EFFECTS OF 13-H0DE AND HETEs ON TUMOR CELL/ENDOTHELIAL CELL INTERACTIONS

Abstract

We and others reported that endothelial cells (ECs) convert linoleic acid into 13-hydroxyoctadecadienoic acid (13-H0DE) under basal conditions, and arachidonic acid into 15-hydroxyeicosatet-raenoic acid (15-HETE) following stimulation (1,2). We also reported that lipoxygenase metabolism influenced platelet (PLT) interactions with ECs, tumor cells (TCs) and extracellular matrix (BM) (1,3,4). Thus, we performed studies to determine i) if TCs also produce 13-H0DE and HETEs, and ii) the effect of TC and EC 13-H0DE and HETEs synthesis on TC/EC adhesion. We measured i) the ratios of 13-H0DE:HETE in 5TC lines, under basal and stimulated conditions, in metastatic and non-metastatic TCs of the same cell line, and TCs treated with salicylate (SAL) or dipyridamole (DIP), and ii) their relationships with TC adhesion to ECs and BM. 13-H0DE and HETEs were assayed by HPLC. TC adhesion was assayed as the # radiolabelled TCs adherent to ECs or BM. cAMP was assayed by RIA. Under basal conditions, TCs produced 13-H0DE and HETEs, the intracellular ratio of which markedly affected their adhesivity; e.g. the least adhesive TC (U87MG glioblastoma) produced 21Xs more 13-H0DE than HETE’s, while a more adhesive TC (A549, adenocarcinoma) produced 4Xs more HETEs than 13-H0DE. Non-metastatic TCs preferentially produced 13-H0DE while metastatic TCs of the same cell line, produced HETEs. Stimulation of TCs or ECs decreased 13-H0DE, and increased HETE synthesis and TC/EC adhesion. Inhibiting intracellular 13-H0DE synthesis in either TCs or EC (SAL RX) enhanced TC/EC and TC/BM adhesion. Enhancing 13-H0DE synthesis by elevating cAMP (DIP RX) inhibited TC/EC and TC/BM adhesion. We conclude that 1) in vitro TCs produce 13-H0DE and HETEs, 2) the ratio of 13-H0DE:HETEs in TCs and ECs affects their adhesivity; and 3) the ratio of intracellular 13-H0DE:HETEs depends upon cAMP. This suggests that 13-H0DE:HETE ratios in TCs and ECs influence the adhesion process in the pathogenesis of thrombosis and metastasis in vivo. (1) Buchanan et al, JBC 30:1985. (2) Hopkins et al, JBC 29:1984. (3) Bastida et al, Int. J. Cane. 1987. (4) Buchanan et al, Prost. Leuk. Med., 1986.

Interleukin 1-induced cancer cell/endothelial cell adhesion in vitro and its relationship to metastasis in vivo: role of vessel wall 13-HODE synthesis and integrin expression

“…This is consistent with in vitro observations [9][10][11][12] demonstrating that enhanced cancer cell/EC adhesion is also elevated at a time when PGI2 plasma levels are elevated. These observations are not consistent with the hypothesis that PGI2 is a naturally occurring antimetastatic agent [28], but rather that PGI2 increases secondary to the metastasis event, such as in response to EC perturbation.…”

“…Cytokine-induced enhanced adhesion is thought to be due to enhanced adhesion molecule expression on the EC surface [5,6,21]. Other studies suggest that the expression of these adhesion molecules, not only on ECs, but also on cancer cells, is regulated, in part, by the intracellular monohydroxide, 13-HODE [9][10][11][12]22]. We have obtained evidence that VnR is one of the endothelial adhesion molecules for human cancer cell lines that is synthesized and expressed following IL-10: treatment [5].…”

“…They adhere to ECs, their adhesion is increased when the ECs are exposed to IL-Io~, and their adhesion is blocked by anti-Vn.R or GRGDS peptides. All of these interactions have been previously shown to be associated inversely with intracellular EC 13-HODE synthesis [9][10][11][12]. The present observations that both the GRGDS peptide and the antiVnR antibody blocked enhanced B16F10 cell/EC adhesion in vitro, whereas the GRGES peptide, anti-fibronectin, and the anti-GPIIb/IIIa antibodies did not or did so to a lesser extent, are consistent with the hypothesis that B16F10 cell/EC adhesion is dependent, in part, upon the expression of VnR on ECs.…”

“…This suggests that any changes in the adhesive properties of the vascular endothelium will influence cancer cell/endothelial cell adhesion and subsequent metastasis. It has been reported that cancer cell/endothelial cell adhesion is enleads to an increased adhesion of neoplastic cells to the endothelium in vitro [4][5][6][7][8][9][10][11][12].…”

Fatty acid metabolism and cell/cell interactions

“…These investigators postulated therefore that the expression of the adhesive sites was, in part, regulated by the lipoxygenase pathway. Subsequent studies demonstrated that a variety of human and animal tumor cells synthesized 13 HODE, as well as the arachidonic acid lipoxygenase metabolites, 5-, 12-and 15-hydroxyeicosatetraenoic acid (HETEs) [20,21]. The intracellular ratio of 13HODE:HETEs directly correlated with the ability of the tumor cells to adhere to both endothelial cells themselves, and to their underlying basement membrane.…”