Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL­8 production in pancreatic cancer.

Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem­R). To elucidate the mechanism of Gem­R, two Gem­R PaCa cell lines were established from AsPC­1 and MIA PaCa­2 cells. It was demonstrated that expression of interleukin­8 (IL­8) mRNA was significantly upregulated in Gem­R PaCa cells by cDNA microarray and RT­qPCR analyses. Increased IL­8 secretion by Gem­R cells was confirmed by cytokine array and enzyme­linked immunosorbent assay. Moreover, we found that co­culture with Gem­R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti­CXCR2 (main receptor for IL­8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL­8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem­R increased IL­8 production and consequently increased tumor angiogenesis, the IL­8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem­R.