The lipoxygenase metabolite 12(S)‐hete promotes αllbβ3integrin‐mediated tumor‐cell spreading on fibronectin

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Abstract
Tumor‐cell interaction with the vessel wall during metastasis involves adhesion, induction of endothelial‐cell retraction and spreading on the exposed sub‐endothelial matrix. The signals for initiation of tumor‐cell spreading and the receptors involved are unknown. A protocol was developed to distinguish between initial tumor‐cell (B16 amelanotic melanoma; B16a) adhesion to and spreading on fibronectin. The time for maximum spreading was 50 min. Treatment with a lipoxygenase metabolite of arachidonic acid [12(S)‐HETE] resulted in maximum spreading in 15 min (max. effect approx. O.1 μM). Other lipoxygenase metabolites were ineffective. 12(S)‐HETE treatment induced a rearrangement of F‐actin, vinculin, vimentin intermediate filaments and integrin α11bβ3, but not integrin α5β1. Antibodies to α11bβ3 but not α5β1 blocked the 12(S)‐HETE effect on B16a spreading. B16a‐cell attachment to fibronectin resulted in increased metabolism of arachidonic acid to 12(S)‐HETE, which was inhibited by lipoxygenase but not by cyclo‐oxygenase inhibitors. Accordingly, lipoxygenase inhibitors but not cyclo‐oxygenase inhibitors blocked spontaneous B16a‐cell spreading. The protein‐kinase‐C inhibitors calphostin C, H7 and staurosporine also inhibited spreading, while the protein‐kinase‐A inhibitor H8 was ineffective. These data suggest that B16a‐cell spreading on fibronectin is initiated by a lipoxygenase metabolite [12(S)‐HETE] of arachidonic acid and is mediated by protein kinase C.

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