title: 3D tissue-engineered bone marrow as a novel model to study pathophysiology and drug resistance in multiple myeloma.
abstract: OBJECTIVE
  Multiple myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable despite the introduction of several novel drugs. The discrepancy between preclinical and clinical outcomes can be attributed to the failure of classic two-dimensional (2D) culture models to accurately recapitulate the complex biology of MM and drug responses observed in patients.
  
  
  METHODS
  We developed 3D tissue engineered bone marrow (3DTEBM) cultures derived from the BM supernatant of MM patients to incorporate different BM components including MM cells, stromal cells, and endothelial cells. Distribution and growth were analyzed by confocal imaging, and cell proliferation of cell lines and primary MM cells was tested by flow cytometry. Oxygen and drug gradients were evaluated by immunohistochemistry and flow cytometry, and drug resistance was studied by flow cytometry.
  
  
  RESULTS
  3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche (such as oxygen and drug gradients), and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems.
  
  
  CONCLUSIONS
  3DTEBM cultures not only provide a better model for investigating the pathophysiology of MM, but also serve as a tool for drug development and screening in MM. In the future, we will use the 3DTEBM cultures for developing personalized therapeutic strategies for individual MM patients.
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Puente
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Muz
authors.affiliation: Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Gilson
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Micah
authors.initials: M
authors.lastname: Luderer
authors.affiliation: Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: King
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
authors.affiliation: Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: aazab@radonc.wustl.edu.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
mesh_terms: D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000503:physiopathology*; D010100:Oxygen / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D053668:Syndecan-1 / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D014148:Tranexamic Acid / Q000737:chemistry; D059016:Tumor Microenvironment
chemical_list: C527276:CXCR4 protein, human; D016207:Cytokines; D019718:Receptors, CXCR4; C508241:SDC1 protein, human; D053668:Syndecan-1; D049452:Green Fluorescent Proteins; D014148:Tranexamic Acid; D004317:Doxorubicin; D010100:Oxygen
keywords: 3D; Culture model; Drug resistance; Multiple myeloma; Tissue-engineering; Tumor microenvironment