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Updated: Oct 9, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice
H Li1, F Lindenmeyer, C Grenet
1DIFEMA, Faculté de Médecine et de Pharmacie de Rouen, 76000 Rouen, France.
Abstract:
TIMP-2 is a natural matrix metalloproteinase (MMP) inhibitor that prevents the degradation of extracellular matrix proteins. It abolishes the hydrolytic activity of all activated members of the metalloproteinase family and in particular that of MT1-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis. Since MMPs have been implicated in both cancer progression and angiogenesis, we generated a recombinant adenovirus to deliver human TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 inhibited the invasion of both tumor and endothelial cells without affecting cell proliferation. Its in vivo efficiency has been evaluated in murine lung cancer LLC, and colon cancer C51 in syngeneic mice as well as in human breast cancer MDA-MB231 in athymic mice. Preinfection of tumor cells by AdTIMP-2 resulted in an inhibition of tumor establishment in more than 50% of mice in LLC and C51 models and in 100% mice in the MDA-MB231 model. A single local injection of AdTIMP-2 into preestablished tumors of these three types significantly reduced tumor growth rates by 60--80% and tumor-associated angiogenesis index by 25--75%. Lung metastasis of LLC tumor was inhibited by >90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged survival in all the cancer models tested. These data demonstrate the potential of adenovirus-mediated TIMP-2 therapy in cancer treatment.
Insights
This study shows that adenovirus-delivered human TIMP-2 (AdTIMP-2) effectively inhibits tumor growth, angiogenesis, and metastasis in multiple cancer models. AdTIMP-2 therapy significantly prolongs survival, demonstrating its potential for cancer treatment.
Area of Science:
- Oncology
- Gene Therapy
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in cancer progression and angiogenesis.
- Tissue inhibitor of metalloproteinases-2 (TIMP-2) is a natural inhibitor of MMPs, including those involved in collagenolysis.
- Overexpression of MMPs contributes to tumor growth, invasion, and metastasis.
Purpose of the Study:
- To evaluate the anticancer efficiency of a recombinant adenovirus carrying human TIMP-2 (AdTIMP-2).
- To assess the therapeutic potential of AdTIMP-2 in inhibiting tumor progression and angiogenesis.
- To determine the impact of AdTIMP-2 on tumor establishment, growth, metastasis, and survival in preclinical cancer models.
Main Methods:
- Generated a recombinant adenovirus for delivering human TIMP-2 (AdTIMP-2).
- Evaluated in vitro effects of TIMP-2 overexpression on tumor and endothelial cell invasion.
- Assessed in vivo anticancer efficacy in murine lung (LLC) and colon (C51) cancer models, and human breast cancer (MDA-MB231) xenografts.
- Administered AdTIMP-2 via preinfection of tumor cells or local injection into established tumors.
Main Results:
- In vitro, TIMP-2 overexpression inhibited invasion without affecting cell proliferation.
- Preinfection with AdTIMP-2 inhibited tumor establishment in >50% of LLC and C51 models, and 100% of MDA-MB231 models.
- Local AdTIMP-2 injection reduced tumor growth rates by 60-80% and angiogenesis by 25-75%.
- Lung metastasis was inhibited by >90%, and survival was significantly prolonged across all models.
Conclusions:
- Adenovirus-mediated delivery of TIMP-2 (AdTIMP-2) demonstrates potent anticancer activity.
- AdTIMP-2 effectively suppresses tumor growth, angiogenesis, invasion, and metastasis.
- TIMP-2 gene therapy holds significant promise for improving cancer treatment outcomes.
