Research Paper (postgraduate) from the year 2014 in the subject
Medicine - Biomedical Engineering, language: English, abstract: Cancer
cells in poorly vascularized tumor regions need to adapt to an
unfavorable metabolic microenvironment. As distance from supplying blood
vessels increases, oxygen and nutrient concentrations decrease and
cancer cells react by stopping cell cycle progression and becoming
dormant. As cytostatic drugs mainly target proliferating cells, cancer
cell dormancy is considered as a major resistance mechanism to this
class of anti-cancer drugs. Therefore, substances that target cancer
cells in poorly vascularized tumor regions have the potential to enhance
cytostatic-based chemotherapy of solid tumors. With three-dimensional
growth conditions, multicellular tumor spheroids (MCTS) reproduce
several parameters of the tumor microenvironment, including oxygen and
nutrient gradients as well as the development of dormant tumor regions.
We here report the setup of a 3D cell culture compatible high-content
screening system and the identification of nine substances from two
commercially available drug libraries that specifically target cells in
inner MCTS core regions, while cells in outer MCTS regions or in 2D cell
culture remain unaffected. We elucidated the mode of action of the
identified compounds as inhibitors of the respiratory chain and show
that induction of cell death in inner MCTS core regions critically
depends on extracellular glucose concentrations. Finally, combinational
treatment with cytostatics showed increased induction of cell death in
MCTS. The data presented here shows for the first time a high-content
based screening setup on 3D tumor spheroids for the identification of
substances that specifically induce cell death in inner tumor spheroid
core regions. This validates the approach to use 3D cell culture
screening systems to identify substances that would not be detectable by
2D based screening in otherwise similar culture co
