Matrix metalloproteinases (
MMPs) and tissue inhibitors of
MMPs (TIMPs) regulate the degradation of extracellular matrix components and play important roles in the progression of select
neoplastic processes. The locally invasive soft tissue
tumor,
aggressive fibromatosis (also called
desmoid tumor), is caused by mutations resulting in
beta-catenin-mediated
T-cell factor (tcf)-dependent transcriptional activity. Because
beta-catenin can regulate
MMP expression, we investigated the expression of several
MMPs and TIMPs in
aggressive fibromatosis tumors that develop in Apc+/Apc1638N mice. Mmp-3 and
Timp-1 were differentially regulated (5-fold and 0.5-fold, respectively) in
tumors compared with normal fibrous tissue.
Conditioned media from
tumor cells showed an increased ability to degrade
collagen, and inhibition of
MMPs using
GM6001 decreased the ability of the
tumor cells to invade through
Matrigel. Both the treatment of Apc/Apc1638N mice with
GM6001 or crossing with a transgenic mouse that overexpresses
Timp-1 resulted in a significant reduction in
tumor volume. Surprisingly, overexpression of
Timp-1 also resulted in a 50% increase in
tumor number. Although
TIMP-1 can induce growth stimulatory effects in some cell types, we found no difference in proliferation or apoptosis rate in cells from
tumors that developed in the Timp-1-transgenic mice compared with mice that did not express the
Timp-1 transgene, suggesting that
TIMP-1 promotes
aggressive fibromatosis tumor formation through an alternate mechanism. These data suggest that
MMPs play a crucial role in regulating the invasiveness of mesenchymal cells and in modulating
aggressive fibromatosis tumor progression. Because this is a locally invasive
tumor,
MMP inhibition could slow
tumor growth and may prove to be an effective adjuvant
therapy.