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

doi:10.1016/j.celrep.2018.10.082

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

Cell Rep. 2018 Nov 20;25(8):2177-2191.e7. doi: 10.1016/j.celrep.2018.10.082.

Authors

Marta Helena Kubala¹, Vasu Punj², Veronica Rae Placencio-Hickok¹, Hua Fang¹, G Esteban Fernandez³, Richard Sposto⁴, Yves Albert DeClerck⁵

Affiliations

¹ 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.
² Division of Hematology, Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³ The Saban Research Institute of Children's Hospital, Los Angeles, CA 90027, USA.
⁴ 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.
⁵ 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. Electronic address: [email protected].

Abstract

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.

Keywords: M2 polarization; PAI-1; STAT3; interleukin 6; plasminogen activator inhibitor-1; tumor microenvironment; tumor-associated macrophages.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
CD163 Antigen
Cell Movement
Cell Polarity*
HEK293 Cells
Humans
Interleukin-6 / metabolism
Macrophages / metabolism*
Macrophages / pathology*
Mice, Inbred C57BL
Monocytes / metabolism
NF-kappa B / metabolism
Neoplasms / metabolism*
Neoplasms / pathology*
Phenotype
Plasminogen Activator Inhibitor 1 / chemistry
Plasminogen Activator Inhibitor 1 / metabolism*
Protein Domains
Receptors, Cell Surface / metabolism
STAT3 Transcription Factor / metabolism
Transplantation, Heterologous
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD163 Antigen
Interleukin-6
NF-kappa B
Plasminogen Activator Inhibitor 1
Receptors, Cell Surface
STAT3 Transcription Factor
p38 Mitogen-Activated Protein Kinases

Grants and funding

R01 CA129377/CA/NCI NIH HHS/United States