Studies on the changes of uPA system in a co-culture model of bone marrow stromal cells-leukemia cells.

Lanxia Zhou,Xiaowei Zhang,Fang Jia,Shouliang Dong,Hong Guo,Li Zhao,Xuan Chen

doi:10.1042/bsr20194044

Abstract

The core of the tumor microenvironment in the hematological system is formed by bone marrow stromal cells (BMSCs). In the present study, we explored the interaction between the urokinase plasminogen activator (uPA) system and the leukemia bone marrow microenvironment (BMM). We established BMSCs–HL60 and HS-5–K562 co-culture models in direct contact mode to simulate the BMM in leukemia. In BMSCs-HL60 co-culture model, the expression levels of uPA, uPA receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) in BMSCs were higher than those in mono-cultured BMSCs. Matrix metalloproteinase (MMP)-9 (MMP-9) was up-regulated in co-cultured HL60 cells. In HS-5–K562 co-culture model, only uPA, PAI-1, and VEGF-A were up-regulated in HS-5 cells. The levels of the uPA protein in the co-culture supernatant were significantly higher than that of mono-cultured BMSCs or HS-5 cells. Our findings demonstrate that the co-culture stimulates the production of uPA, uPAR, PAI-1, MMP-9, and VEGF-A by BMSCs. It could further explain how the uPA system in leukemia cells is involved in the growth, development, and prognosis of leukemia.

Highlights

The urokinase plasminogen activator system consists of uPA, its cognate receptor and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2) [1]
bone marrow stromal cell (BMSC) derived from the B-acute lymphoblastic leukemia (ALL) patients, BMSC–HL60 co-cultures, and HS5–K562 co-cultures were grown in the same culture medium and could be split several times
BMSCs co-cultured with HL60 cells were observed under the inverted microscope, we saw that the HL60 cells adhered to BMSCs and grew well

Summary

Introduction

The urokinase plasminogen activator (uPA) system consists of uPA, its cognate receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2) [1]. This system plays a key role in the degradation of the extracellular matrix (ECM) and basement membrane, stimulating tumor cell invasion and metastasis and allowing malignant cells to invade locally and eventually spread to distant sites [2]. Due to the lack of transmembrane and intracellular domains, uPAR must bind to co-receptors such as integrins, G-protein-coupled receptors, and growth factor receptors to activate cell motility, proliferation, and survival [6,7].

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Conclusion