Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features

Author:

Azab Abdel Kareem1,Hu Jinsong2,Quang Phong1,Azab Feda1,Pitsillides Costas3,Awwad Rana4,Thompson Brian3,Maiso Patricia1,Sun Jessica D.5,Hart Charles P.5,Roccaro Aldo M.1,Sacco Antonio1,Ngo Hai T.1,Lin Charles P.3,Kung Andrew L.6,Carrasco Ruben D.1,Vanderkerken Karin2,Ghobrial Irene M.1

Affiliation:

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;

2. Department of Hematology and Immunology, Myeloma Center,Vrije Universiteit Brussel, Brussels, Belgium;

3. Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA;

4. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;

5. Threshold Pharmaceuticals, Redwood City, CA; and

6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston and Harvard Medical School, Boston, MA

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference50 articles.

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