Abstract
BackgroundThis study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).MethodsThe expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.ResultsPeritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.ConclusionsPECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1763-2) contains supplementary material, which is available to authorized users.
Highlights
This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC)
Our results showed that PECs had much higher levels of cell proliferation when co-cultured with IL-6/soluble interleukin-6 receptor (sIL-6R) by automatically up-regulating their cell surface gp130 levels in vitro and activating JAK2/STAT3 signaling pathway, which had no effect on the PI3K/AKT signaling pathways
Increased levels of IL-6 IL-6R, gp130, CD68, and microvessel density (MVD) in peritumoral liver tissue Compared with HCC tumor tissue, several EC proliferation and angiogenesis-related genes in peritumoral tissue were gradually up-regulated during seven weeks of tumor growth, including IL-6, IL-6R, and gp130, which was confirmed by RT-PCR, IHC staining (Fig. 1a, c) and Western blot (Fig. 1f )
Summary
This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC). The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured. Angiogenesis is a fundamental event in the process of hepatocellular carcinoma (HCC) growth and metastatic dissemination [1, 2]. The activation and proliferation of endothelial cells (ECs) to develop new vessels from pre-existing ones are vital for the process of angiogenesis. ECs may be strictly classified into tumor ECs (TECs) and peritumoral
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