbred BALB C; Drug Evaluation, Preclinical; Radioimmunoassay; Mice, SCID; Xenograft Model Antitumor Assays; Matrix Metalloproteinases; Antibodies, Anti-Idiotypic; Extracellular Matrix; Tumor Burden; 3. Good health; Pancreatic Neoplasms; Antibodies, Monoclonal, Murine-Derived; Mice; 03 medical and health sciences; Ki-67 Antigen; 0302 clinical medicine; Cell Line, Tumor; Gene Knockdown Techniques; Basigin; Animals; Humans; Female; Molecular Targeted Therapy

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.