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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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. Copyright © 2004 John Wiley & Sons, Ltd.
Funding Information
  • Deutsche Forschungsgemeinschaft Sonderforschungsbereich SFB-469
  • Project B13
  • European Union Framework Programme 6 (LSHC-CT-2003-503297)

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