title: Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis.
abstract: Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.
authors.affiliation: Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; andVascular Program, Institute for Cell Engineering.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Vascular Program, Institute for Cell Engineering,Biological Chemistry.
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.affiliation: Biomedical Engineering.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Bishop
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Biomedical Engineering.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Green
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments ofBiological Chemistry,Oncology,Pediatrics,Medicine, andRadiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D020691:rab GTP-Binding Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C484191:RAB22A protein, human
keywords: mammary fat pad implantation; orthotopic transplantation; oxygen; triple negative breast cancer; tumor microenvironment