Plasminogen Activator Inhibitor-1 Promotes the Recruitment and Polarization of Macrophages in Cancer
Marta Helena Kubala,
Vasu Punj,
Veronica Rae Placencio-Hickok,
Hua Fang,
G. Esteban Fernandez,
Richard Sposto,
Yves Albert DeClerck
Affiliations
Marta Helena Kubala
Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
Vasu Punj
Division of Hematology, Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Veronica Rae Placencio-Hickok
Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
Hua Fang
Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
G. Esteban Fernandez
The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA
Richard Sposto
Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA; Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA
Yves Albert DeClerck
Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children’s Hospital, Los Angeles, CA 90027, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90033, USA; Corresponding author
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
