title: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.
abstract: Most cases of breast cancer (BrCa) mortality are due to vascular metastasis. BrCa cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor (HIF) activity in BrCa cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of BrCa cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of BrCa cells to ECs. Interference with HIF, ANGPTL4 or L1CAM expression inhibits vascular metastasis of BrCa cells to the lungs.
authors.affiliation: Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: C C L
authors.initials: CC
authors.lastname: Wong
authors.forename: H
authors.initials: H
authors.lastname: Wei
authors.forename: D M
authors.initials: DM
authors.lastname: Gilkes
authors.forename: P
authors.initials: P
authors.lastname: Korangath
authors.forename: P
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: L
authors.initials: L
authors.lastname: Schito
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Krishnamachary
authors.forename: P T
authors.initials: PT
authors.lastname: Winnard
authors.forename: V
authors.initials: V
authors.lastname: Raman
authors.forename: L
authors.initials: L
authors.lastname: Zhen
authors.forename: W A
authors.initials: WA
authors.lastname: Mitzner
authors.forename: S
authors.initials: S
authors.lastname: Sukumar
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D009368:Neoplasm Transplantation; D034622:RNA Interference; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D051793:Hypoxia-Inducible Factor 1; C030662:N,N',N''-tris(2,3-dihydroxy-5-sulfobenzoyl)-1,5,10-triazadecane; D013095:Spermidine