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CCA/CRC in PSC - Experimental

CCA/CRC in PSC - Experimental. Luca FABRIS (Padua, New Haven) Vincenzo CARDINALE (Rome). Project proposals. # 1 Targeted mutation profiling of PSC-related cholangiocarcinoma. Folseraas T ( Norwegian PSC Research Center)

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CCA/CRC in PSC - Experimental

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  1. CCA/CRC in PSC - Experimental Luca FABRIS (Padua, New Haven) Vincenzo CARDINALE (Rome)

  2. Project proposals #1 Targeted mutation profiling of PSC-related cholangiocarcinoma. Folseraas T (Norwegian PSC Research Center) #2 Role of the Stroma Microenvironment in Promoting Cholangiocarcinogenesis in PSC. Fabris L, Strazzabosco M (Padua, Milan, New Haven) #3 Involvement of peribiliary glands and biliary tree stem cells in the origin of cholangiocarcinoma emerging in PSC patients; potential therapeutic targets. Alvaro D, Gaudio E, Carpino G, Cardinale V (Rome) #4 Evaluation of peribiliary gland lesions predictive of PSC/PSC-CCA: radiologic-pathological correlates. Alvaro D, Gaudio E, Carpino G, Cardinale V (Rome)

  3. Discussion

  4. MOLECULAR PROFILING AND CLASSIFICATION OF CHOLANGIOCARCINOMA • 545 genes with altered expression in EH- vs 2,354 in IH-CCA . Miller et al. J Exp Clin Cancer Res 2009 • Mutations in KRAS by tumor site: 53.3% (8/15) of hilarvs6.7% (9/54) of peripheral type. Andersen et al. Gastroenterology 2012 • Mutations in IDH1 and IDH2 were found only in IH-CCA (n= 9), but not in EH-CCA (n= 22) and gallbladder cancer (n= 75). Borger et al. Oncologist 2012. • IH-CCAs were significantly more frequently bcl-2+ and p16+; EH-CCAs were more often p53+ . Karamitopoulou et al. Am J ClinPathol 2008 • Epigenetic abnormalities: methylation of RASSF1A was more common in EH- than in IH-CCA, while the opposite was demonstrated for methylation of GSTP gene. Yang et al. Mod Pathol 2005.

  5. Etiology-molecular interplay • HBV-related IHCCAs are associated with an extremely high (> than 40%) frequency of somatic mutations in PTPN3 gene (Gao et al Gastroenterology 2014) • Mutations inactivating the phosphatase activity completely abolishes PTPN3-mediated suppression of HBV gene expression and replication. PTPN3 mutations and HBV may exert synergistic effects in the origin of the IHCCA (Alvaro D. Gastroenterology 2014) • PSC-CCA molecular players should be studied in a compared manner

  6. Conclusion remarks Research perspectives

  7. HUMAN ADULT LIVER adult life Bile ducts regeneration (Pdx1 driven embrional transdifferantion) Multiple fates: goblet cells, cholangiocytes, neuro-endocrine Liver parenchyma regeneration Hepatocyte fate (Wnt) Biliary fate (Notch) PSC PSC and UC: Is it a lineage-dependant association? ? Viral Hepatitis ALD NASH PBC ? LINEAGE-DEPENDANT DISEASES!

  8. CANALS OF HERING (hHpSC-derived lineage) PERIBILIARY GLANDS (hBTSC-derived lineage) Human Hepatic Stem Cells Biliary Tree Stem/Progenitor Cell combined HCC-CCA EH-CCA and IH-CCA large bile duct type with mucin production (S100p+) IH-CCA Ductular type or cholangiolocarcinoma (NCAM+) Cholangiocytes of large IH and EH Bile duct & Globet Cells (Mucin-Producing) Immature cholangiocytes Oncogenic Events IH-CCA Small bile duct Type/mixed-CCA (NCAM+/-,S100p-) Interlobular mature cholangiocytes Histology: mixed differentiation features including focal hepatocytic differentiation and CCL features Grossly: peripheral location and mass forming growth Clinical: not IH bile ducts dilatation and jaundice Associated diseases: liver cirrhosis Histology: mucin-production, involvement within the tumour of large ducts and of PBGs Grossly: peri-ductal infiltrating /mass forming growth Clinical: IH bile ducts dilatation and jaundice Associated diseases: large IH and EH bile ducts pathologies Cardinale V, …, Alvaro D. WJGO 2012

  9. The importance to look to the right .... Basic scientist interested in translational research Clinician interested in translational research Colangio-MR with contrast agents 100% accordance In vitro models In vivo models Cherchez le Pathologiste… Human biliary tree stem/progenitor cells (hBTSCs) Large intrahepatic and extrahepatic bile ducts Human hepatic stem/progenitor cells (hHpSCs)

  10. Hypothesis The inflammatory immune-mediated processes underlining PSC and UC could target cells originating from biliary and intestinal lineages indistinguishably ??? Stem cells: CD133, EpCAM, Lgr5 CD133, EpCAM, Lgr5 Colon crypts Peribiliary Glands Cardinale V,…. Alvaro D. Hepatology 2011, J. Anatomy 2012, Nature Rev . 2012.

  11. Genetic predisposition background (Rev by Hirschfield and by Karlsen) Gut microbiota role “leaky gut” in IBD (Rev by Hirschfield and by Karlsen) diet and metabolism (De Minicis et al 2013) cholangiocytes Hepatic and bile ducts TLRs/NF-kB mediated inflamation (Rev by Hirschfield and by Karlsen) goblet cells progenitors . Bile composition alteration and toxicity . . . . BTSCs . . . . . . . . . . . . . . . . . . . . WNT Notch Lymphocytes homing (Rev by Adams DH) and CD28 loss (Liaskou A), FAS/FAS-L apoptosis deregulation (Riccio M) self-renewal and carcinogenesis (cancer stem cells) bile ducts regeneration Stem cell nich microenviroment alteration: Stem cell activation Differentiation inbalance Mucinous metaplasia (Bobrowski A) SHH mediated EMT and fibrosis (Guy CD, Omenetti A) Antigens exposure Vascular suffering Metabolome sufferance Transition to CAF (Fabbris L) BMP Hedgehog . . development, differentiation, bile ducts regeneration endoderm specification

  12. Cholangiocarcinoma . WNT Notch cholangiocytes goblet cells progenitors . . . BTSCs . . . . . . . . . . . . . . . . . Boulter 2010, Spee and Carpino 2010 Stem cells proliferation LGR5, OCT4, CD90, CD13 Cholangiocyte differentiation attempt EpCAM, SOX9, SOX17, HES1 BMP Hedgehog . . . . Omenetti 2010, Day 2012, Bobrowski 2013 Mucinous metaplasia EMT metaplasia S100A, Muc5ac Mucinous metaplasia Modified from Notch/HES1 (Alagille Syndrome, bile ducts regeneration), Sonic hedgehog (development, differentiation, cell proliferation) and Wnt (self-renewal and carcinogenesis) signalling play a major role in regulating stem cell self-renewal, cholangiocyte differentiation, biliary tree development and carcinogenesis.

  13. STEM CELL PERSPECTIVE INTO PCS/CCA TREATMENT • Preservation of stem cell niche micro-environment • Metabolic control • High fibers diet, low fat and low fructose • Reduction of bacteria translocation • Liver health • (reduction of oxisterols, metabolome imbalance, systemic induced alterations mediated by the insulin resistance and obesity) • Early diagnoses by evaluating stem cell activation and PBGs hypertrophy; • Early treatment (conventional, anti inflammatory and immunosuppressive drugs, antibiotics) in an fibrosis stage

  14. Mucin-CCA, Pancreaticcancer and Colorectalcancer. Similarcancersoriginatingfromsimilaraffectedglands in PSC? CSCs: CD133, EpCAM, Lgr5 CD133, EpCAM, Lgr5 CD133, EpCAM, Lgr5 Mucin-CCA Pancreatic ductal adenoK Human ColoRectal Cancer Stem cells: CD133, EpCAM, Lgr5 CD133, EpCAM, Lgr5 CD133, EpCAM, Lgr5 Colon crypts Peribiliary Glands Pancreatic duct glands Cardinale V/Carpino G, …., Gaudio E/Alvaro D. Hepatology 2011, J. Anatomy 2012, Nature Rev . 2012.

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