Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinases-1 in the liver: efficient protection against T-cell lymphoma and colon carcinoma metastasis

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Item Type:	Article
Title:	Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinases-1 in the liver: efficient protection against T-cell lymphoma and colon carcinoma metastasis
Creators Name:	Elezkurtaj, S., Kopitz, C., Baker, A.H., Perez-Canto, A., Arlt, M.J., Khokha, R., Gansbacher, B., Anton, M., Brand, K. and Krueger, A.
Abstract:	Background: Matrix metalloproteinases (MMPs) are critical for metastasis of tumor cells. Tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural MMP inhibitor, was shown to reduce metastasis in different models. Here, we investigated whether increased TIMP-1 levels in the liver achieved by adenoviral gene transfer will effectively inhibit liver metastasis of two independent tumor cell lines. Method: TIMP-1 was transferred with adenoviral vectors into the livers of DBA/2 and Balb/c mice, which were subsequently challenged by hematogenous experimental metastases of the T-cell lymphoma cell line L-CI.5s or the colorectal carcinoma cell line CT-26, respectively. Results: MMP-9 expression in the liver was induced upon metastasis in both tumor types. Adenoviral gene transfer led to high transduction efficacy as indicated by lacZ expression in 60% of hepatocytes. TIMP-1, a key inhibitor of MMP-9, was expressed at 105-fold higher levels by adenoviral gene transfer as compared with levels achieved in TIMP-1 transgenic mice, previously shown to be inefficient to reduce T-cell lymphoma metastasis. High local and systemic (serum) levels of TIMP-1 led to substantial (94%) reduction of T-cell lymphoma and colorectal carcinoma (73%) experimental liver metastasis. Conclusions: Adenoviral gene transfer led to systemic and local TIMP-1 levels sufficient to inhibit metastasis of a highly aggressive T-cell lymphoma, pointing at the requirement of threshold levels for effective anti-metastatic efficacy. This approach was also efficient in a colon carcinoma solid tumor model. We propose that viral gene transfer of TIMP-1 can provide a suitable defense strategy to prevent metastatic spread to the liver.
Keywords:	Gene Therapy, TIMP-1, Liver Metastases, Impregnation, Adenovirus, MMP-9, Animals, Mice
Source:	Journal of Gene Medicine
ISSN:	1099-498X
Publisher:	John Wiley & Sons Ltd
Volume:	6
Number:	11
Page Range:	1228-1237
Date:	23 September 2004
Official Publication:	https://doi.org/10.1002/jgm.637
PubMed:	View item in PubMed

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