title: The role of the 3D environment in hypoxia-induced drug and apoptosis resistance.
abstract: BACKGROUND
  3D tumors express different adhesion receptors from those expressed in monolayers, leading to a distinct microenvironment. The third dimension also brings mass transport into relevance, as inadequate diffusion of oxygen produces hypoxia. This study investigates the effects of distinct 3D environments on hypoxia-associated apoptosis and drug resistance.
  
  
  METHODS
  Under hypoxia and normoxia, U251 glioma cells and U87 astrocytoma cells were grown as spheroids on flat substrates, scaffolds seeded with dispersed cells, and spheroid-seeded scaffolds. The samples were subsequently treated with doxorubicin and resveratrol, known inducers of apoptosis.
  
  
  RESULTS
  All 3D environments induced increased but distinct resistance to apoptosis, as evident by lower caspase-3 activity, and higher production of anti-apoptotic proteins BCL-2 and survivin. Hypoxic monolayers also exhibited higher resistance to doxorubicin and higher production of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), but lower production of BCL-2 and survivin.
  
  
  CONCLUSIONS
  These findings suggest that in vitro, 3D models acquire greater apoptosis resistance via up-regulation of anti-apoptotic proteins, and that the precise mechanism depends on the individual 3D microenvironment.
authors.affiliation: UCLA Bioengineering, 5121 Engineering V, Los Angeles, CA 90095-1600, U.S.A.
authors.forename: Jun W
authors.initials: JW
authors.lastname: Kim
authors.forename: Won Jin
authors.initials: WJ
authors.lastname: Ho
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018874:Spheroids, Cellular / Q000473:pathology; D000077022:Survivin; D054457:Tissue Scaffolds / Q000737:chemistry; D059016:Tumor Microenvironment / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D004317:Doxorubicin