Colangiocarcinoma: uma prova de conceito

Transcription

1 Colangiocarcinoma: uma prova de conceito (A proof of concept) Lúcio Lara Santos MD,PhD

2 Origin of cancer: a new paradigm CSES- chronic stress escape strategy; NCCCT- normal cell cancer cell transition Brücher and Jamall BMC Cancer 2014, 14:331

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4 Model Cholangiocarcinoma Classification

5 Nat. Rev. Gastroenterol. Hepatol. Cholangiocarcinoma incidence in the world Cholangiocarcinoma Portugal 54 cases/year cases /year Banales, J. M. et al. (2016) Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) doi: /nrgastro

6 Opisthorchis Felineus Clonorchis sinensis Opisthorchis Viverrini liver flukes of the family Opisthorchiidae (Ophisthorchis viverrini, O. felineus and Clonorchis sinensis)

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8 Opisthorchis Viverrini Life cycle of Opisthorchis viverrini

9 Opisthorchis Felineus Life cycle of Opisthorchis felineus

10 Opisthorchis Viverrini

11 P. Brindley 2016

12 O. viverrini and C. sinensis are classified as group 1 carcinogens by the International Agency for Research on Cancer

13 However.

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15 Why this issue? In Italy, this parasite was first described in cats and dogs in Tuscany and Piedmont Regions, yet for over 100 years the infection was not detected or reported in humans and no investigation on this pathogen was carried out. This scenario has changed radically in the last decade with the occurrence of several outbreaks of acute human infections

16 Province of Viterbo All infected persons had consumed raw fillets of tench (Tinca tinca) fished from two lakes in central Italy

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19 New cases in cats from the same region

20 Yasunori Sato et al., J. Gasteroenterol, 2013

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22 BilIN3 CCA

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24 Photo A shows a normal portal tract with bile duct, hepatic arteriole, portal venule, and a clearly defined limiting plate. The smaller or interlobular bile ducts are lined by cuboidal or low columnar epithelium. No evidences of inflammation (H&E staining). Photo A1 shows a normal portal tract without fibrosis (Masson s trichrome staining).

25 Photo B1 shows biliary obstruction caused by Opisthorchis felineus with portal area enlargement, (H&E staining). Photo C1, Masson s trichrome stained tissues showing a huge peri-portal fibrosis (blue stained area). Fibrosis is not only the result of necrosis, collapse and scar formation but also the result of derangements in the synthesis and degradation of matrix by injured mesenchymal cells that synthesize the various components of the matrix.

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27 Eggs

28 Flat epithelial lesions of the biliary tract cannot be detected by image analysis..the biliary tract is often affected by inflammatory conditions, and the resultant changes of the biliary epithelium make it difficult to differentiate them from neoplasia. (..) In the biliary tract there are several forms of intraepithelial neoplasia of the flat type, and biliary intraepithelial neoplasia (BilIN) is known as one of such lesions that represent the multistep cholangiocarcinogenesis. Yasunori Sato et al., J. Gasteroenterol, 2013

29 Numerous oxysterols and related DNAadducts detected in the liver fluke eggs and in bile from infected hamsters suggested that infection-associated oxysterols

30 oxysterol-like molecules LC-MS/MS analysis

31 oxysterol-like molecules O. felineus eggs LC-MS/MS analysis

32 Multiple factors likely contribute the carcinogenesis of these helminth-induced cancers. As sterol derivatives, catechol estrogens and oxysterols share a core cyclopentanophenanthrene-4-ring, and the ability to oxidize DNA and other macromolecules. Elevated levels of these metabolites occur in the helminths themselves and in the infected people; and infected cases excrete metabolites of DNA-estrogen adducts and oxysterol-adducts. Elevated levels of oxidized DNA (8- nitroguanine and 8-oxo-2'-deoxyguanosine) during chronic opisthorchiasis and UGS perhaps reflect carcinogenic process initiated by catechol estrogens and oxysterols

33 Liver fluke

34 Model

35 Cholangiocarcinoma (CC) is a complex disease encompassing a group of related but distinct malignancies that may emerge at different anatomic sites along the intrahepatic and extrahepatic biliary tree

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37 Proteomic analysis O Vivirreni O Felineus? Rupp, C., BBA - Molecular Basis of Disease (2017)

38 Treatment of cholangiocarcinoma may include the following : Surgery Stenting Photodynamic therapy (PDT) - Redaporfin Radiation therapy Chemotherapy Selective internal radiation therapy (SIRT) ORPHAN DRUG DESIGNATION FROM EMA and FDA FOR BILIARY TRACT and CCA CANCER We have also portuguese research groups in this field

39 Cholangiocarcinoma Portuguese Task-force

40 Center for the Study in Animal Science, ICETA, University of Porto Lúcio Lara Santos Maria João Gouveia Maria Y.Pakharukova Thewarach Laha Banchob Sripa Galina A.Maksimova Gabriel Rinaldi Paul J.Brindley Paula oliveira Maria dos Anjos Viatcheslav A.Mordvinov Teresina Amaro José Manuel Correia da Costa UCBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto Institute of Cytology and Genetics Novosibirsk State University Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Department of Microbiology, Immunology & Tropical Medicine, Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC Laboratory of Drug Metabolism and Pharmacokinetics, Institute of Molecular Biology and Biophysics, Novosibirsk, Russia Experimental Pathology and Therapeutics Group, Research Center of Instituto Português de Oncologia Centre for Parasite Immunology and Biology, Infectious Diseases Department, INSA Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto UTAD Nuno Vale