ABSTRACT
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.
Subject(s)
Drug Resistance, Multiple , Spheroids, Cellular/drug effects , Cell Cycle , Drug Resistance, Neoplasm , Extracellular Matrix , Neoplasm Metastasis , Spheroids, Cellular/pathologyABSTRACT
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 form 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 apoptose 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.
ABSTRACT
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 form often a necrotic core. A multicellular resistance is related on the cell contact to other cells or to the extracellular matrix. The mechanism of this resistance remains unknown. It seems to be linked to the spheroid centre hypoxia, quiescence of a large fraction of the cell population and to the apoptose inhibition. The "classical" or "unicellular" mechanisms of resistance, as mdr1, MRP, can coexist but are not responsible of this type of resistance. This culture model is a good opportunity to study a resistance which looks close to the patient tumour resistance. A new class of therapeutic molecules appears that can reverse multicellular resistance, inhibit tumours growth and preclude metastases. The mechanism of action of this new pharmacological class is the disruption of the cell adhesion forces.
