Defining rules for cancer cell proliferation in TRAIL stimulation

Area of Science:

• Computational Biology
• Cancer Research
• Cellular Dynamics

Background:

• Cancers exhibit self-organizing plasticity, evading conventional therapies.
• Previous models showed protein kinase C (PKC) inhibition with bisindolylmaleimide I (BIS I) enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy, achieving 95% cell death in HT1080 fibrosarcoma.
• The long-term fate and proliferative potential of the remaining ~5% of cancer cells remain unclear.

Purpose of the Study:

• To investigate the proliferation dynamics of residual cancer cells after TRAIL and BIS I treatment.
• To explore the role of cellular movement and initial cell density in cancer cell proliferation.
• To validate computational model predictions with experimental observations.

Main Methods:

• Development of a discrete spatiotemporal cellular automata model, adapted from Conway's Game of Life.
• Simulations based on three initial conditions: untreated (high), TRAIL only (moderate), and TRAIL + BIS I (low) cell densities.
• Inclusion of rules for fixed cell positions versus random mesenchymal-like movement.
• Experimental verification involving cell counting and characterization of mesenchymal cell proportions.

Main Results:

• Simulations indicated proliferation over time, with rapid growth for high/moderate cell numbers when movement was restricted.
• Introduction of mesenchymal-like cell movement significantly increased proliferation, even for low initial cell numbers.
• Experimental data confirmed a higher proportion of mesenchymal cells in TRAIL + BIS I treated groups, correlating with observed rapid proliferation of remnant cells.
• Re-treatment with TRAIL and BIS I remained effective against the proliferating residual cancer cells.

Conclusions:

• Mesenchymal-like cellular movement is a critical factor driving cancer cell proliferation, particularly in residual cell populations.
• Computational modeling provides valuable insights into the complex dynamics of cancer resistance and relapse.
• Combined TRAIL and BIS I therapy, despite initial effectiveness, requires consideration of residual cell motility for long-term management.