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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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: Stephen J Florczyk; Kui Wang; Soumen Jana; David L Wood; Samara K Sytsma; Jonathan Sham; Forrest M Kievit; Miqin Zhang Journal: Biomaterials Date: 2013-09-26 Impact factor: 12.479
Authors: Manjulata Singh; Shilpaa Mukundan; Maria Jaramillo; Steffi Oesterreich; Shilpa Sant Journal: Cancer Res Date: 2016-05-23 Impact factor: 12.701