title: Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation.
abstract: Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs.
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sachie
authors.initials: S
authors.lastname: Hiratsuka
authors.forename: Shom
authors.initials: S
authors.lastname: Goel
authors.forename: Walid S
authors.initials: WS
authors.lastname: Kamoun
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D019040:E-Selectin / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D015854:Up-Regulation
chemical_list: D019040:E-Selectin; D051416:Focal Adhesion Protein-Tyrosine Kinases