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Enhanced activity of meprin-α, a pro-migratory and pro-angiogenic protease, in colorectal cancer
Daniel Lottaz1, Christoph A Maurer, Agnès Noël
1Department of Rheumatology, Clinical Immunology and Allergology, Inselspital, University Hospital of Bern, Bern, Switzerland. daniel.lottaz@insel.ch
Abstract:
Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is not known. We investigated the effect of this protease on cell migration and angiogenesis in vitro and studied the expression of meprin-α mRNA, protein and proteolytic activity in primary tumors at progressive stages and in liver metastases of patients with colorectal cancer, as well as inhibitory activity towards meprin-α in sera of cancer patient as compared to healthy controls. We found that the hepatocyte growth factor (HGF)-induced migratory response of meprin-transfected epithelial cells was increased compared to wild-type cells in the presence of plasminogen, and that the angiogenic response in organ-cultured rat aortic explants was enhanced in the presence of exogenous human meprin-α. In patients, meprin-α mRNA was expressed in colonic adenomas, primary tumors UICC (International Union Against Cancer) stage I, II, III and IV, as well as in liver metastases. In contrast, the corresponding protein accumulated only in primary tumors and liver metastases, but not in adenomas. However, liver metastases lacked meprin-α activity despite increased expression of the corresponding protein, which correlated with inefficient zymogen activation. Sera from cancer patients exhibited reduced meprin-α inhibition compared to healthy controls. In conclusion, meprin-α activity is regulated differently in primary tumors and metastases, leading to high proteolytic activity in primary tumors and low activity in liver metastases. By virtue of its pro-migratory and pro-angiogenic activity, meprin-α may promote tumor progression in colorectal cancer.
Insights
Meprin-alpha, a metalloprotease, promotes colorectal cancer progression by enhancing cell migration and angiogenesis. Its activity is high in primary tumors but low in liver metastases, suggesting differential regulation during cancer spread.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Meprin-alpha (a metalloprotease) is overexpressed in colorectal cancer cells.
- Its role in tumor progression, particularly cell migration and angiogenesis, is largely unknown.
Purpose of the Study:
- To investigate the impact of meprin-alpha on colorectal cancer cell migration and angiogenesis.
- To analyze meprin-alpha expression, activity, and regulation in colorectal tumors and metastases.
- To assess meprin-alpha inhibitory activity in cancer patient sera.
Main Methods:
- In vitro cell migration assays using meprin-alpha-transfected epithelial cells and hepatocyte growth factor (HGF).
- In vitro angiogenesis assays using organ-cultured rat aortic explants.
- Quantitative analysis of meprin-alpha mRNA, protein, and proteolytic activity in patient-derived tumor samples (adenomas, primary tumors, liver metastases).
- Measurement of meprin-alpha inhibitory activity in sera from colorectal cancer patients and healthy controls.
Main Results:
- Meprin-alpha enhanced HGF-induced cell migration in the presence of plasminogen.
- Exogenous meprin-alpha promoted angiogenesis in rat aortic explants.
- Meprin-alpha mRNA was detected in all tumor stages, but protein accumulated in primary tumors and liver metastases.
- Liver metastases showed low meprin-alpha activity despite protein presence, linked to inefficient zymogen activation.
- Cancer patient sera exhibited reduced meprin-alpha inhibition compared to healthy controls.
Conclusions:
- Meprin-alpha possesses pro-migratory and pro-angiogenic properties, potentially driving colorectal cancer progression.
- Meprin-alpha activity is differentially regulated between primary tumors and liver metastases, with reduced activity in metastases.
- These findings highlight meprin-alpha as a potential therapeutic target in colorectal cancer.
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