AUTHOR=Lederman Emily E. , Hope Jacob M. , King Michael R. 

TITLE=Mass Action Kinetic Model of Apoptosis by TRAIL-Functionalized Leukocytes

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00410

DOI=10.3389/fonc.2018.00410

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. A unique approach to target and kill colon, prostate, and other epithelial-type cancer cells in the blood has been recently developed that uses circulating leukocytes to present the cancer-specific, liposome-bound Tumor Necrosis Factor (TNF)-related apoptosis inducing ligand (<italic>TRAIL</italic>) on their surface along with <italic>E</italic> − <italic>selectin</italic> adhesion receptors. This approach, demonstrated both <italic>in vitro</italic> with human blood and in mice, mimics the cytotoxic activity of natural killer cells. The resulting liposomal TRAIL-coated leukocytes hold promise as an effective means to neutralize circulating tumor cells that enter the bloodstream with the potential to form new metastases.</p><p><bold>Methods:</bold> The computational biology study reported here examines the mechanism of this effective signal delivery, by considering the kinetics of the coupled reaction cascade, from TRAIL binding death receptor to eventual apoptosis. In this study, a collision of bound TRAIL with circulating tumor cells (CTCs) is considered and compared to a prolonged exposure of CTCs to soluble TRAIL. An existing computational model of soluble TRAIL treatment was modified to represent the kinetics from a diffusion-limited 3D reference frame into a 2D collision frame with advection and adhesion to mimic the <italic>E</italic> − <italic>selectin</italic> and membrane bound TRAIL treatment. Thus, the current model recreates the new approach of targeting cancer cells within the blood. The model was found to faithfully reproduce representative observations from experiments of liposomal TRAIL treatment under shear.</p><p><bold>Results:</bold> The model predicts apoptosis of CTCs within 2 h when treated with membrane bound TRAIL, while apoptosis in CTCs treated with soluble TRAIL proceeds much more slowly over the course of 10 h, consistent with previous experiments. Given the clearance rate of soluble TRAIL <italic>in vivo</italic>, this model predicts that the soluble TRAIL method would be rendered ineffective, as found in previous experiments.</p><p><bold>Conclusion:</bold> This study therefore indicates that the kinetics of the coupled reaction cascade of liposomal <italic>E</italic> − <italic>selectin</italic> and membrane bound TRAIL colliding with CTCs can explain why this new approach to target and kill cancer cells in blood is much more effective than its soluble counterpart.</p>