Does Plasminogen Activator Inhibitor-1 Drive Lymphangiogenesis?

Françoise Bruyère,Silvia Blacher,Julie Lecomte,Laurence Melen-Lamalle,Gunilla Høyer-Hansen,Benoît Detry,Jean-Michel Foidart,Vincent Lambert,Agnès Noël,Catherine Maillard,Anne Masset,Leif R Lund,Yihai Cao

doi:10.1371/journal.pone.0009653

Abstract

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis.

Highlights

The lymphatic network is composed of blind-ended lymphatic vessels that regulate tissue homeostasis, the afferent immune response and fat transport
To test the impact of plasminogen activator inhibitor-1 (PAI-1) on lymphatic vessel recruitment in tumors, VEGF-C-overexpressing MCF7 cells or control MCF7 cells were bilaterally injected into the fifth mammary fat pads of immunodeficient RAG-12/2 mice that are deficient in plasminogen activator inhibitors (PAI)-1 (PAI12/2) or not (PAI-1 WT)
At week 16, both PAI-1 WT and PAI-12/2 mice implanted with VEGF-C expressing cells showed higher tumor incidence (P = 0.0051, P,0.0001, respectively; Fig. 1B) and, in PAI-1 WT mice, a tendency to a higher tumor volume (P = 0.1513; Fig. 1C) than mice inoculated with mock

Summary

Introduction

The lymphatic network is composed of blind-ended lymphatic vessels that regulate tissue homeostasis, the afferent immune response and fat transport. After collecting extravasated proteinrich fluid and lymphocytes from the extracellular space or triglycerides from the gut, lymphatic capillaries transport them back to the blood circulation through larger vessels and lymph nodes [1]. Tumoral cell metastasis may occur by invading either the blood circulation or the lymphatic vascular system. Lymphatic vessels offer an easy way for cancer cells to disseminate and form metastasis into the lymph nodes before reaching the blood circulation. This is supported by the clinical investigation of the sentinel lymph node while searching for cancer dissemination in patients [2]. A better understanding of the molecular and cellular basis of lymphatic abnormalities associated with cancers and inflammation is essential for the development of novel therapeutic strategies

Objectives

Methods

Results

Conclusion