The supporting role of
proteases in
tumor progression and invasion is well known; however, the use of
proteases as therapeutic agents has also been demonstrated. In this article, the authors report on the differential effects of exogenous
serine proteases on the motility of
tumor and normal cells. The treatment of normal and
tumor cells with a single dose of pancreatic
serine proteases,
trypsin (TR) and
chymotrypsin (CH), leads to a concentration-dependent response by cells, first accelerating and then slowing mobility.
Tumor cells are 10 to 20 times more sensitive to exogenous TR/CH, suggesting that a single dose of
proteases may cause discordant movements of normal and
tumor cells within the
tumor environment. The inhibitory effects of TR on cell motility are contradicted by
thrombin (TH), particularly in the regulation of normal cells' migration. The purpose of this investigation was to ascertain the role of
protease-activated receptors (PARs) in terms of normal and
tumor cell motility. Duplicate treatments with
proteases resulted in diminished mobility of both normal and
tumor cells. Repeated application of TR and TH in 1-hour treatment intervals initially desensitizes cell surface PARs. However, cell surface PARs reappear regardless of subsequent
protease treatments in both normal and
tumor cells. The resensitization process is retarded in
tumor cells when compared with normal cells. This is evidenced by lower expression of PARs as well as by their relocalization at the
tumor cell surfaces. Under these conditions, normal cells remain responsive to exogenous
proteases in terms of cell motility. Exogenous
proteases do not modulate motility of repeatedly stimulated
tumor cells, and consequently, the migration of
tumor cells appears disconnected from the PAR signaling pathways. The use of activating
peptides in lieu of the cognate
proteases for a given PAR system indicated that
proteases may act through additional targets not regulated by PAR signaling. We hypothesize that the divergent migration patterns of normal and
tumor cells due to exposure to
proteases is in part mediated by PARs. Thus, treatment with exogenous
proteases may cause rearrangement of the
tumor and stromal cells within the tumor microenvironment. Such topographical effects may lead to the inhibition of
tumor progression and
metastasis development.