Senescence, wound healing and cancer: the PAI-1 connection.
Prolonged propagation of primary diploid fibroblasts in culture activates an ageing process known as replicative senescence, which is considered to provide a barrier against oncogenic transformation. Remarkably, both cell autonomous tumor-suppressive and cell nonautonomous tumor-promoting effects of senescent cells have been reported. Recently, we described that the p53 target gene plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of replicative senescence. PAI-1 antagonizes the protease urokinase-type plasminogen activator (uPA). Both are secreted factors and involved in heterotypic signaling processes such as wound healing, angiogenesis and metastasis. Both uPA and PAI-1 are expressed in senescent cells and their relative abundance controls proliferation downstream of p53. Here, we present data that the effects of PAI-1 and uPA in the senescence response are not strictly cell autonomous. We discuss these findings in the context of the emerging roles of PAI-1 and uPA in heterotypic cellular signaling in senescence, wound healing and metastasis.
Kortlever
Roderik M
RM
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Bernards
René
R
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D006706:Homeostasis; D051379:Mice; D008954:Models, Biological; D019899:Paracrine Communication; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017154:Stromal Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53