Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development

Cancer Gene Therapy volume 19, pages 126–134 (2012)Cite this article

Abstract

Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Center MM, Jemal A, Ward E . International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2009; 18: 1688–1694.

    Article  PubMed  Google Scholar 

  2. Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol 2008; 9: 730–756.

    Article  PubMed  Google Scholar 

  3. Alemany R . Cancer selective adenoviruses. Mol Aspects Med 2007; 28: 42–58.

    Article  CAS  PubMed  Google Scholar 

  4. Zwacka RM, Dunlop MG . Gene therapy for colon cancer. Hematol Oncol Clin North Am 1998; 12: 595–615.

    Article  CAS  PubMed  Google Scholar 

  5. Ganly I, Kirn D, Eckhardt G, Rodriguez GI, Soutar DS, Otto R et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 2000; 6: 798–806.

    CAS  PubMed  Google Scholar 

  6. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002; 62: 6070–6079.

    CAS  PubMed  Google Scholar 

  7. Sauthoff H, Hu J, Maca C, Goldman M, Heitner S, Yee H et al. Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points. Hum Gene Ther 2003; 14: 425–433.

    Article  CAS  PubMed  Google Scholar 

  8. Young JS, Lumsden CE, Stalker AL . The significance of the tissue pressure of normal testicular and of neoplastic (Brown–Pearce carcinoma) tissue in the rabbit. J Pathol Bacteriol 1950; 62: 313–333.

    Article  CAS  PubMed  Google Scholar 

  9. Jain RK . Transport of molecules across tumor vasculature. Cancer Metastasis Rev 1987; 6: 559–593.

    Article  CAS  PubMed  Google Scholar 

  10. Jain RK . Transport of molecules in the tumor interstitium: a review. Cancer Res 1987; 47: 3039–3051.

    CAS  PubMed  Google Scholar 

  11. Less JR, Posner MC, Boucher Y, Borochovitz D, Wolmark N, Jain RK . Interstitial hypertension in human breast and colorectal tumors. Cancer Res 1992; 52: 6371–6374.

    CAS  PubMed  Google Scholar 

  12. Heldin CH, Rubin K, Pietras K, Ostman A . High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 2004; 4: 806–813.

    Article  CAS  PubMed  Google Scholar 

  13. Beyer I, Li Z, Persson J, Liu Y, van Rensburg R, Yumul R et al. Controlled extracellular matrix degradation in breast cancer tumors improves therapy by trastuzumab. Mol Ther 2011; 19: 479–489.

    Article  CAS  PubMed  Google Scholar 

  14. Zucker S, Vacirca J . Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 2004; 23: 101–117.

    Article  CAS  PubMed  Google Scholar 

  15. Gronski Jr TJ, Martin RL, Kobayashi DK, Walsh BC, Holman MC, Huber M et al. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J Biol Chem 1997; 272: 12189–12194.

    Article  CAS  PubMed  Google Scholar 

  16. Moses MA . The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 1997; 15: 180–189.

    Article  CAS  PubMed  Google Scholar 

  17. Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK et al. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 1998; 161: 6845–6852.

    CAS  PubMed  Google Scholar 

  18. Gorrin-Rivas MJ, Arii S, Furutani M, Mizumoto M, Mori A, Hanaki K 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.

    CAS  PubMed  Google Scholar 

  19. Gorrin-Rivas MJ, Arii S, Mori A, Kaneda Y, Imamura M . Mouse macrophage metalloelastase gene delivery by HVJ-cationic liposomes in experimental antiangiogenic gene therapy for murine CT-26 colon cancer. Int J Cancer 2001; 93: 731–735.

    Article  CAS  PubMed  Google Scholar 

  20. Kerkela E, Ala-aho R, Klemi P, Grenman S, Shapiro SD, Kahari VM et al. Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome. J Pathol 2002; 198: 258–269.

    Article  CAS  PubMed  Google Scholar 

  21. Yang W, Arii S, Gorrin-Rivas MJ, Mori A, Onodera H, Imamura M . Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer 2001; 91: 1277–1283.

    Article  CAS  PubMed  Google Scholar 

  22. Lavilla-Alonso S, Bauerschmitz G, Abo-Ramadan U, Halavaara J, Escutenaire S, Diaconu I et al. Adenoviruses with an alphavbeta integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases. J Transl Med 2010; 8: 80.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nar H, Werle K, Bauer MM, Dollinger H, Jung B . Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor. J Mol Biol 2001; 312: 743–751.

    Article  CAS  PubMed  Google Scholar 

  24. Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, Dmitriev I et al. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 2002; 62: 1266–1270.

    CAS  PubMed  Google Scholar 

  25. Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 1998; 72: 9706–9713.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Euhus DM, Hudd C, LaRegina MC, Johnson FE . Tumor measurement in the nude mouse. J Surg Oncol 1986; 31: 229–234.

    Article  CAS  PubMed  Google Scholar 

  27. Tomayko MM, Reynolds CP . Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 1989; 24: 148–154.

    Article  CAS  PubMed  Google Scholar 

  28. Yu HK, Kim JS, Lee HJ, Ahn JH, Lee SK, Hong SW et al. Suppression of colorectal cancer liver metastasis and extension of survival by expression of apolipoprotein(a) kringles. Cancer Res 2004; 64: 7092–7098.

    Article  CAS  PubMed  Google Scholar 

  29. Ganesh S, Gonzalez Edick M, Idamakanti N, Abramova M, Vanroey M, Robinson M et al. Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res 2007; 67: 4399–4407.

    Article  CAS  PubMed  Google Scholar 

  30. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993; 4: 197–250.

    Article  CAS  PubMed  Google Scholar 

  31. Kahari VM, Saarialho-Kere U . Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 1999; 31: 34–45.

    Article  CAS  PubMed  Google Scholar 

  32. Eikenes L, Tari M, Tufto I, Bruland OS, de Lange Davies C . Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 2005; 93: 81–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bieth JG . Elastases: Catalytic and biological properties. In: Mecham RP (ed.) Regulation of Matrix Accumulation. Academic Press: New York, 1986, pp 217–320.

    Google Scholar 

  34. Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO . Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 2006; 98: 1482–1493.

    Article  CAS  PubMed  Google Scholar 

  35. Ganesh S, Gonzalez-Edick M, Gibbons D, Van Roey M, Jooss K . Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models. Clin Cancer Res 2008; 14: 3933–3941.

    Article  CAS  PubMed  Google Scholar 

  36. Silvertown JD, Geddes BJ, Summerlee AJ . Adenovirus-mediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells. Endocrinology 2003; 144: 3683–3691.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M et al. Angiostatin. A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–328.

    Article  PubMed  Google Scholar 

  39. Bergers G, Benjamin LE . Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401–410.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Dennis R Stewart (Principal Scientist; Corthera Inc.) for providing relaxin for this study. AH is K Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute. This paper was supported by the European Research Council, EU FP6 APOTHERAPY and THERADPOX, the ASCO Foundation, HUCH Research Funds (EVO), the Sigrid Juselius Foundation, Academy of Finland, Biocentrum Helsinki, Biocenter Finland, University of Helsinki. AH is founder and shareholder in Oncos Therapeutics Ltd.

Author information

Author notes

  1. A Hemminki and S Pesonen: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland

    S Lavilla-Alonso, S Escutenaire, L Ahtiainen, A Hemminki & S Pesonen

  2. Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland

    S Lavilla-Alonso & K Saksela

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    M M T Bauer

  4. Department of Neurology, Experimental MRI Laboratory, Helsinki University Central Hospital, Helsinki, Finland

    U Abo-Ramadan & T Tatlisumak

  5. Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Helsinki, Finland

    A Ristimäki

  6. Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    A Ristimäki

  7. Department of Radiology, Helsinki University Central Hospital and Jorvi Hospital, Helsinki, Finland

    J Halavaara

  8. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    R A Desmond

  9. Biostatistics and Bioinformatics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    D Wang

  10. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    T Tatlisumak

Authors
  1. S Lavilla-Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M M T Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U Abo-Ramadan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Ristimäki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Halavaara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R A Desmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Escutenaire
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Ahtiainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K Saksela
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T Tatlisumak
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Hemminki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Pesonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A Hemminki or S Pesonen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lavilla-Alonso, S., Bauer, M., Abo-Ramadan, U. et al. Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development. Cancer Gene Ther 19, 126–134 (2012). https://doi.org/10.1038/cgt.2011.76

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2011.76

Keywords

This article is cited by

Search

Advanced search

Quick links