Matrix metalloproteinases (
MMPs) degrade
extracellular matrix proteins, and there is evidence that they play a role in
tumor cell growth, invasion and
metastasis.
Matrilysin (MMP-7) is over-expressed in
prostate cancer cells and increases
prostate cancer cell invasion. Prostate stromal fibroblasts secrete
a factor(s), including
fibroblast growth factor-1 (FGF-1), which induces
promatrilysin expression in the prostate
carcinoma cell line LNCaP but not in normal prostate epithelial cells (PrECs). Since
FGF-1 is present in the prostate, an altered sensitivity to
FGF-1 might explain the up-regulation of
matrilysin expression in
prostate cancer cells compared to normal prostate epithelium. FGF receptor-1 (FGFR-1) is not normally expressed by normal prostate epithelial cells; however, aberrant expression of this receptor has been reported in
prostate cancer cells, including the LNCaP cell line. We hypothesized that aberrant expression of FGFR-1 in PrECs would render them sensitive to induction of
promatrilysin expression by recombinant
FGF-1. To test this hypothesis, we transiently transfected PrECs with an FGFR-1 expression vector, which resulted in over-expression of FGFR-1
protein in approximately 40% of cells.
FGF-1 increased
promatrilysin expression in FGFR-1-transfected PrECs 4-fold over mock-transfected cells, and this induction was inhibited by a specific FGFR-1 inhibitor,
SU5402, and by co-expression of a dominant negative FGFR-1
protein. Our results demonstrate that aberrant FGFR-1 expression, an epigenetic phenomenon that has been associated with
prostate cancer progression, allows induction of
promatrilysin expression by
FGF-1 in PrECs.