Tissue Inhibitor of Metalloproteinase-3 Expression from an Oncolytic Adenovirus Inhibits Matrix Metalloproteinase Activity In vivo without Affecting Antitumor Efficacy in Malignant Glioma
Open accessAbstract
Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To assess the effects of TIMP-3 gene transfer to glioma cells, a replication-defective adenovirus encoding TIMP-3 (Ad.TIMP-3) was employed. Ad.TIMP-3 infection of a panel of glioma cell cultures decreased the proliferative capacity of these cells and induced morphologic changes characteristic for apoptosis. Next, a conditionally replicating adenovirus encoding TIMP-3 was constructed by inserting the TIMP-3 expression cassette into the E3 region of the adenoviral backbone containing a 24-bp deletion in E1A. This novel oncolytic adenovirus, AdΔ24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdΔ24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdΔ24TIMP-3 was shown in s.c. glioma xenografts. The functional activity of TIMP-3 was imaged noninvasively using a near-IR fluorescent MMP-2–activated probe. Tumoral MMP-2 activity was significantly reduced by 58% in the AdΔ24TIMP-3–treated tumors 24 hours after infection. A study into the therapeutic effects of combined oncolytic and antiproteolytic therapy was done in both a s.c. and an intracranial model for malignant glioma. Treatment of s.c. (U-87MG) or intracranial (U-87δEGFR) tumors with AdΔ24TIMP-3 and AdΔ24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdΔ24 did not significantly affect the antitumor efficacy of this oncolytic agent.
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TIMP3 inhibits MMP activity and tumor growth in malignant gliomas in vivo.
“It has been demonstrated to inhibit MMP activity and tumor growth in malignant gliomas in vivo (31, 32).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [32]
TIMP3 activates caspases and thereby induces apoptosis of human glioma cells in vitro and growth inhibition of human glioma tumors in a mouse model.
“TIMP3 has been demonstrated to activate caspases and therefore induce apoptosis of human glioma cells in vitro and the growth inhibition of human glioma tumors in a mouse model (31, 32).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [32]
The MMPSense 680 probe allows in vivo imaging of key MMPs, including MMP-2 as well as MMP-3, -9, -7, -12, and -13.
“It allows in vivo imaging of key MMPs, including MMP-2 as well as MMP-3, -9, -7, -12, and -13 (4, 32).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [32]
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MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., & Krichevsky, A. M. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00479-08 · Cited by 888 · see citing works
Novel functions of TIMPs in cell signaling
Chirco, R., Liu, X.-W., Jung, K.-K., & Kim, H.-R. C. (2006) · Cancer and Metastasis Reviews · doi:10.1007/s10555-006-7893-x · Cited by 401 · see citing works
Lost in disruption: Role of proteases in glioma invasion and progression
Mentlein, R., Hattermann, K., & Held-Feindt, J. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2011.12.001 · Cited by 85 · see citing works
- Authors
- Lamfers, M. L. M., Gianni, D., Tung, C.-H., Idema, S., Schagen, F. H. E., Carette, J. E., Quax, P. H. A., Van Beusechem, V. W., Vandertop, W. P., Dirven, C. M. F., Chiocca, E. A., & Gerritsen, W. R.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- 3Molecular Neuro-Oncology Laboratories, Neurosurgery Service;
- Harvard University (US)
- 1Department of Neurosurgery;
- Netherlands Organisation for Applied Scientific Research (NL)
- 2Department of Medical Oncology, Division of Gene Therapy, VU University Medical Center, Amsterdam, the Netherlands;
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2005-10-15
- Volume
- 65
- Issue
- 20
- Pages
- 9398-9405
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2122622689
- Cited by
- 52
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 1 · 2014: 4 · 2013: 2 · 2012: 7
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- green
- research.vumc.nl
- Licence
- other-oa
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- TNO Repository (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- TIMP-3, oncolytic adenovirus, high-grade glioma, MMP-2, tumor-selective replication, E1A deletion, E3 region, gene therapy, apoptosis, tumor growth inhibition, intracranial glioma, glioma xenografts
- MeSH terms
- Adenoviridae, Animals, Glioma, Humans, Mice, Nude, Virus Replication, Gene Transfer Techniques, Tissue Inhibitor of Metalloproteinase-3, Matrix Metalloproteinase 2, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Growth Processes, Mice, Matrix Metalloproteinase Inhibitors
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