Abstract
BackgroundChemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), although their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC.MethodsA total of 22 HCC patients were enrolled randomly. We used immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) to analyse the production of interleukin-8 (IL-8) in a-HSCs derived from HCC tissues. The angiogenic effects of IL-8 in vitro and in vivo were assessed by ELISA, real-time quantitative polymerase chain reaction, capillary tube formation assay, and chick embryo chorioallantoic membrane assay.ResultsThe present study showed that IL-8 was enriched predominantly in the tumour stroma of HCC tissues and was mainly derived from a-HSCs, rather than from hepatoma cells, in vivo and in vitro. Angiogenesis was most active at the invading edge, which was close to the a-HSCs. The angiogenic effect was dramatically attenuated by an IL-8 neutralizing antibody both in vitro and in vivo. Moreover, the IL-8 neutralizing antibody down-regulated Ser727-phosphorylated STAT3 levels in hepatoma cells treated with a-HSCs conditioned medium.ConclusionsThese findings reveal that a-HSCs within the stroma of HCC contribute to tumour angiogenesis via IL-8.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0730-7) contains supplementary material, which is available to authorized users.
Highlights
Chemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), their origins and latent molecular mechanisms remain elusive
Using the Multiplex bead-based Enzyme–Linked Immunosorbent Assay system, the levels of various inflammatory chemokines that are closely associated with angiogenesis, including GRO (α, β, and γ), CXCL-5, CXCL-6, CXCL-7 and IL-8, were detected in the 50 % activated hepatic stellate cells (a-Hepatic stellate cells (HSCs)) conditioned medium (HSC-CM) (CM:HSC-CM = 1:1) [23]
We compared the levels of IL-8 secreted by a-HSCs with those secreted by hepatoma cells
Summary
Chemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC. Hepatocellular carcinoma (HCC) is one of the most common solid malignant neoplasms and a leading cause of cancer-related death worldwide [1, 2]. Angiogenesis plays a pivotal role in tumour growth and metastasis [7,8,9]. Angiogenesis is regulated by transcription factors such as hypoxia inducible factor-1 (HIF-1), nuclear factor κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3) [12]. In HCC, a net excess of angiogenic factors, including vascular endothelial growth factor (VEGF)-A, angiopoietins (Angs), and plateletderived growth factor (PDGF)-B, is produced by tumour cells, vascular endothelial cells, immune cells, and pericytes [8, 13, 14]
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