Tumor Necrosis FactorTumor Necrosis Factor

Ilaria PelassaImmunologia

A.A. 2006-2007

TNF Receptor FamilyTNF 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?Who decides the fate?

DEATH DOMAIN MOLECULESDEATH 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 DomainADAPTORS

TRAFs 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

DIRECT CYTOTOXIC EFFECTS

VASCULAR EFFECTSYNERGISM 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+/+

TNF VASCULAR EFFECTS

TUMOR ANGIOGENESISTUMOR ANGIOGENESIS

Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006

HYPOTHETICAL MECHANISM OF TNF-HYPOTHETICAL MECHANISM OF TNF-αα

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 :

-VASCULAR EFFECT

- SYNERGISM WITH ANTINEOPLASTIC AGENTS

ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTSISOLATED 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 PERFUSIONISOLATED LIMB PERFUSION

ADVANTAGESADVANTAGES- 80-90% Complete Response80-90% Complete Response- Avoid amputation of the limbAvoid amputation of the limb- Used in Sarcoma, Melanoma and Used in Sarcoma, Melanoma and

liver with Hepatic Perfusionliver with Hepatic Perfusion- No toxicity of TNFNo toxicity of TNF- Selective accumulation of drugs Selective accumulation of drugs

inside the tumorinside the tumor

DISADVANTAGESDISADVANTAGES- In metastatic stage the patient dies In metastatic stage the patient dies

- Only local administrationOnly local administration- Low concentration of TNF Low concentration of TNF

promotes angiogenesis promotes angiogenesis - Surgical ApproachSurgical 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?

TNF

LTFAS 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

BIBLIOGRAPHYBIBLIOGRAPHY

Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006Pfeffer K. , Biological functions of tumor necrosis factor cytokines and their

receptors, Cytokine & Growth Factor Reviews 14 : 185 , 2003Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF

superfamily, Cytokine & Growth Factor Reviews , 14 :193 ,2003Wajant H. et al. TNF receptor associated factors in cytokine signaling / Cytokine &Growth Factor Reviews 10: 15, 1999Locksley 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, 2:736,2003Atish T. P.et al., Modulating TNF-a signaling with natural products, Drug

Discovery Today 11:15,2006Lejeune 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, 2005Dunn G. P. et al., The Immunobiology of Cancer Immunosurveillance and Immunoediting, Immunity, 21 : 137, 2004Kumar 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 1996EckS M.J. et al., The Structure of Tumor Necrosis Factor-alpha at 2.6 A Resolution, The Journal of Biological Chemistry, 264: 17595,1989Wiley S. R. et al., TWEAK a member of the TNF superfamily, Cytokine & Growth Factor Reviews 14 : 241,2003Benedict C. A..,Viruses and the TNF-related cytokines, an evolving battle, Cytokine & Growth Factor Reviews 14 : 349,2003