Role of IL-6 in colon cancer development

Role of IL-6 in colon cancer
development
Janoš Terzić
School of Medicine in
Splitu
IL-6
• 
• 
• 
• 
B cell maturation
Acute phase protein
Elevated in different cancers
Secreted by:
–  lymphocytes T, macrophages, fibroblasts,
keratinocytes, hepatocytes, synovial and
endothelial cells
•  IL-6 release is stimulated by:
–  IL-1, TNF-α, LPS, stress
VIA
NF-κB, AP1 i C/EPBβ
Tadimitsu Kishimoto
IL-6 signaling
Chronic inflamma,on and cancer •  1863. Rudolf Virchow: “limforeticular infiltrate”
reflects cancer origin
•  20% cancers are connected to infection and
inflammation
•  Inflammation: chemicals (nikotin, azbest), infections
(HPV, H.pylori, HCV…), autoimmunity (IBD), obesity
(3%-8%).
•  NSAID (Aspirin)
Immunity, Inflammation, and Cancer, Cell Volume 140, Issue 6 2010 883 – 899
Inflammation
affects all
aspects of
tumorigenesis
Immunity, Inflammation, and Cancer, Cell Volume 140, Issue 6 2010 883 – 899
Colon cancer •  Incidence 1 million per year
•  2. most common
•  20% familiar form
Inflammatory bowl disease
•  Over 30.y, 20% will develop CAC
•  CAC mortality rate is 50%
•  Cancer Cell
Knock-­‐out modes • 
• 
• 
• 
• 
IL-6
TNF-α
IL-12/23
TRAF3
TRAF6
AOM – DSS
•  Azoxymethane (AOM):
–  1. dan; i.p., 12,5 mg/kg
•  Dextran sulfate sodium (DSS):
–  Polimer glucose with 17-20% sulphur
–  1,5% do 2,5% in drinking water
–  5 d. drinking and 14 d. rest
AOM – DSS protokol
AOM
DSS
DSS
1d. 5d. 24d. 43.d
DSS
100.d
SAC.
tretmtment
time
•  Dan 100.
–  BrdU (100 mg/kg)
–  Tissue for pathology and proteins & RNA
–  Tumor counts
•  Acute and chronic
First results IL-6 initiates cancer ?!
Do we need IL-6 at all?
Main finding of the study
Ki67
Proliferation of tumor cells
Origin of IL-­‐6 Chimeras by bone marrow transplanta,on WT WT
WT IL-6
IL-6 WT
IL-6 IL-6
Origin of IL-6
αIL-6
Cellular sources of IL-6
Which pathway protumorigenic IL-6
signals uses?
STAT3
Stat3 Δ IEC
Stat3 is important
Last experiments
Conclusions • 
• 
• 
• 
IL-6 stimulates proliferation
IL-6 is anti-apoptotic
Stat3 is main signaling pathway in CAC
IL-6 i STAT3 inhibitors could be beneficial
in CAC
Is there connection with real, human
cancers ?
IL-6 expression in colon
zdr. sluznica
at risk
colon cancer
Ki-67 expression in colon
norm. sluznica
sluznica at risk
Other KO modes used
•  IL-6
•  TNF α
•  IL12 / 23
•  TRAF3
•  TRAF6
Support
Collaborators
•  SERGEI GRIVENNIKOV
•  ELIAD KARIN
•  MICHAEL KARIN
•  FULBRIGHT PROGRAM
•  EMBO S. F.
•  MINISTARSTVO
ZNANOSTI RH
About the Cover
CTLA- 4 :
cytotoxic T-lymphocyte-associated antigen 4
•  CTLA-4 discovered in 1986, inhibits T cells
•  Testied on mice in 1997, ništa do 2010
•  Metastatic melanoma life expectancy :
–  6 months on standrad therapy
–  10 months on anti-CTL-4
–  25% of patients survives for 2 years.
•  For the first time that some therapy extends life
•  In 2012. FDA aproval for melanoma
PD-1: programmed death 1 receptor
•  Discovered in 1992.
•  Could be engaged with PD-L1 and PD-L2 in
tumor microenvironment
•  PD-L1 and PD-L2 are present of cancer cells
•  Could be better than CTLA-4 inhibition
•  anti- PD-1 or anti-PD-L1 •  Efficient even in lung cancer