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

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.


RefSeq
Gene description fold-4hr fold-24hr    a . For clarity and simplicity, only representative (i.e. the one with least P value) in each group of similar GO terms were given. For example, "blood vessel development" and "vasculature development" are similar to "blood vessel morphogenesis" and thus omitted from this list. Similarly, "regulation of apoptosis", "regulation of programmed cell death", "induction of programmed cell death" and "regulation of cell death" overlaps "induction of apoptosis" thus omitted in this table. For the whole lists of GO, please refer to supplementary  Shown were mean of three arrays in each group. b.Mean and standard deviation of ratios in three arrays were give.
gastric cancer MS S100A8, A9 and α defensin 1, 2 were over-expressed in tumor biopsies compared with normal tissues.
invasive ductal carcinoma of the breast IHC S100A8 is S100A9-dependently expressed. Co-expression of both proteins was associated with poor tumor differentiation, vessel invasion, node metastasis, and advanced stage.
Co-expression of the proteins was also observed in MCF-7 cells. RT-PCR S100A8 and S100A9 were over-expressed in both CRC tumor samples and serum. IHC showed that S100A8/A9 were mainly in tumor infiltrating immune cells rather than in tumor cells. RT-qPCR S100A8 may contribute to the generation of certain aspects of the aggressive phenotype rather than simply promoting cell proliferation in NMIBC.

RT-qPCR
Together with IL1B and EGFR, S100A8 and S100A9 form a four-gene indicator of tumor progression.
human prostate cancers IHC, ISH, ELISA S100A8, S100A9, and their potential receptor RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins.
There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively.
bladder cancer HPLC, S100A8 was over-expression more often in tumor with bladder (12) 2DE-MS, IHC wall muscle invasion than in those without invasion. Abnormal expression of S100A8 and A9 are correlated with poor prognosis pancreatic adenocarcino ma 2DE-MS Enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH
21 common tumor types Tissue array A8 and A9 were expressed in 12% and 28% of breast cancers, respectively. S100A11 exclusively expressed in nuclear in normal tissues but translocated to cytoplasmic and nuclear in all common cancers.
a.2DE-MS, two dimension gel electrophoresis followed by mass spectrum of interested protein spors.
WB, western blotting. IHC, immunohisotchemistry. RT-PCR, reverse transcription-PCR. RT-qPCR, RT-quantitative PCR. MA, microarray. ISH, in situ hybridization. HPLC, high performance liquid chromatography. b.some of the statements were directly copied from original references while others edited from references. Figure S1. Downregulated genes that belong to the Ribosome pathways. Red stars indicate the genes that were downregulated at both 4 hr and 24 hr, blue ovals indicate the genes that were downregulated only at 4 hr. No genes were downregulated at 24 hr only without change at 4 hr.