title: A quantitative microfluidic angiogenesis screen for studying anti-angiogenic therapeutic drugs.
abstract: Anti-angiogenic therapy, which suppresses tumor growth by disrupting oxygen and nutrient supply from blood to the tumor, is now widely accepted as a treatment for cancer. To investigate the mechanisms of action of these anti-angiogenesis drugs, new three dimensional (3D) cell culture-based drug screening models are increasingly employed. However, there is no in vitro high-throughput screening (HTS) angiogenesis assay that can provide uniform culture conditions for the quantitative assessment of physiological responses to chemoattractant reagents under various concentrations of anti-angiogenesis drugs. Here we describe a method for screening and quantifying the vascular endothelial growth factor (VEGF)-induced chemotactic response on human umbilical vein endothelial cells (HUVECs) cultured with different concentrations of bortezomib, a selective 26S proteasome inhibitor. With this quantitative microfluidic angiogenesis screen (QMAS), we demonstrate that bortezomib-induced endothelial cell death is preceded by a series of morphological changes that develop over several days. We also explore the mechanisms by which bortezomib can inhibit angiogenesis.
authors.affiliation: Departments of Biological Engineering and Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. rdkamm@mit.edu.
authors.forename: Choong
authors.initials: C
authors.lastname: Kim
authors.forename: Junichi
authors.initials: J
authors.lastname: Kasuya
authors.forename: Jessie
authors.initials: J
authors.lastname: Jeon
authors.forename: Seok
authors.initials: S
authors.lastname: Chung
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation* / Q000379:methods; D009389:Neovascularization, Pathologic; D011719:Pyrazines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001897:Boronic Acids; D011719:Pyrazines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib