Plasminogen Activator Inhibitor-1 Promotes the Recruitment and Polarization of Macrophages in Cancer

Abstract

Summary: 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. : The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) has a paradoxical pro-angiogenic and protective effect on cancer cells. Kubala et al. provide evidence for a third pro-tumorigenic function by demonstrating that PAI-1 promotes recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages. Keywords: plasminogen activator inhibitor-1, PAI-1, tumor-associated macrophages, M2 polarization, interleukin 6, STAT3, tumor microenvironment