No abstract

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Advanced prostate cancer (PCa) commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. PCa cells roll on E-selectin+ BMEC through E-selectin ligand-binding interactions under shear flow, and PCa cells exhibit firm adhesion to BMEC via β1, β4 and αVβ3 integrins in static assays. However, whether these discrete PCa cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Herein, we describe how metastatic PCa cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. PCa cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic PCa tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. PCa cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1 and Rap1 were constitutively active. In homing studies, PCa cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases (α1,3 FT) in transgenic adenoma of mouse prostate (TRAMP) mice dramatically reduced PCa incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins and Rac/Rap1 GTPases in mediating PCa cell homing and entry into bone and offer new insight on the role of α1,3 fucosylation in PCa development.