title: Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features.
abstract: The spread of multiple myeloma (MM) involves (re)circulation into the peripheral blood and (re)entrance or homing of MM cells into new sites of the BM. Hypoxia in solid tumors was shown to promote metastasis through activation of proteins involved in the epithelial-mesenchymal transition (EMT) process. We hypothesized that MM-associated hypoxic conditions activate EMT-related proteins and promote metastasis of MM cells. In the present study, we have shown that hypoxia activates EMT-related machinery in MM cells, decreases the expression of E-cadherin, and, consequently, decreases the adhesion of MM cells to the BM and enhances egress of MM cells to the circulation. In parallel, hypoxia increased the expression of CXCR4, consequently increasing the migration and homing of circulating MM cells to new BM niches. Further studies to manipulate hypoxia to regulate tumor dissemination as a therapeutic strategy are warranted.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hu
authors.forename: Phong
authors.initials: P
authors.lastname: Quang
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Costas
authors.initials: C
authors.lastname: Pitsillides
authors.forename: Rana
authors.initials: R
authors.lastname: Awwad
authors.forename: Brian
authors.initials: B
authors.lastname: Thompson
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Sun
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002633:Chemotaxis; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000097:blood / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: C527276:CXCR4 protein, human; D015820:Cadherins; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4