Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor)

Abstract

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.

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

“…While the mechanisms are unclear, the available data suggest that the anti-apoptotic action of PAI-1 plays a crucial role in drug resistance in multiple cancers, likely involving activation of the PI3K/AKT or ERK1/2 signaling pathways, suppression of plasmin generation or caspase-3 activity or regulation of vitronectin-mediated cell adhesion [ 139 , 143 , 216 , 217 ]. It appears, moreover, that the PAI-1-mediated rescue from spontaneous apoptosis in response to serum deprivation or plasminogen-induced cell detachment ( Figure 5 ) may be dependent, in part, on control of plasmin activation and/or inhibition of Fas/Fas ligand-mediated cell death [ 218 , 219 ].…”

Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing

“…For example, when FVB-PymT mice prone to develop mammary tumors were crossed with PAI-1 null mice, there was no effect on the development of mammary tumors, metastasis, or survival (24). Similarly, genetic ablation of PAI-1 had no effect on tumor development in Apc/Apc1638N mice prone to develop colon cancer (25), in TRP-1SV40 Tag/PAI-1 −/− mice prone to develop ocular tumors (26), and in K14-HPV16/PAI-1 −/− mice prone to develop skin cancer (27). An explanation for this difference of effect between transplanted and GEM mice is the possible presence of compensatory serpins including PAI-2, protein C inhibitor, protease nexin-1, or maspin (28–31), whose overexpression in transformed cells may have compensated for a lack of PAI-1 (27–31).…”

PAI1 is a Marker of Bad Prognosis in Rectal Cancer but Predicts a Better Response to Treatment with PIM Inhibitor AZD1208

“…In contrast to the pro-angiogenic role of PAI1 in physiological conditions, its overexpression in tumoral tissues has an anti-angiogenic function [25]. The effect on proliferation is variable, since PAI1 inhibits proliferation in prostate cancer [26] but increases the tumor size of Hela xenografts, fibromatosis or pheochromocytoma [27][28][29]. Besides, several studies have reported the role of PAI1 as anti-apoptotic in Head-and-Neck Cancer Cells (HNCC), ovarian or breast cancer [19,30].…”