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