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Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo

Cancer Gene Therapy volume 8, pages 869–878 (2001)Cite this article

Abstract

Pancreatic carcinomas overexpress several matrix metalloproteinases (MMPs), in particular MMP2 and MMP9. These enzymes are involved in the degradation of the extracellular matrix to aid tumor cell invasion. The aim of this study was to investigate the effect of TIMP gene therapy on human pancreatic cancer. Human TIMP1 or TIMP2 has been introduced in pancreatic tumor cells under the control of a constitutive promoter using adenoviral vectors, and the effect on tumor invasion observed. It has been demonstrated in vitro that the TIMP-expressing pancreatic tumor cells were significantly less invasive than those cells transfected with a control vector. In vivo , adenoviral delivery of TIMP1 or TIMP2 to nude mice harboring intraperitoneal human pancreatic cancers resulted in prolonged survival compared with control mice if the gene therapy was given early ( P <.009 and P <.0293, respectively). The in vivo experiments demonstrated evidence of gene transfer by adenoviral vectors to tumor cells and murine mesenteric cells. There was no evidence of transgene expression in distant organs. These experiments have proved the hypothesis that TIMP overexpression in pancreatic cancer cells can modify the invasive phenotype. Also, TIMP gene transfer to human tumor cells is possible both in vitro and in vivo. Cancer Gene Therapy (2001) 8, 869–878

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References

  1. Monitor Population and Health, Office for National Statistics, UK . 1998

  2. Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr . Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis FASEB J 1993 7: 1434–1441

    Article  CAS  PubMed  Google Scholar 

  3. Matrisian L . The matrix-degrading metalloproteinases Bioessays 1992 14: 455–463

    Article  CAS  PubMed  Google Scholar 

  4. Senger D . Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines Am J Pathol 1996 149: 1–7

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Murphy G, Docherty AJP . The matrix metalloproteinases and their inhibitors Am J Respir Cell Mol Biol 1992 7: 120–125

    Article  CAS  PubMed  Google Scholar 

  6. Docherty AJP, Lyons A, Smith BJ, et al . Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity Nature 1985 318: 66–69

    Article  CAS  PubMed  Google Scholar 

  7. Stetler-Stevenson WG, Krutzsch H, Liotta LA . Tissue inhibitor of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family J Biol Chem 1989 264: 17374–17378

    CAS  PubMed  Google Scholar 

  8. Uria JA, Ferrando AA, Velasco G, Freije JMP, Lopez-Otin C . Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family Cancer Res 1994 54: 2091–2094

    CAS  PubMed  Google Scholar 

  9. Leco KJ, Apta SS, Taniguchi GT, et al . Murine tissue inhibitor of metalloproteinases 4 (TIMP-4): cDNA isolation and expression in adult mouse tissues FEBS Lett 1997 401: 213–217

    Article  CAS  PubMed  Google Scholar 

  10. Gress TM, Muller-Pillasch F, Lerch MM, Friess H, Buchler M, Adler G . Expression and in situ localization of genes encoding for extracellular matrix degrading proteases in pancreatic cancer Int J Cancer 1995 62: 407–413

    Article  CAS  PubMed  Google Scholar 

  11. Satoh K, Ohtani H, Shimosegawa T, Koizumi M, Sawai T, Toyota T . Infrequent stromal expression of gelatinase A and intact basement membrane in intraductal neoplasms of the pancreas Gastroenterology 1994 107: 1488–1495

    Article  CAS  PubMed  Google Scholar 

  12. Bramhall SR, Neoptolomemos J, Stamp GWH, Lemoine NR . Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma J Pathol 1997 182: 347–355

    Article  CAS  PubMed  Google Scholar 

  13. Schultz RM, Silberman S, Persky B, Bajkowski AS, Carmichael DF . Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells Cancer Res 1988 48: 5539–5545

    CAS  PubMed  Google Scholar 

  14. Alvarez OA, Carmichael DF, DeClerck YA . Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases J Natl Cancer Inst 1990 82: 589–595

    Article  CAS  PubMed  Google Scholar 

  15. DeClerck YA, Yean T-D, Chan D, Shimada H, Langley KE . Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor Cancer Res 1991 51: 2151–2157

    CAS  PubMed  Google Scholar 

  16. Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler-Stevenson WG . Tumor cell invasion inhibited by TIMP-2 J Natl Cancer Inst 1991 83: 775–779

    Article  CAS  PubMed  Google Scholar 

  17. DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM . Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases Cancer Res 1992 52: 701–708

    CAS  PubMed  Google Scholar 

  18. Khokha R . Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinase-1 J Natl Cancer Inst 1994 86: 299–304

    Article  CAS  PubMed  Google Scholar 

  19. Montgomery AMP, Mueller BM, Riesfeld RA, Taylor SM, DeClerck YA . Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line Cancer Res 1994 54: 5467–5473

    CAS  PubMed  Google Scholar 

  20. Imren S, Kohn DB, Shimada H, Blavier L, DeClerck YA . Overexpression of tissue inhibitor of metalloproteinases-2 by retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion Cancer Res 1996 56: 2891–2895

    CAS  PubMed  Google Scholar 

  21. Koop S, Khokha R, Schmidt EE, et al . Overexpression of metalloproteinase inhibitor in B16F10 cels does not affect extravasation but reduces tumor growth Cancer Res 1994 54: 4791–4797

    CAS  PubMed  Google Scholar 

  22. Ahonen M, Baker AH, Kahari V-M . Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells Cancer Res 1998 58: 2310–2315

    CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Albini A, Fontanini G, Masiello L, et al . Angiogenic potential in vivo by Kaposi's sarcoma cell-free supernatants and HIV-1 tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2 AIDS 1994 8: 1237–1244

    Article  CAS  PubMed  Google Scholar 

  25. Anand-Apte B, Pepper MS, Voest E, et al . Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3 Invest Ophthalmol Vis Sci 1997 38: 817–823

    CAS  PubMed  Google Scholar 

  26. Johnson MD, Kim HR, Chesler L, Tsao Wu G, Bouck N, Polverini PJ . Inhibition of angiogenesis by tissue inhibitor of metalloproteinase J Cell Physiol 1994 160: 194–202

    Article  CAS  PubMed  Google Scholar 

  27. Murphy AN, Unsworth EJ, Stetler-Stevenson WG . Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation J Cell Physiol 1993 157: 351–358

    Article  CAS  PubMed  Google Scholar 

  28. Takigawa M, Nishida Y, Suzuki F, Kishi J, Yamashita K, Hayakawa T . Induction of angiogenesis in chick yolk sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2) Biochem Biophys Res Commun 1990 171: 1264–1271

    Article  CAS  PubMed  Google Scholar 

  29. Gerald R, Meidel RS . Adenoviral vectors In: Glover DM, Hames BD, eds. DNA Cloning 4. A Practical Approach Oxford: Oxford Univ. Press 1996 285–305

  30. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy J Virol 1996 70: 7498–7509

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Freeman SM, Abboud CN, Whartenby KA, et al . The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res 1993 53: 5274–5283

    CAS  PubMed  Google Scholar 

  32. George SJ, Baker AH, Angelini GD, Newby AC . Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointimal formation in human saphenous veins Gene Ther 1998 5: 1552–1560

    Article  CAS  PubMed  Google Scholar 

  33. George SJ, Lloyd CT, Angelini GD, Newby AC, Baker AH . Inhibition of late vein graft neointimal formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3 Circulation 2000 101: 296–304

    Article  CAS  PubMed  Google Scholar 

  34. Guedez L, Stetler-Stevenson WG, Wolff L, et al . In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1 J Clin Invest 1998 102: 2002–2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang L, Hwang R, Pandit L, Gordon EM, French Anderson W, Parekh D . Gene therapy of metastatic pancreas cancer with intraperitoneal injections of concentrated retroviral herpes simplex thymidine kinase vector supernatant and ganciclovir Ann Surg 1996 224: 405–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aoki K, Yoshida T, Sugimura T, Terada M . Liposome-mediated in vivo gene transfer of antisense K- ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity Cancer Res 1995 55: 3810–3816

    CAS  PubMed  Google Scholar 

  37. Aoki K, Yoshida T, Matsumoto N, et al . Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated transfer of herpes simplex thymidine kinase gene Hum Gene Ther 1997 8: 1105–1113

    Article  CAS  PubMed  Google Scholar 

  38. Rosenfeld ME, Vickers SM, Raben D, et al . Pancreatic carcinoma cell killing via adenoviral mediated delivery of the herpes simplex virus thymidine kinase gene Ann Surg 1997 225: 609–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Anderson IC, Shipp MA, Docherty AJP, Teicher BA . Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine lewis lung carcinoma Cancer Res 1996 56: 715–718

    CAS  PubMed  Google Scholar 

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Acknowledgements

Anne Rigg was supported by the Mike Stone Cancer Research Fund. The authors thank Gillian Murphy for her guidance, and Bruce Roberts and Rhonda Doll at Genzyme for donation of the adenoviral vector system and advice on its usage.

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  1. Imperial Cancer Research Fund Molecular Oncology Unit, Imperial College School of Medicine, London, W12 0NN, UK

    Anne S Rigg & Nicholas R Lemoine

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  1. Anne S Rigg
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Correspondence to Nicholas R Lemoine.

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Rigg, A., Lemoine, N. Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo. Cancer Gene Ther 8, 869–878 (2001). https://doi.org/10.1038/sj.cgt.7700387

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