Abstract
Considerable studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in leukemia dissemination and extramedullary infiltration. Tissue inhibitors of matrix metalloproteinases (TIMPs) are multifunctional proteins with MMPs inhibitory effects. However, little is known about the application of TIMPs in the treatment of leukemia. Here, we investigated the effects of TIMP-3 overexpression via adenoviral gene delivery on the in vitro growth and invasiveness of leukemic cells and the in vivo progress of K562-derived xenografts in nude mice. The in vitro invasiveness of K562 cells was markedly impaired by AdTIMP-3 infection. Moreover, TIMP-3 significantly inhibited K562-derived angiogenic factors-induced proliferation, migration and bFGF-induced tube formation of endothelial cells (ECs) in vitro, and reduced VEGF-induced gelatinases expression and activation in ECs. Although TIMP-3 overexpression had no direct effect on the growth of K562 cells in vitro, repeated intratumoral injection of AdTIMP-3 significantly inhibited the growth of K562 xenografts in nude mice. Furthermore, lower microvessel density, less vessel maturity and increased apoptosis were observed in AdTIMP-3-treated K562 xenografts, suggesting the importance of antiangiogenic action of TIMP-3. These data demonstrated the potential of applying AdTIMP-3 as an effective antiangiogenic adjuvant in the treatment of leukemia progression.
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References
John A, Tuszynski G . The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 2001; 7: 14–23.
Hidalgo M, Eckhardt SG . Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–193.
Brand K . Cancer gene therapy with tissue inhibitors of metalloproteinases (TIMPs). Curr Gene Ther 2002; 2: 255–271.
Freireich EJ . Acute leukemia. A prototype of disseminated cancer. Cancer 1984; 53: 2026–2033.
Sawyers CL, Denny CT, Witte ON . Leukemia and the disruption of normal hematopoiesis. Cell 1991; 64: 337–350.
Guedez L, Lim MS, Stetler-Stevenson WG . The role of metalloproteinases and their inhibitors in hematological disorders. Crit Rev Oncog 1996; 7: 205–225.
Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC . Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 1999; 79: 1347–1355.
Ahonen M, Ala-Aho R, Baker AH, George SJ, Grenman R, Saarialho-Kere U et al. Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. Mol Ther 2002; 5: 705–715.
Spurbeck WW, Ng CY, Strom TS, Vanin EF, Davidoff AM . Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. Blood 2002; 100: 3361–3368.
Tran PL, Vigneron JP, Pericat D, Dubois S, Cazals D, Hervy M et al. Gene therapy for hepatocellular carcinoma using non-viral vectors composed of bis guanidinium-tren-cholesterol and plasmids encoding the tissue inhibitors of metalloproteinases TIMP-2 and TIMP-3. Cancer Gene Ther 2003; 10: 435–444.
Ma DH, Chen JI, Zhang F, Hwang DG, Chen JK . Inhibition of fibroblast-induced angiogenic phenotype of cultured endothelial cells by the overexpression of tissue inhibitor of metalloproteinase (TIMP)-3. J Biomed Sci 2003; 10: 526–534.
Baker AH, Zaltsman AB, George SJ, Newby AC . Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 1998; 101: 1478–1487.
Bond M, Murphy G, Bennett MR, Amour A, Knäuper V, Newby AC et al. Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus: metalloproteinase inhibition is associated with proapoptotic activity. J Biol Chem 2000; 275: 41358–41363.
Amour A, Slocombe PM, Webster A, Butler M, Knight CG, Smith BJ et al. TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998; 435: 39–44.
Wild A, Ramaswamy A, Langer P, Celik I, Fendrich V, Chaloupka B et al. Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors. J Clin Endocrinol Metab 2003; 88: 1367–1373.
Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 2000; 106: 511–521.
Lynch CC, McDonnell S . The role of matrilysin (MMP-7) in leukaemia cell invasion. Clin Exp Metast 2001; 18: 401–406.
Weidner N, Semple JP, Welch WR, Folkman J . Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1–8.
Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M . Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 2001; 61: 2145–2153.
Moses MA . The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 1997; 15: 180–189.
Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240–2245.
Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE et al. Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene 2003; 22: 2121–2134.
Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407–415.
Liuzzo JP, Moscatelli D . Human leukemia cell lines bind basic fibroblast growth factor (FGF) on FGF receptors and heparan sulfates: downmodulation of FGF receptors by phorbol ester. Blood 1996; 87: 245–255.
Nakamura Y, Sato K, Wakimoto N, Kimura F, Okuyama A, Motoyoshi K . A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis. Leukemia 2001; 15: 1217–1224.
Narla RK, Dong Y, Klis D, Uckun FM . Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium (I.V.) as a novel antileukemic agent with matrix metalloproteinase inhibitory activity. Clin Cancer Res 2001; 7: 1094–1101.
Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ . CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 2000; 96: 2917–2924.
Liu P, Wang Y, Li YH, Yang C, Zhou YL, Li B et al. Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice. Leuk Res 2003; 27: 701–708.
Nilsson M, Ljungberg J, Richter J, Kiefer T, Magnusson M, Lieber A et al. Development of an adenoviral vector system with adenovirus serotype 35 tropism; efficient transient gene transfer into primary malignant hematopoietic cells. J Gene Med 2004; 6: 631–641.
Acknowledgements
This work was supported by the grants of National Development Plan of High Technology 863 (2003AA205060) and 973 (001CB5101) projects from the Ministry of Science & Technology of China to Han ZC.
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Yu, X., Yang, C., Liang, L. et al. Inhibition of human leukemia xenograft in nude mice by adenovirus-mediated tissue inhibitor of metalloproteinase-3. Leukemia 20, 1–8 (2006). https://doi.org/10.1038/sj.leu.2404021
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DOI: https://doi.org/10.1038/sj.leu.2404021
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