[Multicellular resistance: another mechanisms of pleiotropic resistance?]

Cells cultured as spheroids present an heterogeneity similar to that of tumours in vivo. In the spheroid peripheral layers, cells are proliferating, deeper cells are non-cycling, when in the aggregate centre, cells from often a necrotic core. A multicellular resistance appears in spheroids, it is a result of the cell contact to other cells (homogeneous or heterogeneous cells) and/or to the extracellular matrix. The mechanism of this resistance is not known, nevertheless, it can be hypothesised to be linked to the spheroid centre hypoxia, to the quiescence of a large fraction of the cell population and to the apoptosis inhibition due to the cell contact. The "classical" or "unicellular" mechanisms of resistance, as mdr1, MRP, can coexist with the multicellular resistance, but are not responsible for this resistance. The spheroid model of culture is a good opportunity to study a resistance type which looks close to the tumour resistance found in vivo in mice and in patients. A new class of therapeutic molecules appears that can reverse this multicellular resistance, inhibit tumours growth and preclude metastases. The principal mechanism of action of this new pharmacological class appears to be the disruption of the intercellular adhesion forces. Preliminary results obtained with these compounds in patients are promising.