Multicellular spheroids as an in vitro tumor model.

Multicellular spheroids (MCS) have been used as an in vitro model system of micrometastases and avascular tumor regions for studying cell adhesion-dependent resistance to cytotoxic drugs and possible reversal by chemosensitizers and adhesion-reversing agents. Multicellular drug resistance has been linked to limited accessibility of cell subpopulations, active drug efflux, quiescence of cells in deeper layers due to cell contact inhibition and adverse microenvironmental conditions like acidic extracellular pH, hypoxia and nutritional depletion. The shortcomings of MCS as a tumor model include limited knowledge of the mechanisms leading to necrosis/apoptosis of core cells, the production of an extracellular matrix (ECM) by tumor cells instead of intratumoral normal cell populations and the complex relationship of MCS parameters like size, growth regulation, synthesis of ECM components and others on the origin and pretreatment of the tumor cells and specific culture conditions.