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