Cells behaving badly: a theoretical model for the Fas/FasL system in tumour immunology.
One proposed mechanism of tumour escape from immune surveillance is tumour up-regulation of the cell surface ligand FasL, which can lead to apoptosis of Fas receptor (Fas) positive lymphocytes. Based upon this 'counterattack', we have developed a mathematical model involving tumour cell-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. The model predicts that (a) the production of soluble forms of Fas and FasL will lead to the down-regulation of the immune response; (b) matrix metalloproteinase (MMP) inactivation should lead to increased membrane FasL and result in a higher rate of Fas-mediated apoptosis for lymphocytes than for tumour cells. Recent studies on cancer patients lend support for these predictions. The clinical implications are two-fold. Firstly, the use of broad spectrum MMP inhibitors as anti-angiogenic agents may be compromised by their adverse effect on tumour FasL up-regulation. Also, Fas/FasL interactions may have an impact on the outcome of numerous ongoing immunotherapeutic trials since the final common pathway of all these approaches is the transduction of death signals within the tumour cell.
Webb
Steven D
SD
Department of Mathematical Sciences, Loughborough University, Leicestershire, LE11 3TU, UK. s.d.webb@lboro.ac.uk
Sherratt
Jonathan A
JA
Fish
Reginald G
RG
D017209:Apoptosis / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D008213:Lymphocyte Activation; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D019014:fas Receptor