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.