Role of bacteria in
carcinogenesis
Riccardo Guidi
Frontiers in Translational Medicine
Karolinska Institutet
Dec 17 , 2013
...
epidemiological evidence
Helicobacter pylori
Barry J. Marshall and J. Robin Warren - Nobel 2005

increase risk of peptic u...
tumorigenesis is a step-wise transformation

small tubular
adenoma

KRas
activaiton

carcinoma

PIK3CA/PTEN
activation
TP5...
tumorigenic barrier
1. senescence
2. cell death

normal colon’s crypts

small tubular
adenoma

large tubular
adenoma

carc...
the tumorigenic barrier mechanisms
mutation

signal

genomic instability
oncogene
activation
cell proliferation

replicati...
genomic instability is not the only enabling characteristic of tumorigenesis

Cell 144, 646–674 (2011)
6
chronic inflammation contributes to carcinogenesis
epidemiological evidence

NSAID

placebo
1-3y

?
[RR 0.77 (95% CI 0.61, ...
chronic inflammation contributes to carcinogenesis
animal model evidence (example from colorectal carcinoma)
(kills enteroc...
dissecting the inflammatory pathway: NF-kB
Dangerous Signals
Inflammation
TNF receptors
Pattern Recognition Receptors

PP

I...
block of NF-κB reduces CRC progression
AOM

+

Azoxymethane

WT

=

Adenocarcinoma

Dextran
sulfate
sodium

Ikk KO

Ikkβ w...
but...
does NF-κB influence tumor
progression also in the context of
bacteria?

11
overview of bacterial-induced inflammation
TLR1: Lipopeptides!
TLR2: PGN, LTA (G+)!(lipoteichoic acid)
TLR3: dsRNA (virus)!...
Myd88 KO model
TLR1: Lipopeptides!
TLR2: PGN, LTA (G+)!
TLR3: dsRNA (virus)!
TLR4: LPS (G-)!
TLR5: Flagellin!
TLR9: CpG!

...
TRUC model for Ulcerative Colitis
T-bet -/- + RAG2 -/- = TRUC --> Ulcerative colitis
host-commensal
homeostasis
(high TNF-...
H. pylori cause chronic inflammation in the stomach
1) H. pylori induce COX2 gene transcription

in vitro
epithelial cells
...
you got it now:

bacterial-induced inflammation contributes
to cancer onset!

but is that all...?

16
Can bacterial toxins directly contribute to cancer?

Toxins

• invade the epithelial layer
• enter the cell
• avoid lysoso...
H. pylori toxin CagA contributes to cancer
1) CagA translocates b-catenin to the nucleus

b-catenin

2) CagA interacts wit...
Bacterial genotoxins: cytolethal distending toxin (CDT) and Colibactin!
CDT is a trimeric toxin. CdtB: active subunit,
hom...
genotoxin effects in vitro
CDT

CDT

CDT

CDT

CDT
6 months

1. genomic instability

2. gene mutations

3. anchorage indep...
genotoxin effects in vivo

Clb +

+ AOM +
il10-/germ-free

Clb -

Clb + Clb -

Clb + Clb -

Does this have a relevance in ...
Home-taking messages
1) Genomic instability and chronic inflammation
are enabling hallmarks of cancer

2) Chronic NF-kB act...
Thanks
riccardo.guidi@ki.se
@riccardoguidi87

23
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Bacteria&cancer biomed dec_2013

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Bacteria&cancer biomed dec_2013

  1. 1. Role of bacteria in carcinogenesis Riccardo Guidi Frontiers in Translational Medicine Karolinska Institutet Dec 17 , 2013 1
  2. 2. epidemiological evidence Helicobacter pylori Barry J. Marshall and J. Robin Warren - Nobel 2005 increase risk of peptic ulcers --> gastric cancer Salmonella enterica serovar Typhi Inflammatory Bowel Disease for IBD: Cell Host & Microbe 3, 417–427 (2008) Cancer 91, 854–862 (2001) Cancer 67, 2015–2020 (2006) for Salmonella: Lancet 343, 83–84 (1994) Am. J. Gastroenterol. 95, 784–787 (2000) J. Surg. Oncol. 93, 633–639 (2006) for H. pylori: Nat. Rev. Cancer 2, 28–37 (2002) 2
  3. 3. tumorigenesis is a step-wise transformation small tubular adenoma KRas activaiton carcinoma PIK3CA/PTEN activation TP53/BAX loss TSG101 loss MOLECULAR LEVEL loss of APC beta-catetin large tubular adenoma HISTOLOGICAL LEVEL normal colon’s crypts DNA hypomethylation Genomic Instability Weinberg RA, “The Biology of Cancer”, GS edition, 2007 3
  4. 4. tumorigenic barrier 1. senescence 2. cell death normal colon’s crypts small tubular adenoma large tubular adenoma carcinoma 4
  5. 5. the tumorigenic barrier mechanisms mutation signal genomic instability oncogene activation cell proliferation replicative stress DDR detection limit cell proliferation DNA damage DNA damage cell senescence/death cell senescence/death normal pre-cancer lesion cancer Science 319, 1352–1355 (2008) 5
  6. 6. genomic instability is not the only enabling characteristic of tumorigenesis Cell 144, 646–674 (2011) 6
  7. 7. chronic inflammation contributes to carcinogenesis epidemiological evidence NSAID placebo 1-3y ? [RR 0.77 (95% CI 0.61, 0.96), (NNT 12.5 (95% CI 7.7, 25)]* “three pooled RCTs that aspirin significantly reduces the recurrence of sporadic adenomatous polyps after one to three years.” *RR: risk ratio;NNT: number needed to treat The Cochrane Library , 26 Jan 2004 7
  8. 8. chronic inflammation contributes to carcinogenesis animal model evidence (example from colorectal carcinoma) (kills enterocytes)/ promoter + = Adenocarcinoma Dextran sulfate sodium Azoxymethane AOM DSS DSS DSS DSS 10 weeks chronic inflammation cyclin D1 DNA damage tumor beta-catenin AOM normal c-myc mutagen/initiator WHY does chronic inflammation contribute to cancer? Greten, F. R., et al. (2004). Cell, 118(3), 285–296. 8
  9. 9. dissecting the inflammatory pathway: NF-kB Dangerous Signals Inflammation TNF receptors Pattern Recognition Receptors PP IKK cytosol tumorigenic barrier IkB NF-κB NF-κB nucleus *prostaglandin E2 -> inflammatory signal + fever IkB TNF IL6 IL23 gene transcription inflammation proliferation Chemokines Cytokines Cox2* CycD1 Myc Cox2 anti-apoptosis Bcl-XL IAP-1 Tumor progression Nat. Immunol. 12, 715–723 (2011) 9
  10. 10. block of NF-κB reduces CRC progression AOM + Azoxymethane WT = Adenocarcinoma Dextran sulfate sodium Ikk KO Ikkβ wt ! DSS IkkβΔ Ep ! In this model, NF-kB plays a role in protecting cell from apoptosis! NF-KB Tunnel staining# Greten, F. R., et al. (2004). Cell, 118(3), 285–296. 10
  11. 11. but... does NF-κB influence tumor progression also in the context of bacteria? 11
  12. 12. overview of bacterial-induced inflammation TLR1: Lipopeptides! TLR2: PGN, LTA (G+)!(lipoteichoic acid) TLR3: dsRNA (virus)! TLR4: LPS (G-)! TLR5: Flagellin! TLR9: CpG! TLRs! PRR MUCOSAL EPITHELIUM! Intraepitelial T cells! IL1! TNFα! IL6 ! M cell! IL6! NFκB! STAT3! IL8! TNFα! DC! LAMINA PROPRIA! Peyer’s patch! Macrophage! PMN! 12
  13. 13. Myd88 KO model TLR1: Lipopeptides! TLR2: PGN, LTA (G+)! TLR3: dsRNA (virus)! TLR4: LPS (G-)! TLR5: Flagellin! TLR9: CpG! TLRs Myd88 APCmin/+ Myd88 WT APCmin/+ Myd88 KO Science (2007): 317, 124 -127! 13
  14. 14. TRUC model for Ulcerative Colitis T-bet -/- + RAG2 -/- = TRUC --> Ulcerative colitis host-commensal homeostasis (high TNF-alfa) lack adaptive immunity (lack of Treg) CTR TRUC Garrett, W. S., et al. Cancer Cell, 16(3), 208–219. 14
  15. 15. H. pylori cause chronic inflammation in the stomach 1) H. pylori induce COX2 gene transcription in vitro epithelial cells NB in vivo WB 2) H. pylori induce IL1-beta, pro-inflammatory cytokine that contributes to gastric cancer controls esophageal cancer gastric cancer H. pylori + pro-inflammatory polymorphisms? (increased expression of IL-1B) Conclusion: increased expression of IL-1B higher the risk of gastric cancer in H. pylori patients, strengthening the link: bacteria -> inflammation -> cancer Romano, M. et al. J. Biol. Chem. 273, 28560–28563 (1998) Fu, S. et al. Gastroenterology 116, 1319–1329 (1999) El-Omar, E. M. et al., Gastroenterology 124, 1193–1201 (2003) 15
  16. 16. you got it now: bacterial-induced inflammation contributes to cancer onset! but is that all...? 16
  17. 17. Can bacterial toxins directly contribute to cancer? Toxins • invade the epithelial layer • enter the cell • avoid lysosomal digestion • move the cell • change the cell cytoskeleton • decrease inflammation • avoid the immunosystem 17
  18. 18. H. pylori toxin CagA contributes to cancer 1) CagA translocates b-catenin to the nucleus b-catenin 2) CagA interacts with E-cadherin 50% gastric cancer has increased b-catenin expression b-catenin model of action in epithelial cells: b-catenin cagA E-cadherin b-catenin proliferaiton proliferation genes Peek, R. M. & Blaser, M. J. Nat. Rev. Cancer 2, 28–37 (2002). Oncogene. 2007 Jul 12;26(32):4617-26 18
  19. 19. Bacterial genotoxins: cytolethal distending toxin (CDT) and Colibactin! CDT is a trimeric toxin. CdtB: active subunit, homologous to DNase I, CdtA/CdtC: binding to cell surface!   CdtC! CdtA! Produced by several Gram negative bacteria, including Escherichia coli, Salmonella typhi, Campylobacter sp, Helicobacter sp!   Colibactin produced by commensal strains of E. coli! (and pathogenic)   Synthesized by a cluster of genes encoding for non ribosomal peptide synthetases (polyketide peptide) !   CdtB! clbQ ! clbP! clbM! clbL! clbG! clbF!clbE! clbD! clbR! clbA! ORF21! ORF22! ORF23! ORF2! intP4! clbO ! clbN! clbK! clbJ! clbI! clbH! clbC! Polyketide magasynthase PKS! Non ribosomal peptide magasynthase (NRPS)! Hybrid NRPS/PKS! clbB! Accessory proteins! 19
  20. 20. genotoxin effects in vitro CDT CDT CDT CDT CDT 6 months 1. genomic instability 2. gene mutations 3. anchorage independent growth Cell. Microbiol. (2012).doi:10.1111/cmi.12034 20
  21. 21. genotoxin effects in vivo Clb + + AOM + il10-/germ-free Clb - Clb + Clb - Clb + Clb - Does this have a relevance in humans? 21
  22. 22. Home-taking messages 1) Genomic instability and chronic inflammation are enabling hallmarks of cancer 2) Chronic NF-kB activation helps overcoming the tumorigenic barrier • G.I.: tumor is a step-wise disease • Inflammation promotes proliferation and • epidemiology • CRC mice model blocks apoptosis 3) Bacteria may contribute to cancer via Inflammation • Myd88 mice model • TRUC mice model • H.pylori infection Toxins • H. pylori CagA • bacterial genotoxins 22
  23. 23. Thanks riccardo.guidi@ki.se @riccardoguidi87 23

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