Abstract
Background and Aim
Previous studies have shown that overexpression of macrophage metalloelastase (MME) suppresses tumor growth in mice. The purpose of this study was to investigate the effects of MME on basic fibroblast growth factor (bFGF) expression and tumor angiogenesis in murine colon cancer.
Methods
Murine CT-26 colon cancer cells stably transfected with MME were inoculated subcutaneously. Reverse-transcriptase polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemistry were used to explore the bFGF mRNA and protein expression. Immunohistochemical staining of CD34 was used to measure the microvessel density (MVD).
Results
bFGF mRNA levels in tumor tissues of CT-26-EGFP and nontransfected cells were respectively 2.7-fold (0.56 ± 0.063 vs. 0.21 ± 0.042) and 2.5-fold (0.53 ± 0.066 vs. 0.21 ± 0.042) higher than that in tumors of CT-26-EGFP-MME cells (p < 0.01). bFGF protein levels exhibited a similar trend. Tumors of CT-26-EGFP-MME cells demonstrated a lower microvessel density (9.35 ± 2.79) than control tumors of CT-26-EGFP cells (22.85 ± 3.80) and nontransfected cells (23.45 ± 4.49) (p < 0.001).
Conclusions
We found that expression of MME inversely correlates with the expression of bFGF and tumor angiogenesis in a model of murine colon cancer. These data indicate that manipulation of MME expression could be a novel modality approach to colon cancer therapy.
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References
DeClerck YA, Mercurio AM, Stack MS, et al. Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol. 2004;164:1131–1139.
Burg-Roderfeld M, Roderfeld M, Wagner S, et al. MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cells. Int J Oncol. 2007;30:985–992.
Werb Z, Gordon S. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med. 1975;142:361–377.
Fu JY, Lyga A, Shi H, Blue ML, Dixon B, Chen D. Cloning, expression, purification, and characterization of rat MME. Protein Expr Purif. 2001;21:268–274.
Zhang H, Li Y, Xu G. Human macrophage metalloelastase expression in gastric cancer and its relationship with gastric cancer prognosis. J Exp Clin Cancer Res. 2007;26:361–366.
Toshimichi A, Mitsuhiro T, Shaoqiang CH, et al. Prognostic values of matrix metalloproteinase family expression in human colorectal carcinoma. J Surg Res. 2008;146:32–42.
Dong Z, Kumar R, Yang X, Fidler IJ. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell. 1997;88:801–810.
Cornelius LA, Nehring LC, Harding E, et al. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol. 1998;161:6845–6852.
Dong Z, Yoneda J, Kumar R, Fidler IJ, et al. Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony-stimulating factor. J Exp Med. 1998;188:755–763.
Xu ZW, Shi H, Li Q, et al. Mouse macrophage metalloelastase generates angiostatin from plasminogen and suppresses tumor angiogenesis in murine colon cancer. Oncol Rep. 2008;20:81–88.
O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315–328.
Vlodavsky I, Fuks Z, Ishai-Michaeli R, et al. Extracellular matrix-resident basic fibroblast growth factor: implication for the control of angiogenesis. J Cell Biochem. 1991;45:167–176.
Mader JS, Smyth D, Marshall J, Hoskin DW. Bovine lactoferricin inhibits basic fibroblast growth factor-and vascular endothelial growth factor165-induced angiogenesis by competing for heparin-like binding sites on endothelial cells. Am J Pathol. 2006;169:1753–1766.
Ribatti D. The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review. Br J Haematol. 2005;128:303–309.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408.
Dong Y, Wang J, Sheng Z, et al. Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol. 2009;22:151–160.
Shi H, Xu JM, Hu NZ, Xie HJ. Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol. 2003;9:1421–1426.
Kirsch M, Schackert G, Black PM. Metastasis and angiogenesis. Cancer Treat Res. 2004;117:285–304.
Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185–188.
Yonemura Y, Endo Y, Fujita H, et al. Inhibition of peritoneal dissemination in human gastric cancer by MMP-7-specific antisense oligonucleotide. J Exp Clin Cancer Res. 2001;20:205–212.
Gorrin-Rivas MJ, Arii S, Furutani M, et al. Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: correlation with angiostatin generation and its clinical significance. Hepatology. 1998;28:986–993.
Peng Ch, Fo HJ, Li MZ, et al. Human macrophage metalloelastase correlates with angiogenesis and prognosis of gastric carcinoma. Dig Dis Sci. 2010;55:3138–3146.
Gorrin-Rivas MJ, Arii S, Mori A, et al. Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma. Ann Surg. 2000;23:67–73.
Yang W, Arii S, Gorrin-Rivas MJ, Mori A. Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer. 2001;91:1277–1283.
Kassam G, Kwon M, Yoon CS, et al. Purification and characterization of A61. An angiostatin-like plasminogen fragment produced by plasmin autodigestion in the absence of sulfhydryl donors. J Biol Chem. 2001;276:8924–8933.
Kwon M, Yoon CS, Fitzpatrick S, et al. p22 is a novel plasminogen fragment with antiangiogenic activity. Biochemistry. 2001;40:13246–13253.
Gorrin-Rivas MJ, Arii S, Furutan M, et al. Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis. Clin Cancer Res. 2000;6:1647–1654.
Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264:569–571.
Sepp NT, Li LJ, Lee KH, et al. Basic fibroblast growth factor increases expression of avb3 integrin complex on human microvascular endothelial cells. J Invest Dermatol. 1994;103:295–299.
Balbín M, Pendás AM, Uría JA, Jiménez MG, Freije JP, López-Otín C. Expression and regulation of collagenase-3 (MMP-13) in human malignant tumors. APMIS. 1999;107:45–53.
Houghton AM, Grisolano JL, Baumann ML, et al. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases. Cancer Res. 2006;66:6149–6155.
Tozer GM. Measuring tumour vascular response to antivascular and antiangiogenic drugs. Br J Radiol. 2003;76:23–35.
Acknowledgments
This work was supported by the Natural Science and Technology Foundation of Anhui Province (01043904) and the Natural Science Foundation of Education Department of Anhui Province (2003 KG199). We sincerely thank The Key Laboratory of Gene Resource Utilization for Genetic Ministry of Education and Anhui Province and especially M. Haiping Wang, Qi Li, and Lijie Feng.
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Xu, Z., Shi, H., Mei, Q. et al. Effects of Macrophage Metalloelastase on the Basic Fibroblast Growth Factor Expression and Tumor Angiogenesis in Murine Colon Cancer. Dig Dis Sci 57, 85–91 (2012). https://doi.org/10.1007/s10620-011-1838-0
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DOI: https://doi.org/10.1007/s10620-011-1838-0