ANGIOGENESIS AND NEUROBLASTOMAS: INTERLEUKIN-8 AND INTERLEUKIN-8 RECEPTOR EXPRESSION IN HUMAN NEUROBLASTOMA

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Abstract
Studies have demonstrated that the pro-angiogenic cytokine interleukin-8 (IL-8) and the IL-8 receptors likely have a role in the growth and metastasis of various solid tumors. We hypothesized that in vivo neuroblastoma expresses IL-8 and the IL-8 receptors A and B, and that factors known to regulate IL-8 expression are present and active in the neuroblastoma microenvironment. To confirm the presence of IL-8/IL-8 receptors in neuroblastoma, immunohistochemical analysis for IL-8 and its receptors was performed on 10 archival specimens, including benign adrenal and well to poorly differentiated neuroblastoma samples. Immunohistochemical analysis was also performed for interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha. Cultured neuroblastoma cells SK-N-MC and SK-N-SH were stimulated with 10 ng./ml. IL-1beta or tumor necrosis factor-alpha and control media (15 each). Cell culture supernatants were analyzed with enzyme-linked immunosorbant assay for IL-8 levels at 24 and 48 hours. Minimal expression of IL-8 was noted in benign adrenal tissue but expression for IL-8 was present in all neuroblastoma specimens. Microvessel staining was present in 30% of the specimens. All tumor specimens expressed IL-8 receptor B, and both receptors were expressed in the tumor microvasculature. Immunohistochemical analysis confirmed the presence of IL-1beta and tumor necrosis factor in the neuroblastoma microenvironment. In vitro studies demonstrated that SK-N-MC and SK-N-SH cells express low levels of IL-8 under normal conditions and that IL-1beta and tumor necrosis factor-alpha significantly increased expression of IL-8 at 24 and 48 hours. Our results indicate that IL-8 and its receptors are expressed in neuroblastoma tumor specimens. In addition, the fact that IL-1beta and tumor necrosis factor-alpha are expressed in the neuroblastoma microenvironment combined with our in vitro results suggests that these cytokines may be involved in in vivo regulation of IL-8 in human neuroblastoma. Understanding the angiogenic factors and regulatory cascade promoting angiogensis in neuroblastoma may lead to the development of effective anti-angiogenic strategies.