Abstract
BackgroundIt is well documented that cancer cells secrete angiogenic factors to recruit and sustain tumor vascular networks. However, little is known about the effects of endothelial cells on the behavior of tumor cells. The study here was to determine the roles of endothelial cells in HCC cell growth, migration and invasion.MethodsA mixture of highly metastatic MHCC97H cells and HUVEC cells, as well as MHCC97H cells alone were subcutaneously injected into nude mice to observe the effects of HUVECs on HCC growth. The biological characteristics of MHCC97H cells respectively treated with conditioned medium (CM) derived from HUVECs and endothelial cell basal medium (EBM) in vitro, such as proliferation, migration and invasion, invasion/metastasis associated gene expression, were comparatively analyzed. Differential cytokines between CM and EBM were screened and identified using human cytokine array. Effects of the interested differential cytokine CCL2, IL-8 and CXCL16 and its related signaling pathways were further investigated in HCC cells.ResultsSubcutaneous tumorigenicity of MHCC97H cells in nude mice was promoted by HUVECs and its invasion/metastasis associated genes were significantly upregulated. The in vitro, proliferation, migration and invasion of HCC cells treated with CM were all significantly enhanced as compared to those with EBM stimulation. Simultaneously, PI3K/Akt and ERK1/2 pathway in HCC cells were activated by CM. Total of 25 differential cytokines were identified between CM and EBM such as angiopoietin-2, CCL2 (MCP-1), uPA, endostatin, CXCL16, IL-8, pentraxin 3 etc. The selected differential cytokines CCL2, IL-8 and CXCL16 all modulated the expressions of HCC invasion/metastasis genes, especially MMP2 and MMP9. In exposure to CCL2 or CXCL16 alone, upregulation in AKT phosphorylation but no change in ERK phosphorylation were found in MHCC97H cells, moreover the contents of nuclear transcription factor NF-κB were increased as compared to the control. However, no effects on the activation of Akt and ERK pathway in MHCC97H were found in exposure to IL-8.ConclusionThis study expands the contribution of endothelial cells to the progression of HCC. It unveils a new paradigm in which endothelial cells function as initiators of molecular crosstalks that enhance survival, migration and invasion of HCC cells.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related death [1]
We provided some evidences that endothelial cells (ECs)-initiated signaling directly affected the malignant progression of HCC cells in vitro and in vivo, and that the induction of PI3K/Akt and nuclear factor-κB (NF-κB) activation may be responsible for these effects
The tumor size in mice implanted with a mixture of HUVECs and MHCC97H cells were much larger than that in mice implanted with MHCC97H cells alone (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related death [1]. More evidences suggest that HCC metastasis involves a complex cascade of signal events between tumor cells and host stroma microenvironment. These crosstalking might modulate or determine the process of HCC invasion and metastasis. Some secreted factors from TAMs induce cancer cell motility, thereby enhancing tumor cell invasion capacity [7]. These data demonstrate that stromal cells can actively modulate the malignant characteristics of HCC cells and further determine the outcome of HCC. The study here was to determine the roles of endothelial cells in HCC cell growth, migration and invasion
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