title: Definition of molecular determinants of prostate cancer cell bone extravasation.
abstract: 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.
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Barthel
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Hays
authors.forename: Erika M
authors.initials: EM
authors.lastname: Yazawa
authors.forename: Matthew
authors.initials: M
authors.lastname: Opperman
authors.forename: Kempland C
authors.initials: KC
authors.lastname: Walley
authors.forename: Leonardo
authors.initials: L
authors.lastname: Nimrichter
authors.forename: Monica M
authors.initials: MM
authors.lastname: Burdick
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Gillard
authors.forename: Michael T
authors.initials: MT
authors.lastname: Moser
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Dimitroff
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D019040:E-Selectin; D039302:Integrin alphaVbeta3; D019012:Integrin beta1