3552

IL1A

interleukin 1, alpha;IL1A;interleukin 1, alpha

IL-1 alpha|hematopoietin-1|interleukin-1 alpha|preinterleukin 1 alpha|pro-interleukin-1-alpha

2q14

protein-coding

BACKGROUND: To better understand the underlying mechanism of liver metastasis formation in human gastric cancer, we evaluated the angiogenic capabilities of human gastric cancer cell lines with different metastatic potentials as well as the role of interleukin (IL)-1alpha in the angiogenic process. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction was used to detect the expression of IL-1alpha and vascular endothelial growth factor (VEGF) mRNA in gastric cancer cell lines with different liver metastatic potentials. Levels of VEGF secreted by human gastric cancer cells were measured by enzyme-linked immunosorbent assay. We also examined how gastric cancer cells with different metastatic potentials influence the proliferation and tube formation of human umbilical vein endothelial cells (HUVECs) using the Premix WST-1 cell proliferation assay system and an angiogenesis assay, respectively. RESULTS: IL-1alpha expression levels were significantly correlated with liver metastatic potential in gastric cancer cell lines. Levels of VEGF secreted by gastric cancer cells appear to be regulated by IL-1alpha through IL-1 receptor Type 1 and were correlated with liver metastatic potential. Both HUVEC proliferation and tube formation were strongly enhanced by coculture with high liver-metastatic gastric cancer cells and were enhanced to a similar extent by culture in the presence of IL-1alpha. In contrast, blockade of IL-1alpha inhibited both HUVEC proliferation and angiogenesis. CONCLUSIONS: IL-1alpha may play a role in liver metastasis of gastric cancer via enhanced vascular endothelial cell proliferation and angiogenesis.

tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1alpha, with similarly augmented expression of IL-1alpha and IL-1beta by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1alpha-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.

BACKGROUND: Previously we reported the critical role of interleukin (IL)-1alpha in liver metastasis from pancreatic cancer (PaCa). However, its role in angiogenesis and metastasis, particularly as it relates to the interaction between tumor and stromal cells, was not clearly elucidated. To further investigate, we initially compared vascular endothelial cell migration and tube formation in human PaCa cell lines that differed in metastatic potential. We then compared the effects of IL-1alpha derived from PaCa cells on the same processes. MATERIALS AND METHODS: expression of IL-1alpha mRNA and protein in PaCa cells was measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. IL-1alpha mRNA and protein were detected only in predominantly liver-metastatic PaCa cells. Next, we examined differences in migration and tube formation by human umbilical vein endothelial cells (HUVECs) in the various PaCa cells using invasion and angiogenesis assays, respectively. Furthermore, we determined the effects of IL-1alpha secreted by PaCa cells on migration and tube formation by HUVECs using coculture experiments. RESULTS: expression of IL-1alpha mRNA and protein was observed only by the highly liver-metastatic PaCa cell lines BxPC-3 and SW 1990. Both HUVEC migration and tube formation were significantly enhanced by coculture with metastatic PaCa cells and IL-1alpha (P < 0.01). Similarly, blockade of IL-1alpha by its antagonist inhibited HUVEC migration and tube formation (P < 0.01). CONCLUSIONS: Our results indicate that IL-1alpha secreted by PaCa cells plays an important role in metastasis through vascular endothelial cell invasion and angiogenesis. Thus, blocking IL-1alpha is a potential novel therapeutic strategy in PaCa.