Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice

✍ Scribed by M J Anasagasti; A Alvarez; J J Martin; L Mendoza; F Vidal-Vanaclocha

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 371 KB
• Volume: 25
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510250410

✦ Synopsis

HSE-CM. Melanoma cell damage was ob-The hepatic sinusoidal endothelium (HSE) releases served from the second hour of adhesion to HSE and large amounts of reactive oxygen species (ROS) in resignificantly (P õ .01) increased when the cells adhered sponse to endotoxins and interleukin-1 (IL-1). Such proto rHuIL-1b-stimulated HSE. This increase was abroinflammatory mediators have been shown to promote gated by catalase. Cytolysis of the HSE was not observed hepatic metastasis. We have investigated the involveduring melanoma cell adhesion. Neither was the enment of ROS released by IL-1-stimulated HSE in this hancement of B16 melanoma hydrogen peroxide producpromoting effect. Recombinant human interleukin-1b tion observed in response to rHuIL-1b. Thus, the effects (rHuIL-1b) (5 mg/kg) was intravenously injected into of IL-1 in the liver may consist of a balance between the C57BL/6J mice, and the hepatic metastasizing ability of prometastatic effect of enhanced adherence to the HSE B16 melanoma cells following intrasplenic injection was and the antimetastatic effect of H 2 O 2 -mediated cytotoxstudied in the presence of ROS scavengers. rHuIL-1bicity. Our results suggest that the enhancement of H 2 O 2 promoted hepatic metastases were significantly (P õ production by the rHuIL-1b-stimulated HSE may con-.01) reduced by catalase (1 mg/kg) and enhanced by retribute to the hepatic metastasis progression of ROScombinant human superoxide dismutase (rHuSOD) (5 resistant melanoma cells. Results in vitro indicate that mg/kg). rHuIL-1b-stimulated HSE-conditioned medium this progression is associated with a H 2 O 2 -mediated in-(HSE-CM) significantly (P õ .01) enhanced B16 melacrease in melanoma cell adhesion to HSE. (HEPATOLOGY noma cell adhesion to HSE compared with unstimulated 1997;25:840-846.) HSE-CM, which in turn also significantly (P õ .01) increased with melanoma cell adherence compared with basal medium. The addition of catalase completely abro-

Recent studies suggest that reactive oxygen species (ROS) gated proadhesive effects induced by rHuIL-1b-stimureleased by either host 1 or cancer cells 2,3 play an important lated HSE-CM with respect to unstimulated HSE-CM, role in the progression of cancer metastasis. 4 Thus, various but did not affect the proadhesive effects induced by studies have reported the up-regulation of specific cell adheunstimulated HSE-CM over basal medium. The rat sion molecules in both endothelium 5 and cancer cells, 6 and monoclonal antibody to mouse vascular cell adhesion of cancer 7,8 and endothelial cell 3 metalloproteinases, which molecule-1 (VCAM-1) significantly (P õ .01) inhibited the may promote cancer cell invasion. 9 However, there have also enhanced melanoma cell adherence effects of both unbeen reports of the direct cytotoxic effects of ROS on cancer stimulated and rHuIL-1b-stimulated HSE-CM, indicatcells, 1,10 which may reduce cancer cell survival at their initial ing that adherence was very late antigen-4 (VLA-4)-mesites of adhesion to capillaries, as has been proposed prediated. Not surprisingly, the percentage of VLA-4 viously. 11 expressing B16 melanoma cells significantly (P õ .05)

The hepatic sinusoidal endothelium (HSE) releases large increased in response to unstimulated (21% of controls) amounts of ROS in response to lipopolysaccharides and inand rHuIL-1b-stimulated (32% of controls) HSE-CM.

terleukin-1 (IL-1). 12,13 Moreover, the HSE also produces ROS Catalase addition abrogated these effects of rHuIL-1bin response to melanoma cell contact. This HSE activation is mediated by a juxtacrine action of IL-1, which is released by adhered melanoma cells. 14 Such inflammatory mediators Abbreviations: ROS, reactive oxygen species; HSE, hepatic sinusoidal endothelium; ILhave been shown to promote hepatic metastasis formation in 1, interleukin-1; rHuIL-1b, recombinant human interleukin-1b; rHuSOD, recombinant hudifferent experimental models. 15,16 man superoxide dismutase; VLA-4, very late antigen-4; VCAM-1, vascular cell adhesion molecule-1; CM, conditioned medium; BCECF-AM, 2,7-bis-(2-carboxyethyl)-5,6-carboxy-To investigate the involvement of ROS released by recombifluorescein, acetoxymethyl ester; DCFH-DA, 2,7-dichlorofluorescein-diacetate; GBSS, nant human IL-1b (rHuIL-1b)-stimulated HSE in enhanced Gey's balanced salt solution; FALS, forward-angle light scatter; ISS, integrated side scatter;

metastasis formation in vivo, we induced systemic inflamma-LIGFL, logarithms of the integrated fluorescent light.