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Drug and radiation resistance in spheroids: cell contact and kinetics
1British Columbia Cancer Research Centre, Vancouver, Canada.
Abstract:
Cells from multicellular spheroids are often more resistant than monolayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the drug to penetrate the spheroid, or the presence of hypoxic cells, these mechanisms do not adequately explain resistance to all agents. Small spheroids (containing about 25-50 cells) exposed to ionizing radiation, hyperthermia, photodynamic therapy, or topoisomerase II inhibitors, are more resistant to killing than monolayers; the close three-dimensional contact in spheroids has been implicated in this resistance. Proposed mechanisms for the 'contact effect' include gap junctional 'reciprocity', cell shape mediated changes in (repair-related) gene expression, and alterations in chromatin packaging which influence DNA repair. The consequences of the contact effect are especially important for multifraction exposures. Another form of resistance can be demonstrated during repetitive treatments; 'regrowth resistance' reflects the capacity of spheroid cells to proliferate more efficiently to compensate for cell killing.
Insights
Multicellular spheroids exhibit enhanced resistance to cancer therapies compared to cell monolayers. This increased resistance, particularly from cell-cell contact, impacts treatment efficacy and requires further investigation for improved therapeutic strategies.
Area of Science:
- * Cell biology
- * Cancer research
- * Radiation oncology
Background:
- * Multicellular spheroids, unlike cell monolayers, display inherent resistance to various cancer therapies, including drugs and radiation.
- * Existing explanations like altered cell cycles, poor drug penetration, and hypoxia do not fully account for this observed resistance.
- * The three-dimensional architecture and close cell-cell contact in spheroids are increasingly recognized as critical factors influencing therapeutic resistance.
Purpose of the Study:
- * To investigate the mechanisms underlying enhanced resistance in multicellular spheroids compared to monolayers.
- * To explore the role of cell-cell contact, termed the 'contact effect', in mediating resistance to cytotoxic agents and radiation.
- * To understand 'regrowth resistance' as a distinct mechanism of spheroid cell proliferation following treatment.
Main Methods:
- * Comparative studies exposing both multicellular spheroids and cell monolayers to various cytotoxic agents and radiation.
- * Investigation of small spheroids (25-50 cells) to isolate the effects of close cell-cell contact.
- * Analysis of proposed 'contact effect' mechanisms, including gap junction communication, gene expression changes, and chromatin alterations impacting DNA repair.
Main Results:
- * Spheroids demonstrated significantly greater resistance to killing by ionizing radiation, hyperthermia, photodynamic therapy, and topoisomerase II inhibitors compared to monolayers.
- * The 'contact effect', driven by close three-dimensional cell interactions, was implicated as a key contributor to this resistance.
- * A phenomenon termed 'regrowth resistance' was identified, highlighting the enhanced proliferative capacity of spheroid cells post-treatment.
Conclusions:
- * Multicellular spheroids possess intrinsic resistance mechanisms beyond those typically observed in 2D cultures.
- * The 'contact effect' plays a crucial role in spheroid resistance, influencing DNA repair and cellular response to therapy.
- * Understanding spheroid resistance, including regrowth capacity, is vital for optimizing cancer treatment strategies, especially for fractionated therapies.