Virchow s Hypothesis 1863 lymphorecticular infiltration of cancer reflected the origin of cancer at sites of inflammation
Barrett s esophagus/ Esophageal adenocarcinoma PSC / Cholangiocarcinoma Viral hepatitis / Hepatocellular cancer Gastritis/ Gastric cancer Colitis / Colon cancer
Gastrointestinal Cancers and Chronic Infection EBV nasopharyngeal cancer H. Pylori gastric adenocarcinoma MALT Clonorchis Sinesis cholangiocarcinoma HPV anogenital cancer
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 CP1222559-2
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 CP1221050-1
Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP1221050-2
Incidence of Cholangiocarcinoma Incidence of Cholangiocarcinoma 10.0 7.5 5.0 2.5 0.0 0 2 4 6 Years since PSC diagnosis CP1042831-1 Cumulative incidence of cholangiocarcinoma (%)
Survival factors Growth factors Oxidative, nitrosative stress Genetic mutations Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP1221050-2
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
Oxidative DNA Lesion H H 2 N O N 6 N 7 1 5 8 H 2 4 9 3 N N deoxyribose Oxidative Stress ROS H 2 N OH H N 6 N 1 5 7 8 o 2 4 9 3 N N deoxyribose Deoxyguanosine dg 8-oxo-deoxyguanosine 8-oxo-dG
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, 190-199, 2001
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
Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP1221050-2
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;128:2054-65
Normal Mcl-1 is Overexpressed in PSC and Cholangiocarcinoma ALC 8%(2/25) 20%(3/15) PSC CCA 48%(14/29) 70%(23/33)
anti-il-6 0 2 3 (Hours) Mcl-1 actin
Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP1221050-2
Developmental Signaling Pathways and Cancer Notch Wnt Hedgehog
Notch Signaling Pathway Sending cell Jagged Notch Receiving cell γ-secretase NICD (Intracellular domain) Cytoplasm Notch precursor Golgi CSL Nucleus Target Genes
Cholangiocyte Inflammation inos NO Notch Cancer phenotype Cell proliferation Anti-apoptosis Angiogenesis
Notch-1 Protein is Enhanced in PSC and CCA Normal Liver PSC CCA Staining Intensity (% of 2) 100 80 60 40 20 0 Normal PSC CCA (n=15) (n=16) (n=12)
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 1.4 1.2 1 0.8 0.6 0.4 0.2 0 ** 603B ** p<0.01 603B-iNOS AS Non-specific band
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
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 CP1222559-1
Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling and Oncogenesis Angiogenic factors CP1221050-2
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 P50 265 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 CP1271074-1
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 CP1220459-2
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 P50 265 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 CP1271074-1
Colitis-Associated Cancer Is Reduced By Deleting IKKß From Intestinal Epithelial Cells Greten et al Cell, 2004 Model of AOM plus DSS tumorigenesis
NF-κB B and Tumorigenesis in Colitis Enterocyte NF-κB intact Cancer Genetic mutations IKKβ deficient Greten FR et al: Cell, 2004 Apoptosis CP1228720-1
AN Mitosis AB Inflammatory cells
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
DEN Hepatocarcinogenesis and Hepatocye NF-κB Hepatocyte Cancer IKK-β deficiency Genetic mutations Growth/survival factors Kupffer cell cell death NF-κB activation CP1228720-2
DEN Hepatocarcinogenesis and Kupffer Cell NF-κB Hepatocyte cancer Genetic mutations NF-κB IKK-β deficient cell death Kupffer cell activation CP1228720-3
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 P50 265 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 CP1271074-1
Arrows indicate large tumors Cancer Cell 11:119, 2007 CP1266381-3
AN Mitosis AB Inflammatory cells
Fas N TNF-R1 N TRAIL-R1/2 N C C C Extracellular Cysteine-rich Domain Transmembrane Domain Cytoplasmic Death Domain
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
NEMO LPC-KO NEMO/FADD LPC-KO Tunel (LPS 10 hr) Cancer Cell 11:119, 2007 CP1266381-1
Serum ALT 1,000 800 600 400 200 P<0.05 0 Cancer Cell 11:119, 2007 NEMO LPC-KO NEMO/ FADD LPC-KO CP1266381-2
NF-κB B in Different Cancer Models NFκB hi M S CP1262985-1
NF-κB B in Different Cancer Models Tonic signals Inflammatory signals NFκB hi IKK NFκB Kupffer cells M S CP1262985-2
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 CP1262985-3
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 CP1222559-2
Survival factors Growth factors Genetic mutations Oxidative stress Cytokines Inflammatory Cells Tissue remodeling Migration, invasion Angiogenic factors CP1221050-2
Tumor Associated Macrophages (TAM)
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 CP1221406-1
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, 2005 2005 Paracrine chemotaxis CP1225113-1 CP1225113-1
The Cancer Ecosystem Neoangiogenesis TAM TIL APC Connective tissue Fibroblasts CP1224433-1
CP1224433-2
Dead snake CP1224433-3