Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor).
Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations, resulting in beta-catenin-mediated transcriptional activation. We found that plasminogen activator inhibitor-1 (PAI-1) was upregulated fourfold in aggressive fibromatosis. We investigated the ability of beta-catenin to regulate a PAI-1 reporter, and found that PAI-1 is an indirect target. To determine the role of PAI-1 in vivo, a mouse containing a targeted deletion in Pai-1 was crossed with a mouse that develops aggressive fibromatosis and gastrointestinal tumors (Apc/Apc1638N mouse). Pai-1 deficiency reduced the number of aggressive fibromatosis tumors formed, but not the number of gastrointestinal tumors. Deficiency of Pai-1 reduced tumor cell proliferation and motility rate. Although PAI-1 can alter cell motility by competing for a common binding site on vitronectin, blocking this site did not alter the motility rate. The number of cells moving through matrigel (invasion rate) did not change with Pai-1 deficiency, but because of the low motility rate the invasion index (invasion rate/motility) was increased in Pai-1-deficient cells. This suggests a proteolytic effect for PAI-1 regulating cell invasiveness. Our study found that, although PAI-1 has cellular effects that could inhibit or enhance tumor growth, on balance, it acts as a tumor enhancer in aggressive fibromatosis.
Fen Li
Catherine
C
Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Kandel
Christopher
C
Baliko
Frank
F
Nadesan
Puviindran
P
Brünner
Nils
N
Alman
Benjamin A
BA
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D018222:Desmoid Tumors / Q000473:pathology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1