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Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.

ABSTRACT: Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a(+/+) fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer.

SUBMITTER: Foley CJ

PROVIDER: S-EPMC4221191 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.

Foley C J CJ Fanjul-Fernández M M Bohm A A Nguyen N N Agarwal A A Austin K K Koukos G G Covic L L López-Otín C C Kuliopulos A A

Oncogene 20130527 17

Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient m ...[more]

PMID: 23708660

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Project description:BackgroundIncreased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions.ResultsIn an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME), inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE) cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE) cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P < 0.01).Conclusions6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.

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Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.

Publications

Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.

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