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Enhanced Angiogenesis Due to Inflammatory Cytokines from Pancreatic Cancer Cell Lines and Relation to Metastatic Potential

Objectives: To investigate the mechanisms of metastasis formation in human pancreatic carcinoma, we examined the angiogenic capabilities of human pancreatic cancer cell lines with different metastatic potentials and the roles of inflammatory cytokines. Methods: Interleukin (IL)-8 secretion by human pancreatic cancer cells stimulated with IL-1&agr; or IL-1 receptor antagonist (IL-1ra) was measured by enzyme-linked immunosorbent assay (ELISA). We then examined how cancer cells with different metastatic potentials influenced the proliferation and tube formation of human umbilical vein endothelial cells (HUVECs) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction method (MTT assay) and an angiogenesis assay, respectively. We also examined the role of inflammatory cytokines in relation to tumor metastatic potential and angiogenesis. Results: IL-8 secretion levels by pancreatic cancer cells were regulated by IL-1&agr; and correlated with metastatic potential. Both HUVEC proliferation and tube formation were strongly enhanced by coculture with metastatic pancreatic cancer cells and were enhanced to a similar extent by culture in the presence of IL-1&agr; and IL-8. In contrast, blockade of IL-1&agr; or IL-8 inhibited HUVEC proliferation and angiogenesis. Conclusions: The inflammatory cytokines IL-1&agr; and IL-8 may have an important role in metastasis via vascular endothelial cell proliferation and angiogenesis.