3D tissue-engineered bone marrow as a novel model to study pathophysiology and drug resistance in multiple myeloma

Biomaterials. 2015 Dec:73:70-84. doi: 10.1016/j.biomaterials.2015.09.017. Epub 2015 Sep 12.

Abstract

Purpose: 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.

Experimental design: 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.

Keywords: 3D; Culture model; Drug resistance; Multiple myeloma; Tissue-engineering; Tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bone Marrow / pathology*
  • Bone Marrow Cells / cytology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / metabolism
  • Doxorubicin / chemistry
  • Drug Resistance, Neoplasm*
  • Flow Cytometry
  • Green Fluorescent Proteins / chemistry
  • Humans
  • Immunohistochemistry
  • Microscopy, Confocal
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / physiopathology*
  • Oxygen / chemistry
  • Receptors, CXCR4 / metabolism
  • Stromal Cells / cytology
  • Syndecan-1 / metabolism
  • Tissue Engineering / methods*
  • Tranexamic Acid / chemistry
  • Tumor Microenvironment

Substances

  • CXCR4 protein, human
  • Cytokines
  • Receptors, CXCR4
  • SDC1 protein, human
  • Syndecan-1
  • Green Fluorescent Proteins
  • Tranexamic Acid
  • Doxorubicin
  • Oxygen