The role of apoptosis-inducing receptors of the tumor necrosis factor family in thyroid cancer.
The tumor necrosis factor (TNF) family comprises several ligands, such as the prototype TNF-alpha, the Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), which trigger apoptosis in susceptible cells by activating respective cell-surface receptors. The study of these cell death pathways has attracted significant attention in several fields, including that of thyroid cancer, because they participate in immune system function, as an arm of cell-mediated cytotoxicity, and because recombinant ligands are available for pharmacological use. TNF-alpha is a pluripotent cytokine that induces both pro-apoptotic and anti-apoptotic effects on thyroid carcinoma cells. FasL triggers apoptosis in other tumor types, but thyroid carcinoma cells are resistant to this effect. On the other hand, TRAIL potently and selectively kills thyroid carcinoma cells. Consequently, TRAIL is the only member of the family with significant anticancer activity and an acceptable toxicity profile to be used as a novel therapy for thyroid cancer. The caspase inhibitor FLIP plays a significant role in negatively regulating receptor-induced apoptosis. Thelper 1-type cytokines, such as interferon-gamma, TNF-alpha and interleukin-1beta increase the sensitivity of both normal and neoplastic thyrocytes to FasL and TRAIL. On the other hand, IGF-I and other growth/survival factors produced in the local tumor microenvironment activate the phosphatidylinositol 3-kinase/Akt kinase pathway and exert an anti-apoptotic effect by upregulating several apoptosis inhibitors, including FLIP. Pharmacological modulation of apoptosis induced by FasL and TRAIL/Apo2L holds promise of therapeutic applications in human malignancies.
Mitsiades
C S
CS
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. mitsiades@netscape.net
Poulaki
V
V
Mitsiades
N
N
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins / Q000378:metabolism; D002450:Cell Communication; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D018417:Th1 Cells / Q000276:immunology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology* / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C074890:FliP protein, Bacillus; D007371:Interferon-gamma