Tumor Necrosis Factor Tumor Necrosis Factor A.A. 2006- 2007 TNF - - PowerPoint PPT Presentation
Immunologia Ilaria Pelassa Tumor Necrosis Factor Tumor Necrosis Factor A.A. 2006- 2007 TNF Receptor Family TNF Receptor Family Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF superfamily Cytokine & Growth Factor
Ilaria Pelassa Immunologia A.A. 2006- 2007
Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF superfamily Cytokine & Growth Factor Reviews , 14 :193 ,2003
LIFE OR DEATH ?
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11 : 397, 2006
DEATH DOMAIN MOLECULES DEATH DOMAIN MOLECULES
Locksley R.M. , et al., The TNF and TNF Receptor Superfamilies , Cell, 104 : 487, 2001
FADD FAS Associated Death Domain TRADD TNFR Associated Death Domain
ADAPTORS
Wajant H. et al. TNF receptor associated factors in cytokine signaling/ Cytokine & Growth Factor Reviews, 10 : 15, 1999
ITS PLEIOTROPIC PROPERTIES LEAD TO….
TNF ANTI-NEOPLASTIC EFFECTS
DIRECT CYTOTOXIC EFFECTS VASCULAR EFFECT SYNERGISM WITH ANTINEOPLASTIC AGENTS ANTITUMOR IMMUNITY
TNF TUMOR PROMOTING EFFECTS
UPREGULATION RAS and C-MYC DOWNREGULATION Cdk-Inhibitors LOW DOSE TNF IN VITRO: ACTIVATION OF: NF-KB PI3K-PKB MAPK PRO-SURVIVAL PATHWAYS K.O. EXPERIMENTS: HIGHER INCIDENCE OF CANCER IN ANIMAL TNF+/+
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006
HYPOTHETICAL MECHANISM OF TNF- HYPOTHETICAL MECHANISM OF TNF-α α
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006 TNFR1 UPREGULATION INTACT HEALTHY ENDOTHELIUM
NEW AND INNOVATIVE APPROACH WHICH COMBINES :
ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTS ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTS (ILP) (ILP)
Lejeune F.J., Efficiency of recombinant human TNF in human cancer therapy Cancer Immunity, 6: 6 , 2006
RESULTS COMBINATION TREATMENTS: TNF , INF-γ , Melphalan (TIM-ILP) TNF , Melphalan (TM-ILP) Melphalan (M-ILP) Efficacy of TIM-ILP on bulky melanoma metastasis
ISOLATED LIMB PERFUSION ISOLATED LIMB PERFUSION ADVANTAGES ADVANTAGES
80-90% Complete Response
Avoid amputation of the limb
Used in Sarcoma, Melanoma and liver with Hepatic Perfusion liver with Hepatic Perfusion
No toxicity of TNF
Selective accumulation of drugs inside the tumor inside the tumor
DISADVANTAGES DISADVANTAGES
In metastatic stage the patient dies
Only local administration
Low concentration of TNF promotes angiogenesis promotes angiogenesis
Surgical Approach
Smyth M.J. et al.,Nature’s TRAIL On a Path to Cancer Immunotherapy, Immunity, 18: 1 , 2003
Lu G. et al.,Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. The Journal of Immunology, 168: 1831, 2002
WHAT HAPPENS?
TNF LT FAS L TRAIL TNFR LTR FASLR TRAILR APOPTOSIS DENDRITIC CELL TUMOR CELL
“ Defining the role of TNF in cancer therapy is a challenging task. The pleiotropic nature of the cytokine, which can stimulate multiple, complexly interconnected pathways often involved in opposing phenomena, makes it difficult to discern the ultimate effect of TNF ”
Mocellin S. et al. , Tumor necrosis factor, cancer and anticancer therapy, Cytokine & Growth Factor Reviews, 16:35 , 2005
BIBLIOGRAPHY BIBLIOGRAPHY
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006 Pfeffer K. , Biological functions of tumor necrosis factor cytokines and their receptors, Cytokine & Growth Factor Reviews 14 : 185 , 2003 Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF superfamily, Cytokine & Growth Factor Reviews , 14 :193 ,2003 Wajant H. et al. TNF receptor associated factors in cytokine signaling / Cytokine & Growth Factor Reviews 10: 15, 1999 Locksley R.M., et al. , The TNF and TNF Receptor Superfamilies, Cell, 104:487, 2001 Mocellin S. et al. , Tumor necrosis factor, cancer and anticancer therapy, Cytokine & Growth Factor Reviews, 16:35 , 2005 Palladino M.A.et al. , Anti-Tnf-α therapies : the next generation, Nature, 2:736,2003 Atish T. P.et al., Modulating TNF-a signaling with natural products, Drug Discovery Today 11:15,2006 Lejeune F.J.,et al., Efficiency of recombinant human TNF in human cancer therapy, Cancer Immunity, 6: 6 , 2006 Smyth M.J. et al.,Nature’s TRAIL On a Path to Cancer Immunotherapy, Immunity, 18: 1 , 2003 Lu G. et al.,Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. The Journal of Immunology, 168: 1831, 2002
Kanduc D. et al, Cell death: Apoptosis versus necrosis, Int Journal of Oncology , 21: 165 , 2002 Lucas R. et al. , Tumor Necrosis Factor : How to make a killer molecule tumor- specific? , Curr Can Drug Targets, 5:381, 2005 Schreiber R.D., Cancer Vaccines 2004 opening address: The molecular and cellular basis of cancer immunosurveillance and immunoediting, Cancer Immunity, 5: 1, 2005 Dunn G. P. et al., The Immunobiology of Cancer Immunosurveillance and Immunoediting, Immunity, 21 : 137, 2004 Kumar A. et al.,Tumor Necrosis Factor et and Interleukin 1 Are Responsible for In Vitro Myocardial Cell Depression Induced by Human Septic Shock Serum, j. Exp. Med.,183 1996 EckS M.J. et al., The Structure of Tumor Necrosis Factor-alpha at 2.6 A Resolution, The Journal of Biological Chemistry, 264: 17595,1989 Wiley S. R. et al., TWEAK a member of the TNF superfamily, Cytokine & Growth Factor Reviews 14 : 241,2003 Benedict C. A..,Viruses and the TNF-related cytokines, an evolving battle, Cytokine & Growth Factor Reviews 14 : 349,2003