Download Tumor Necrosis Factor

Immunologia
Ilaria Pelassa
Tumor Necrosis Factor
A.A. 20062007
TNF Receptor Family
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
Who decides the fate?
DEATH DOMAIN MOLECULES
FADD
TRADD
FAS Associated Death Domain
TNFR Associated Death Domain
ADAPTORS
Locksley R.M. , et al., The TNF and TNF Receptor Superfamilies , Cell, 104 : 487, 2001
TRAFs
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
ANTITUMOR
IMMUNITY
DIRECT
CYTOTOXIC
EFFECTS
VASCULAR EFFECT
SYNERGISM WITH
ANTINEOPLASTIC AGENTS
TNF TUMOR PROMOTING EFFECTS
LOW DOSE TNF IN VITRO:
ACTIVATION OF:
UPREGULATION RAS and C-MYC
NF-KB
DOWNREGULATION Cdk-Inhibitors
K.O. EXPERIMENTS:
HIGHER INCIDENCE OF
CANCER IN ANIMAL
TNF+/+
PI3K-PKB
MAPK
PRO-SURVIVAL
PATHWAYS
TNF VASCULAR EFFECTS
TUMOR ANGIOGENESIS
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006
HYPOTHETICAL MECHANISM OF TNF-α
TNFR1
UPREGULATION
INTACT HEALTHY ENDOTHELIUM
Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006
NEW AND INNOVATIVE APPROACH WHICH COMBINES :
-VASCULAR EFFECT
- SYNERGISM WITH ANTINEOPLASTIC AGENTS
ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTS
(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
ADVANTAGES
-
-
80-90% Complete Response
Avoid amputation of the limb
Used in Sarcoma, Melanoma and
liver with Hepatic Perfusion
No toxicity of TNF
Selective accumulation of drugs
inside the tumor
DISADVANTAGES
-
In metastatic stage the patient dies
-
Only local administration
Low concentration of TNF
promotes angiogenesis
Surgical Approach
-
-
CANCER IMMUNOTHERAPY
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?
TRAIL
TNF
TNFR
TRAILR
LT
FAS L
FASLR
DENDRITIC CELL
LTR
TUMOR CELL
APOPTOSIS
“ 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
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 tumorspecific? , 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