Virchow s Hypothesis lymphorecticular infiltration of cancer reflected the origin of cancer at sites of inflammation

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1 Virchow s Hypothesis 1863 lymphorecticular infiltration of cancer reflected the origin of cancer at sites of inflammation

2 Barrett s esophagus/ Esophageal adenocarcinoma PSC / Cholangiocarcinoma Viral hepatitis / Hepatocellular cancer Gastritis/ Gastric cancer Colitis / Colon cancer

3 Gastrointestinal Cancers and Chronic Infection EBV nasopharyngeal cancer H. Pylori gastric adenocarcinoma MALT Clonorchis Sinesis cholangiocarcinoma HPV anogenital cancer

4 A Generalized Scheme of Chronic Inflammation Pathogens Physical injury Normal microflora Epithelial layer Toxins PAMPs Host cell apoptosis Host cell necrosis PRRs + Endogenous ligands + Macrophage Genetic factors Chemokines Cytokines Lymphocytes Anti-inflammatory controls Karin, M Cell, 2006 Persistent inflammation CP

5 Angiogenesis (VEGF) Hallmarks of Cancer (Intrinsic Genetic Process) Uncontrolled selfsufficiency in growth (oncogenes) Death signals (tumor suppressor genes p53) Limitless replication (? stem cell) Tissue invasion Hanoham D: Cell 100:57, 2000 CP

6 Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP

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8 Incidence of Cholangiocarcinoma Incidence of Cholangiocarcinoma Years since PSC diagnosis CP Cumulative incidence of cholangiocarcinoma (%)

9 Survival factors Growth factors Oxidative, nitrosative stress Genetic mutations Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP

10 inos Expression is Upregulated in PSC and CCA Normal PSC Cholangiocarcinoma inos positive 0/30 inos positive 30/30 inos positive 20/20 Jaiswal et al. Cancer Res, 2000

11 Oxidative DNA Lesion H H 2 N O N 6 N H N N deoxyribose Oxidative Stress ROS H 2 N OH H N 6 N o N N deoxyribose Deoxyguanosine dg 8-oxo-deoxyguanosine 8-oxo-dG

12 inos Expression in PSC and Cholangiocarcinoma is Associated with Oxidatively Damaged DNA Normal PSC Cholangiocarcinoma 8-oxodG Positive: 0/10 8-oxodG Positive: 10/10 8-oxodG Positive: 10/10 Jaiswal et al, Gastroenterology,120, , 2001

13 p16 Point Mutations in PSC-associated Cholangiocarcinoma Promoter/ Enhancer 5 Exon 1 Exon 2 Exon 3 3 8/10 3/10 None None A A G A G G T C Patients T C A G A G A G A G A G A G T C T C T C A G A G A G A G

14 Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP

15 IL-6 Increases Expression of the Anti-Apoptotic Protein Mcl-1 Autocrine/paracrine pathway IL-6 Nucleus Cholangiocarcinoma cell Mcl-1 Kobayashi S et al, Gastroenterology 2005;128:

16 Normal Mcl-1 is Overexpressed in PSC and Cholangiocarcinoma ALC 8%(2/25) 20%(3/15) PSC CCA 48%(14/29) 70%(23/33)

17 anti-il (Hours) Mcl-1 actin

18 Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP

19 Developmental Signaling Pathways and Cancer Notch Wnt Hedgehog

20 Notch Signaling Pathway Sending cell Jagged Notch Receiving cell γ-secretase NICD (Intracellular domain) Cytoplasm Notch precursor Golgi CSL Nucleus Target Genes

21 Cholangiocyte Inflammation inos NO Notch Cancer phenotype Cell proliferation Anti-apoptosis Angiogenesis

22 Notch-1 Protein is Enhanced in PSC and CCA Normal Liver PSC CCA Staining Intensity (% of 2) Normal PSC CCA (n=15) (n=16) (n=12)

23 Notch-1 Expression in Cholangiocyte is inos dependent Immunoblot analysis 250K 150K 100K 603B 603B-iNOS AS Notch-1 (FL) NICD * Actin Notch-1 / 18S ratio Real-time PCR ** 603B ** p< B-iNOS AS Non-specific band

24 Cellular Mechanisms Linking Inflammation to Cholangiocarcinoma Inflammation COX-2 Bile duct inos Cholangiocarcinoma COX-2; Sirica AE, et al. Semin Liver Dis, 2002 inos; Jaiswal M, et al. Gastroenterology, 2001

25 β-catenin Pathway Activation in Response to PGE2 COX-2 EP2 PGE2 Axin α s GTP γ β P13K PIP 3 AKT PDK1 -P β- catenin β- catenin GSK-3β -P Science, 2005 Tcf Lef β- catenin Gene expression cell growth CP

26 Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling and Oncogenesis Angiogenic factors CP

27 Cytokines Bacterial/viral infection Stress Cytoplasm IKK complex IKK1 IKK2 NEMO NEMO P P IKK1 IKK2 P P NF-κB:IκB P65 P50 IκB P65 P50 IκB P P Ub-Ub-Ub-Ub-Ub-Ub NF-κB P65 P proteasome IκB P P Ub-Ub-Ub-Ub-Ub-Ub P65 NF-κB responsive gene Nucleus P50 J Clin Inves 107(2):140, 2001 Cytokines Chemokines Adhesion molecules Receptors Cell hb proteins, etc Cell proliferation Cell growth Cell ditherentiation CP

28 Nuclear Factor-κB B has Various Tumour-Promoting Functions Depending on Cell Type in Which it is Activated Growth factors (such as TNF and IL-1) Inflammatory cell TNF TNFR IL-1 IL-1R IκB p50 p65 NF-κB- binding site TNF IL-1 IL-6 CXCL8 VEGF CSF1 Tumour cell Classical pathway NF-κB activation p50 p65 NF-κB- binding site Survival BCL-X L GADD45β BFL1 SOD2 Survival factors Karin M et al Nature Reviews in Immunology, 2005 CP

29 Cytokines Bacterial/viral infection Stress Cytoplasm IKK complex IKK1 IKK2 NEMO NEMO P P IKK1 IKK2 P P NF-κB:IκB P65 P50 κb P65 P50 IκB P P Ub-Ub-Ub-Ub-Ub-Ub NF-κB P65 P proteasome IκB P P Ub-Ub-Ub-Ub-Ub-Ub P65 NF-κB responsive gene Nucleus P50 J Clin Inves 107(2):140, 2001 Cytokines Chemokines Adhesion molecules Receptors Cell hb proteins, etc Cell proliferation Cell growth Cell ditherentiation CP

30 Colitis-Associated Cancer Is Reduced By Deleting IKKß From Intestinal Epithelial Cells Greten et al Cell, 2004 Model of AOM plus DSS tumorigenesis

31 NF-κB B and Tumorigenesis in Colitis Enterocyte NF-κB intact Cancer Genetic mutations IKKβ deficient Greten FR et al: Cell, 2004 Apoptosis CP

32 AN Mitosis AB Inflammatory cells

33 HCC is increased in DEN Treated Mice Deficient in Hepatocyte IKKß DEN and WT Mice DEN and Hepatocyte IKKß Δ Mice Maeda et al. Cell, 2005

34 DEN Hepatocarcinogenesis and Hepatocye NF-κB Hepatocyte Cancer IKK-β deficiency Genetic mutations Growth/survival factors Kupffer cell cell death NF-κB activation CP

35 DEN Hepatocarcinogenesis and Kupffer Cell NF-κB Hepatocyte cancer Genetic mutations NF-κB IKK-β deficient cell death Kupffer cell activation CP

36 Cytokines Bacterial/viral infection Stress Cytoplasm IKK complex IKK1 IKK2 NEMO NEMO P P IKK1 IKK2 P P NF-κB:IκB P65 P50 IκB P65 P50 IκB P P Ub-Ub-Ub-Ub-Ub-Ub NF-κB P65 P proteasome IκB P P Ub-Ub-Ub-Ub-Ub-Ub P65 NF-κB responsive gene Nucleus P50 J Clin Inves 107(2):140, 2001 Cytokines Chemokines Adhesion molecules Receptors Cell hb proteins, etc Cell proliferation Cell growth Cell ditherentiation CP

37 Arrows indicate large tumors Cancer Cell 11:119, 2007 CP

38 AN Mitosis AB Inflammatory cells

39 Fas N TNF-R1 N TRAIL-R1/2 N C C C Extracellular Cysteine-rich Domain Transmembrane Domain Cytoplasmic Death Domain

40 FasL/CD95L Fas/CD95 The Fas DISC Pro-Caspase 8 DED DED DED DD FADD DD DD DD DED DD DED FADD DED Pro-Caspase 10 DD DED Death Domain Death Effector Domain Active Caspase 8 Active Caspase 10

41 NEMO LPC-KO NEMO/FADD LPC-KO Tunel (LPS 10 hr) Cancer Cell 11:119, 2007 CP

42 Serum ALT 1, P< Cancer Cell 11:119, 2007 NEMO LPC-KO NEMO/ FADD LPC-KO CP

43 NF-κB B in Different Cancer Models NFκB hi M S CP

44 NF-κB B in Different Cancer Models Tonic signals Inflammatory signals NFκB hi IKK NFκB Kupffer cells M S CP

45 NF-κB B in Different Cancer Models JNK hi IKK NFκB Kupffer cells IKK NFκB TNF IL-6 JNK hi ROS hi M S Cancer CP

46 A Generalized Scheme of Chronic Inflammation Pathogens Physical injury Normal microflora Epithelial layer Toxins PAMPs Host cell apoptosis Host cell necrosis PRRs + Endogenous ligands + Macrophage Genetic factors Chemokines Cytokines Lymphocytes Anti-inflammatory controls Karin, M Cell, 2006 Persistent inflammation CP

47 Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP

48 Tumor Associated Macrophages (TAM)

49 Macrophage Condeelis, J et al Cell, 2006 Common functions Angiogenic factors Tissue remodeling and repair Growth and migration factors Macrophogenesis Ductal invasion Normal epithelial cells Tumor cells Metastasis Tumor invasion Blood vessel CP

50 Contribution of Macrophages to Metastasis Blood vessel EGF EGF CSF-1 CSF-1 CSF-1 CSF-1 EGF EGF CC Wang Wang et et al: al: Trends Trends in in cell cell biology biology 15:141, 15:141, Paracrine chemotaxis CP CP

51 The Cancer Ecosystem Neoangiogenesis TAM TIL APC Connective tissue Fibroblasts CP

52 CP

53 Dead snake CP