RESUMO
The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.
Assuntos
Neoplasias/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Humanos , Modelos Moleculares , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neoplasias/patologia , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here, we demonstrate that PAI-1 promotes the recruitment and M2 polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and nuclear factor κB (NF-κB) and induction of an autocrine interleukin (IL)-6/STAT3 activation pathway. We then show in several experiments in mice that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6, and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6, and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer.
