Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice

Abstract

The plasminogen activator inhibitor-1 (PAI-1) blocks the activation of plasmin(ogen), an extracellular protease vital to cancer invasion. PAI-1 is like the corresponding plasminogen activator uPA (urokinase-type plasminogen activator) consistently expressed in human breast cancer. Paradoxically, high levels of PAI-1 as well as uPA are equally associated with poor prognosis in cancer patients. PAI-1 is thought to play a vital role for the controlled extracellular proteolysis during tumor neovascularization. We have studied the effect of PAI-1 deficiency in a transgenic mouse model of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth and vascular density were unaffected by PAI-1 status. PAI-1 deficiency also did not significantly affect the lung metastatic burden. These results agree with the virtual lack of spontaneous phenotype in PAI-1-deficient mice and humans and may reflect that the plasminogen activation reaction is not rate limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency.

Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth

“…However, there are apparent discrepancies between these data and (1) the lack of impact of PAI-1 deficiency on metastasis of melanoma cells (Eitzman et al, 1996), on MMTVPym T-induced breast cancer progression (Almholt et al, 2003), and (2) the antiangiogenic effect of PAI-1 observed in the chicken chorioallantoid membrane (CAM) and in the Matrigel implant assay . Taken together, these findings indicate that the role of PAI-1 as a determinant of tumoral angiogenesis might vary with experimental setting (tumor-type or injection-site dependent) and might depend on its cellular origin (tumor cells versus host cells).…”

Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells

“…However, its function is not limited to fibrinolysis, since plasmin (the active product of u-PA and t-PA catalysis) performs additional functions such as degradation of extracellular matrix and activation of growth factors (including vascular endothelial growth factor required for neovascularization) (14). Through these systems, PAI-1 has the ability to modulate cell adhesion/migration and neovascularization; and expectedly it has been implicated in tumor invasion, metastasis and angiogenesis, processes characteristic of high-grade malignancy (15,16). In addition, PAI-1 was shown to inhibit apoptosis and thus promote tumor growth and aggressiveness (17).…”

Senescence, Wound Healing, and Cancer: the PAI-1 Connection

“…However, absence of host PAI-1 has been shown to reduce tumor burden in tumor transplant or transgenic tumor-induction models. 80,81 Furthermore, both uPA transgenic and uPA knockout mice show reduced metastasis in syngeneic or xenograft mammary tumor models [82][83][84] and this might be related to hyperactive protease activity or the normal growth promoting role of uPA activity, respectively. In an MMTV-PymT transgenic mouse model of metastasizing breast cancer, PAI-1 knockout in the host has been reported not to lead to metastasis, 81 although in other models it has been shown that in xenograft experiments the PAI-1 levels of the host do seem to be most important in invasion and vascularisation.…”

“…80,81 Furthermore, both uPA transgenic and uPA knockout mice show reduced metastasis in syngeneic or xenograft mammary tumor models [82][83][84] and this might be related to hyperactive protease activity or the normal growth promoting role of uPA activity, respectively. In an MMTV-PymT transgenic mouse model of metastasizing breast cancer, PAI-1 knockout in the host has been reported not to lead to metastasis, 81 although in other models it has been shown that in xenograft experiments the PAI-1 levels of the host do seem to be most important in invasion and vascularisation. 80,85 These data appear confusing but probably highlight the complex roles of PAI-1 and uPA in cancer etiology, as it is also not readily explained why both high uPA and high PAI-1 expression are poor-prognosis markers in breast cancer.…”