Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma

Ozlem Kutlu, Humeyra Nur Kaleli, Ebru Ozer, Ozlem Kutlu, Humeyra Nur Kaleli, Ebru Ozer

Abstract

The proportion of obese or diabetic population has been anticipated to increase in the upcoming decades, which rises the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Recent evidence indicates that NASH is the main cause of chronic liver diseases and it is an important risk factor for development of hepatocellular carcinoma (HCC). Although the literature addressing NASH-HCC is growing rapidly, limited data is available about the etiology of NASH-related HCC. Experimental studies on the molecular mechanism of HCC development in NASH reveal that the carcinogenesis is relevant to complex changes in signaling pathways that mediate cell proliferation and energy metabolism. Genetic or epigenetic modifications and alterations in metabolic, immunologic, and endocrine pathways have been shown to be closely related to inflammation, liver injury, and fibrosis in NASH along with its subsequent progression to HCC. In this review, we provide an overview on the current knowledge of NASH-related HCC development and emphasize molecular signaling pathways regarding their mechanism of action in NASH-derived HCC.

Figures

Figure 1
Figure 1
Development of NASH and HCC from healthy liver.
Figure 2
Figure 2
The proposed mechanisms in NASH-related HCC progression.
Figure 3
Figure 3
Molecular signaling pathways involved in NASH-related HCC.
Figure 4
Figure 4
Interaction of oncogenic pathways in NASH-HCC progression.

References

    1. Baffy G., Brunt E. M., Caldwell S. H. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. Journal of Hepatology. 2012;56(6):1384–1391. doi: 10.1016/j.jhep.2011.10.027.
    1. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver International. 2017;37:81–84. doi: 10.1111/liv.13299.
    1. Michelotti G. A., Machado M. V., Diehl A. M. NAFLD, NASH and liver cancer. Nature Reviews Gastroenterology & Hepatology. 2013;10(11):656–665. doi: 10.1038/nrgastro.2013.183.
    1. Ascha M. S., Hanouneh I. A., Lopez R., Tamimi T. A.-R., Feldstein A. F., Zein N. N. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–1978. doi: 10.1002/hep.23527.
    1. Said A., Ghufran A. Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma. World Journal of Clinical Oncology. 2017;8(6):429–436. doi: 10.5306/wjco.v8.i6.429.
    1. Margini C., Dufour J. F. The story of HCC in NAFLD: From epidemiology, across pathogenesis, to prevention and treatment. Liver International. 2016;36(3):317–324. doi: 10.1111/liv.13031.
    1. Day C. P., James O. F. W. Steatohepatitis: A Tale of Two ‘Hits’? Gastroenterology. 1998;114(4):842–845. doi: 10.1016/s0016-5085(98)70599-2.
    1. Gentile C. L., Pagliassotti M. J. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. The Journal of Nutritional Biochemistry. 2008;19(9):567–576. doi: 10.1016/j.jnutbio.2007.10.001.
    1. Sumida Y., Niki E., Naito Y., Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radical Research. 2013;47(11):869–880. doi: 10.3109/10715762.2013.837577.
    1. Kawano Y., Cohen D. E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. Journal of Gastroenterology. 2013;48(4):434–441. doi: 10.1007/s00535-013-0758-5.
    1. Al-Busafi S. A., Bhat M., Wong P., Ghali P., Deschenes M. Antioxidant therapy in nonalcoholic steatohepatitis. Hepatitis Research and Treatment. 2012;2012:8. doi: 10.1155/2012/947575.947575
    1. Browning J. D., Horton J. D. Molecular mediators of hepatic steatosis and liver injury. The Journal of Clinical Investigation. 2004;114(2):147–152. doi: 10.1172/JCI200422422.
    1. Brunt E. M., Kleiner D. E., Wilson L. A., Belt P., Neuschwander-Tetri B. A. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810–820. doi: 10.1002/hep.24127.
    1. Tilg H., Moschen A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–1846. doi: 10.1002/hep.24001.
    1. Takaki A., Kawai D., Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH) International Journal of Molecular Sciences. 2013;14(10):20704–20728. doi: 10.3390/ijms141020704.
    1. Peverill W., Powell L. W., Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. International Journal of Molecular Sciences. 2014;15(5):8591–8638. doi: 10.3390/ijms15058591.
    1. Sookoian S., Pirola C. J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883–1894. doi: 10.1002/hep.24283.
    1. Dongiovanni P., Donati B., Fares R., et al. PNPLA3 I148M polymorphism and progressive liver disease. World Journal of Gastroenterology. 2013;19(41):6969–6978. doi: 10.3748/wjg.v19.i41.6969.
    1. Yopp A. C., Choti M. A. Non-alcoholic steatohepatitis-related hepatocellular carcinoma: A growing epidemic? Digestive Diseases. 2015;33(5):642–647. doi: 10.1159/000438473.
    1. Smagris E., BasuRay S., Li J., et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61(1):108–118. doi: 10.1002/hep.27242.
    1. Mondul A., Mancina R. M., Merlo A., et al. PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. Journal of Nutrition. 2015;145(8):1687–1691. doi: 10.3945/jn.115.210633.
    1. Pirazzi C., Valenti L., Motta B. M., et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Human Molecular Genetics. 2014;23(15):4077–4085. doi: 10.1093/hmg/ddu121.
    1. Bruschi F. V., Tardelli M., Claudel T., Trauner M. PNPLA3 expression and its impact on the liver: current perspectives. Hepatic Medicine: Evidence and Research. 2017;Volume 9:55–66. doi: 10.2147/HMER.S125718.
    1. Kozlitina J., Smagris E., Stender S., et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics. 2014;46(4):352–356. doi: 10.1038/ng.2901.
    1. Liu Y.-L., Reeves H. L., Burt A. D., et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature Communications. 2014;5, article 4309 doi: 10.1038/ncomms5309.
    1. Chen L. Z., Xia H. H., Xin Y. N., Lin Z. H., Xuan S. Y. TM6SF2 E167K Variant, a novel genetic susceptibility variant, contributing to nonalcoholic fatty liver disease. Journal of Clinical and Translational Hepatology. 2015;3(4):265–270. doi: 10.14218/JCTH.2015.00023.
    1. Bugianesi E., Manzini P., D'Antico S., et al. Relative contribution of iron burden, HFE mutation and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology. 2004;39(1):179–187. doi: 10.1002/hep.20023.
    1. Nelson J. E., Bhattacharya R., Lindor K. D., et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in caucasians with nonalcoholic steatohepatitis. Hepatology. 2007;46(3):723–729. doi: 10.1002/hep.21742.
    1. Ye Q., Qian B.-X., Yin W.-L., Wang F.-M., Han T. Association between the HFE C282Y, H63D polymorphisms and the risks of non-alcoholic fatty liver disease, liver cirrhosis and hepatocellular carcinoma: An updated systematic review and meta-analysis of 5,758 cases and 14,741 controls. PLoS ONE. 2016;11(9)e0163423
    1. Mancina R. M., Dongiovanni P., Petta S., et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5):1219–1230. doi: 10.1053/j.gastro.2016.01.032.
    1. Thabet K., Chan H. L. Y., Petta S., et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology. 2017;65(6):1840–1850. doi: 10.1002/hep.29064.
    1. Schulze K., Imbeaud S., Letouzé E., et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature Genetics. 2015;47(5):505–511. doi: 10.1038/ng.3252.
    1. Liang X.-T., Pan K., Chen M.-S., et al. Decreased expression of XPO4 is associated with poor prognosis in hepatocellular carcinoma. Journal of Gastroenterology and Hepatology. 2011;26(3):544–549. doi: 10.1111/j.1440-1746.2010.06434.x.
    1. Zain S. M., Mohamed R., Cooper D. N., et al. Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease. PLoS ONE. 2014;9(4)e95604
    1. Iacobazzi V., Castegna A., Infantino V., Andria G. Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Molecular Genetics and Metabolism. 2013;110(1-2):25–34. doi: 10.1016/j.ymgme.2013.07.012.
    1. Tryndyak V. P., Han T., Muskhelishvili L., et al. Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl-deficient diet. Molecular Nutrition & Food Research. 2011;55(3):411–418. doi: 10.1002/mnfr.201000300.
    1. Liu F., Li H., Chang H., Wang J., Lu J. Identification of hepatocellular carcinoma-associated hub genes and pathways by integrated microarray analysis. TUMORI. 2015;101(2):206–214. doi: 10.5301/tj.5000241.
    1. Erstad D. J., Fuchs B. C., Tanabe K. K. Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy. Cancer. 2018;124(15):3084–3104. doi: 10.1002/cncr.31257.
    1. Cheung O., Puri P., Eicken C., et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology. 2008;48(6):1810–1820. doi: 10.1002/hep.22569.
    1. Takaki Y., Saito Y., Takasugi A., et al. Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. Cancer Science. 2014;105(10):1254–1260. doi: 10.1111/cas.12498.
    1. de Conti A., Ortega J. F., Tryndyak V., et al. MicroRNA deregulation in nonalcoholic steatohepatitisassociated liver carcinogenesis. Oncotarget . 2017;8(51):88517–88528.
    1. Khalid A., Hussain T., Manzoor S., Saalim M., Khaliq S. PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma. Tumor Biology. 2017;39(6) doi: 10.1177/1010428317705754.101042831770575
    1. Liu Y., Qi X., Zeng Z., et al. CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice. Scientific Reports. 2017;7(1, article 2796) doi: 10.1038/s41598-017-03070-8.
    1. Xu Z., Hu J., Cao H., et al. Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway. Experimental & Molecular Medicine. 2018;50(1, article e417) doi: 10.1038/emm.2017.158.
    1. De Minicis S., Agostinelli L., Rychlicki C., et al. HCC development is associated to peripheral insulin resistance in a mouse model of NASH. PLoS ONE. 2014;9(5)e97136
    1. Janku F., Kaseb A. O., Tsimberidou A. M., Wolff R. A., Kurzrock R. Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget . 2014;5(10):3012–3022. doi: 10.18632/oncotarget.1687.
    1. Yang S., Liu G. Targeting the RAS/RAF/MEK/ERK pathway in hepatocellular carcinoma. Oncology Letters. 2017;13(3):1041–1047. doi: 10.3892/ol.2017.5557.
    1. Kudo Y., Tanaka Y., Tateishi K., et al. Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway. Journal of Hepatology. 2011;55(6):1400–1408. doi: 10.1016/j.jhep.2011.03.025.
    1. Chettouh H., Lequoy M., Fartoux L., Vigouroux C., Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver International. 2015;35(10):2203–2217. doi: 10.1111/liv.12903.
    1. Hirsova P., Ibrabim S. H., Gores G. J., Malhi H. Thematic review series: Lipotoxicity: Many roads to cell dysfunction and cell death lipotoxic lethal and sublethal stress signaling in hepatocytes: Relevance to NASH pathogenesis. Journal of Lipid Research. 2016;57(10):1758–1770. doi: 10.1194/jlr.R066357.
    1. Afonso M. B., Rodrigues P. M., Carvalho T., et al. Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clinical Science. 2015;129(8):721–739. doi: 10.1042/CS20140732.
    1. Gautheron J., Vucur M., Reisinger F., et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Molecular Medicine. 2014;6(8):1062–1074. doi: 10.15252/emmm.201403856.
    1. Fu S., Yang L., Li P., et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011;473(7348):528–531. doi: 10.1038/nature09968.
    1. Bozaykut P., Sahin A., Karademir B., Ozer N. K. Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis. Mechanisms of Ageing and Development. 2016;157:17–29. doi: 10.1016/j.mad.2016.07.001.
    1. Novo E., Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis & Tissue Repair. 2008;1, article 5
    1. Nelson J. E., Wilson L., Brunt E. M., et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53(2):448–457. doi: 10.1002/hep.24038.
    1. Onal G., Kutlu O., Gozuacik D., Dokmeci Emre S. Lipid droplets in health and disease. Lipids in Health and Disease. 2017;16, article 128
    1. Liu L., Liao J.-Z., He X.-X., Li P.-Y. The role of autophagy in hepatocellular carcinoma: Friend or foe. Oncotarget . 2017;8(34):57707–57722.
    1. Mao Y., Yu F., Wang J., Guo C., Fan X. Autophagy: a new target for nonalcoholic fatty liver disease therapy. Hepatic Medicine: Evidence and Research. 2016;8:27–37. doi: 10.2147/HMER.S98120.
    1. He G., Karin M. NF-κB and STAT3- key players in liver inflammation and cancer. Cell Research. 2011;21(1):159–168. doi: 10.1038/cr.2010.183.
    1. Park E. J., Lee J. H., Yu G.-Y., et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. doi: 10.1016/j.cell.2009.12.052.
    1. Jia L., Vianna C. R., Fukuda M., et al. Hepatocyte toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nature Communications. 2014;5, article 3878 doi: 10.1038/ncomms4878.
    1. Min H., Mirshahi F., Verdianelli A., et al. Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2015;308(9):G794–G803. doi: 10.1152/ajpgi.00390.2014.
    1. Sun Q., Jiang N., Sun R. Leptin signaling molecular actions and drug target in hepatocellular carcinoma. Drug Design, Development and Therapy. 2014;8:2295–2302. doi: 10.2147/DDDT.S69004.
    1. Stefanou N., Papanikolaou V., Furukawa Y., Nakamura Y., Tsezou A. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase. BMC Cancer. 2010;10, article 442
    1. Xing S.-Q., Zhang C.-G., Yuan J.-F., Yang H.-M., Zhao S.-D., Zhang H. Adiponectin induces apoptosis in hepatocellular carcinoma through differential modulation of thioredoxin proteins. Biochemical Pharmacology. 2015;93(2):221–231. doi: 10.1016/j.bcp.2014.12.001.
    1. Shen J., Yeh C.-C., Wang Q., Gurvich I., Siegel A. B., Santella R. M. Plasma adiponectin and hepatocellular carcinoma survival among patients without liver transplantation. Anticancer Reseach. 2016;36(10):5307–5314. doi: 10.21873/anticanres.11103.
    1. Carbone F., la Rocca C., Matarese G. Immunological functions of leptin and adiponectin. Biochimie. 2012;94(10):2082–2088. doi: 10.1016/j.biochi.2012.05.018.
    1. Nannipieri M., Cecchetti F., Anselmino M., et al. Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis. Obesity Surgery. 2009;19(4):467–474. doi: 10.1007/s11695-008-9701-x.
    1. Ma C., Kesarwala A. H., Eggert T., et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–257. doi: 10.1038/nature16969.
    1. Wolf M., Adili A., Piotrowitz K., et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26(4):549–564. doi: 10.1016/j.ccell.2014.09.003.
    1. Lanthier N. Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: why and how? World Journal of Hepatology. 2015;7(19):2184–2188. doi: 10.4254/wjh.v7.i19.2184.
    1. Martin-Murphy B. V., You Q., Wang H., et al. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS ONE. 2014;9(1) doi: 10.1371/journal.pone.0080949.e80949
    1. Tian Z., Chen Y., Gao B. Natural killer cells in liver disease. Hepatology. 2013;57(4):1654–1662. doi: 10.1002/hep.26115.
    1. Zheng X., Zeng W., Gai X., et al. Role of the Hedgehog pathway in hepatocellular carcinoma (Review) Oncology Reports. 2013;30(5):2020–2026. doi: 10.3892/or.2013.2690.
    1. Della Corte C. M., Viscardi G., Papaccio F., et al. Implication of the Hedgehog pathway in hepatocellular Carcinoma. World Journal of Gastroenterology. 2017;23(24):4330–4340. doi: 10.3748/wjg.v23.i24.4330.
    1. Noverr M. C., Huffnagle G. B. Does the microbiota regulate immune responses outside the gut? Trends in Microbiology. 2004;12(12):562–568. doi: 10.1016/j.tim.2004.10.008.
    1. Żak-Gołąb A., Olszanecka-Glinianowicz M., Kocełak P., Chudek J. The role of gut microbiota in the pathogenesis of obesity. Postepy Higieny i Medycyny Doswiadczalnej. 2014;68:84–90. doi: 10.5604/17322693.1086419.
    1. Valentini M., Piermattei A., Di Sante G., Migliara G., Delogu G., Ria F. Immunomodulation by gut microbiota: Role of toll-like receptor expressed by T cells. Journal of Immunology Research. 2014;2014:8.586939
    1. Brandl K., Schnabl B. Intestinal microbiota and nonalcoholic steatohepatitis. Current Opinion in Gastroenterology. 2017;33(3):128–133. doi: 10.1097/MOG.0000000000000349.
    1. Bashiardes S., Shapiro H., Rozin S., Shibolet O., Elinav E. Non-alcoholic fatty liver and the gut microbiota. Molecular Metabolism. 2016;5(9):782–794. doi: 10.1016/j.molmet.2016.06.003.
    1. Ruiz A. G., Casafont F., Crespo J., et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obesity Surgery. 2007;17(10):1374–1380. doi: 10.1007/s11695-007-9243-7.
    1. Brun P., Castagliuolo I., Pinzani M., Palù G., Martines D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2005;289(3):G571–G578. doi: 10.1152/ajpgi.00537.2004.
    1. Borrelli A., Bonelli P., Tuccillo F. M., et al. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biology. 2018;15:467–479. doi: 10.1016/j.redox.2018.01.009.
    1. Yoshimoto S., Loo T. M., Atarashi K., et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101. doi: 10.1038/nature12347.
    1. Nagasue N., Yu L., Yukaya H., Kohno H., Nakamura T. Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: Impact on intrahepatic recurrence after hepatic resection. British Journal of Surgery. 1995;82(4):542–547. doi: 10.1002/bjs.1800820435.
    1. Awuah P. K., Monga S. P. Cell cycle-related kinase links androgen receptor and β-catenin signaling in hepatocellular carcinoma: Why are men at a loss? Hepatology. 2012;55(3):970–974. doi: 10.1002/hep.24774.
    1. Kanda T., Jiang X., Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World Journal of Gastroenterology. 2014;20(28):9229–9236.
    1. Lin H.-Y., Yu I.-C., Wang R.-S., et al. Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology. 2008;47(6):1924–1935. doi: 10.1002/hep.22252.
    1. Norlin M., Pettersson H., Tang W., Wikvall K. Androgen receptor-mediated regulation of the anti-atherogenic enzyme CYP27A1 involves the JNK/c-jun pathway. Archives of Biochemistry and Biophysics. 2011;506(2):236–241. doi: 10.1016/j.abb.2010.11.023.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren