Combination of Serum Amyloid A and C-Reactive Protein Exhibit Synergistic Effect in Angiogenesis by Inducing Inflammation and Vascular Network

Haibiao Lin,Wanli Liu,Wen Shi,Mangjuan Lei,Rongliang Liang,Fujia Lin,Lina Wang,Yunxiu Wang,Yonghe Chen,Zhaomin Cheng,Dan Liu,Huimin Wang,Lin Chen,Li Lin

doi:10.3389/fonc.2020.576207

Abstract

The role of angiogenesis in tumor progression has been recognized as one of the hallmarks of cancer, but the mechanism of its action remains unclear. Inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) are proposed to play causal roles in the development of various disorders, including malignancies. Previously, we identified the complex of CRP and SAA (CRP-SAA) with diagnostic and prognostic value better than either one of them in the serum of lung cancer patients. In this study, we further explored the stimulation function of CRP-SAA on angiogenesis and inflammation. To explore possible mechanisms, microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and multi-bioinformatics analysis revealed that THP-1 and human umbilical vein endothelial cells (HUVECs) responded to SAA stimulation with upregulation of two pro-angiogenic cytokines in common, i.e., C-X-C motif ligand 6 (CXCL6) and CXCL8, which were validated by subsequent experiments in vitro. CRP had weak effects as a single stimulus, but it can efficiently potentiate the SAA induction of cytokines, which was stronger than the sum of the both (P < 0.001). The synergistical effect of the combination of CRP and SAA enhanced HUVECs transwell and constricted morphology by upregulating the pro-angiogenic genes. These results indicated that the binding of CRP and SAA acted synergistically in pro-angiogenesis by increasing inflammation and inducing vascular network.

Highlights

Lung cancer (LC) is the most common cause of cancer-associated death worldwide
The synergistical effect of the combination of C-reactive protein (CRP) and serum amyloid A (SAA) enhanced human umbilical vein endothelial cells (HUVECs) transwell and constricted morphology by upregulating the pro-angiogenic genes. These results indicated that the binding of CRP and SAA acted synergistically in pro-angiogenesis by increasing inflammation and inducing vascular network
A Venn-diagram-based analysis framework showed six genes, including tumor necrosis factor, alpha-induced protein 6 (TNFAIP6), CXCL8, serpin family b member 2 (SERPINB2), tumor necrosis factor, alpha-induced protein 2 (TNFAIP2), and C-X-C motif ligand 6 (CXCL6) were upregulated both in stimulated THP-1 (8 h) and HUVEC (4 h), which suggested that the genes were closely associated with activation and communication of the two types of cells stimulated by SAA (Figure 1A)

Summary

Introduction

Lung cancer (LC) is the most common cause of cancer-associated death worldwide. Angiogenesis has aroused strong clinical interest [1]. Anti-angiogenic therapy has been widely administered in several types of human cancers, but is still limited by the challenges of cytotoxicity and reduced efficiency [1]. New anti-angiogenic drugs that may help prevent (“angio-prevention”) or treat advanced tumor stages by inducing tumor regression or inhibiting tumor progression have been clinically investigated [2]. Various factors and cellular mechanisms have been described as responsible for the initiation of blood vessel formation in tumors [3]. The angiogenic switch can be triggered by genetic changes in tumor cells, or by recruitment of immune cells in tumor-associated inflammation [4]. Inflammation is long thought to involve the progress of vascular epithelial cells response and proliferation, which make it as important as angiogenesis [5]

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Conclusion