Low Concentration of S100A8/9 Promotes Angiogenesis-Related Activity of Vascular Endothelial Cells: Bridges among Inflammation, Angiogenesis, and Tumorigenesis?

Changyou Li,Siyuan Li,Lingling Yang,Changkai Jia,Zicheng Song,Yiqiang Wang

doi:10.1155/2012/248574

Abstract

Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC) line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation. In the low concentration range up to 10 μg/mL, either each alone or in combination, S100A8 and S100A9 proteins promoted proliferation of HUVEC cells in a dose-dependent manner. The presence of both proteins in culture showed additive effects over each single protein. Both proteins enhanced HUVEC cells to migrate across the transwell membrane and to form tube-like structures on the Matrigel surface. When mixed in Matrigel and injected subcutaneously in Balb/c mice, both proteins increased vessel development in the gel plugs. Microarray assay of HUVEC cells treated with 10 μg/mL S100A8 revealed that ribosome pathway, pathogenic Escherichia coli infection pathway, apoptosis, and stress response genes were modulated by S100A8 treatment. We propose that S100A8 and S100A9 proteins from either infiltrating inflammatory cells or tumor cells play an important role in the interplay among inflammation, angiogenesis, and tumorigenesis.

Highlights

While angiogenesis is fundamental to embryonic development and regeneration of injured tissues, unwanted angiogenesis, which is usually referred to as neovascularization, is a common pathological process of diseases such as cancer, autoimmune disorders, and transplant rejection
Many of the key molecules or pathways that are previously proven vital for inflammation or immunity, such as Nod1 [6], IKKβ [7], SOCS3 [8], nitric oxide [9], TLR-MyD88 pathway [10], epigenetics [11, 12], or even T-cell activation [13] are shown to be involved in inflammation-associated tumorigenesis, though the very first step at molecular level for inflammationinduced neoplastic transformation is yet to be determined
When looking into the potential mechanisms for such activity of S100A8/A9, we found that low concentrations of S100A8/A9 promoted proliferation, migration, and tube formation of vascular endothelial cells

Summary

Introduction

While angiogenesis is fundamental to embryonic development and regeneration of injured tissues, unwanted angiogenesis, which is usually referred to as neovascularization, is a common pathological process of diseases such as cancer, autoimmune disorders, and transplant rejection. The triangular relationship among inflammation, angiogenesis, and tumor development in the fields of cancer biology and immunology have been studied extensively, and the most encouraging progress is the gradual uncovering of the molecular mechanisms for inflammation-associated tumorigenesis [1,2,3,4,5]. A large number of cytokines, chemokines, or enzymes produced by inflammatory cells modulate tumor cells growth or the formation of blood vessels in tumor mass. Mediators of Inflammation mediators mainly produced by infiltrating neutrophils in such models, namely, S100A8 and S100A9, as potential promoters of neovascularization [20]. Taking into account the fact that many tumors produce S100A8/A9 to a certain extent [21,22,23], we proposed that S100A8/A9, from either tumor cells or infiltrating leukocytes, promote the transformed cells to create a blood vessel supply for themselves

Materials and Methods

Results

Discussions