title: Hypoxia promotes dissemination and colonization in new bone marrow niches in Waldenström macroglobulinemia.
abstract: Waldenström macroglobulinemia, a rare and indolent type of non-Hodgkin lymphoma, is characterized by widespread lymphoplasmacytic B cells in the bone marrow. Previous studies have shown that hypoxic conditions play a key role in the dissemination of other hematologic malignancies. In this study, the effect of hypoxia was tested on the progression and spread of Waldenström macroglobulinemia. Interestingly, tumor progression correlated with hypoxia levels in Waldenström macroglobulinemia cells and other cells in the bone marrow and correlated with the number of circulating tumor cells in vivo. Mechanistic studies demonstrated that hypoxia decreased cell progression and cell cycle, did not induce apoptosis, and reduced the adhesion between Waldenström macroglobulinemia cells and bone marrow stroma, through downregulation of E-cadherin expression, thus explaining increased egress of Waldenström macroglobulinemia cells to the circulation. Moreover, hypoxia increased the extravasation and homing of Waldenström macroglobulinemia cells to new bone marrow niches in vivo, by increased CXCR4/SDF-1-mediated chemotaxis and maintaining the VLA4-mediated adhesion. Re-oxygenation of hypoxic Waldenström macroglobulinemia cells enhanced the rate of proliferation and cell cycle progression and restored intercellular adhesion between Waldenström macroglobulinemia cells and bone marrow stroma. This study suggests that targeting hypoxic response is a novel strategy to prevent dissemination of Waldenström macroglobulinemia.
  
  
  CONCLUSIONS
  This study provides a better understanding of the biology of dissemination of Waldenström macroglobulinemia and opens new windows for investigation of new therapeutic targets in Waldenström macroglobulinemia based on tumor hypoxia mechanisms.
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri.
authors.forename: Barbara
authors.initials: B
authors.lastname: Muz
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Puente
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri.
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri. aazab@radonc.wustl.edu.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment; D008258:Waldenstrom Macroglobulinemia / Q000378:metabolism / Q000473:pathology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4