Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?
2008; Elsevier BV; Volume: 172; Issue: 4 Linguagem: Inglês
10.2353/ajpath.2008.070910
ISSN1525-2191
AutoresFabio Marongiu, Silvia Doratiotto, Stefania Montisci, P. Pani, Ezio Laconi,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoLiver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation. Liver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation. The liver is the only solid organ that can be efficiently repopulated through transplantation of normal isolated hepatocytes. A number of experimental systems have been developed over the past 10 to 15 years describing this remarkable phenomenon.1Sandgren EP Palmiter RD Heckel JL Daugherty CC Brinster RL Degen JL Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256Abstract Full Text PDF PubMed Scopus (341) Google Scholar, 2Rhim JA Sandgren EP Degen JL Palmiter RD Brinster RL Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Crossref PubMed Scopus (525) Google Scholar, 3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar, 4Laconi E Sarma DSR Pani P Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine.Carcinogenesis. 1995; 16: 139-142Crossref PubMed Scopus (49) Google Scholar, 5Laconi E Oren R Mukhopadhyay DK Hurston E Laconi S Pani P Dabeva MD Shafritz DA Long term, near total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine.Am J Pathol. 1998; 158: 319-329Abstract Full Text Full Text PDF Scopus (353) Google Scholar, 6Laconi S Pillai S Porcu PP Shafritz DA Pani P Laconi E Massive liver replacement by transplanted hepatocytes in the absence of exogenous growth stimuli in rats treated with retrorsine.Am J Pathol. 2001; 158: 771-777Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 7Guha C Sharma A Gupta S Alfieri A Gorla GR Gagandeep S Rana S Roy-Chowdhury N Tanka KE Vikram B Roy-Chowdhury J Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation.Cancer Res. 1999; 59: 5871-5874PubMed Google Scholar, 8Mignon A Guidotti J-E Mitchell C Fabre M Wernet A De LaCoste A Soubrane O Gilgenkrantz H Kahn A Selective repopulation of a normal mouse liver by Fas/CD95-resistant hepatocytes.Nat Med. 1998; 4: 1185-1188Crossref PubMed Scopus (151) Google Scholar, 9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 10Karnezis AN Dorokhov M Grompe M Zhu L Loss of p27Kip1 enhances the transplantation efficiency of hepatocytes transferred into diseased livers.J Clin Invest. 2001; 108: 383-390Crossref PubMed Scopus (49) Google Scholar, 11Joseph B Kumaran V Berishvili E Barghava KK Palestro CJ Gupta S Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning.Hepatology. 2006; 44: 1411-1420Crossref PubMed Scopus (57) Google Scholar The analysis of these systems has revealed that two key requirements must be fulfilled for the process to occur: (1) transplanted cells must be endowed with a growth and/or survival advantage compared with the hepatocytes in the recipient organ, and (2) there must be space for donor-derived cells to expand, in that transplanted cells only divide at the expense of preexisting resident hepatocytes.12Laconi S Laconi E Principles of hepatocyte transplantation.Semin Cell Dev Biol. 2002; 13: 433-438Crossref PubMed Scopus (40) Google Scholar In fact, liver repopulation is a coordinated process of cell replacement, during which no increase in total liver mass is observed, whereas normal transplanted hepatocytes take the lead over the endogenous damaged counterpart. The above paradigm applies to virtually all available models of liver repopulation via transplanted cells, including the albumin-urokinase-plasminogen activator (uPA) transgenic mouse,1Sandgren EP Palmiter RD Heckel JL Daugherty CC Brinster RL Degen JL Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256Abstract Full Text PDF PubMed Scopus (341) Google Scholar, 2Rhim JA Sandgren EP Degen JL Palmiter RD Brinster RL Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Crossref PubMed Scopus (525) Google Scholar the fumaryl-acetoacetate-hydroxylase (Fah)-null mouse,3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar the multidrug resistance-2 (mdr-2) knockout mouse,9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar the bcl-2-transduced mouse hepatocyte model,8Mignon A Guidotti J-E Mitchell C Fabre M Wernet A De LaCoste A Soubrane O Gilgenkrantz H Kahn A Selective repopulation of a normal mouse liver by Fas/CD95-resistant hepatocytes.Nat Med. 1998; 4: 1185-1188Crossref PubMed Scopus (151) Google Scholar the retrorsine-treated4Laconi E Sarma DSR Pani P Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine.Carcinogenesis. 1995; 16: 139-142Crossref PubMed Scopus (49) Google Scholar, 5Laconi E Oren R Mukhopadhyay DK Hurston E Laconi S Pani P Dabeva MD Shafritz DA Long term, near total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine.Am J Pathol. 1998; 158: 319-329Abstract Full Text Full Text PDF Scopus (353) Google Scholar, 6Laconi S Pillai S Porcu PP Shafritz DA Pani P Laconi E Massive liver replacement by transplanted hepatocytes in the absence of exogenous growth stimuli in rats treated with retrorsine.Am J Pathol. 2001; 158: 771-777Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar or monocrotaline-treated11Joseph B Kumaran V Berishvili E Barghava KK Palestro CJ Gupta S Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning.Hepatology. 2006; 44: 1411-1420Crossref PubMed Scopus (57) Google Scholar rat model, and the radiation-treated7Guha C Sharma A Gupta S Alfieri A Gorla GR Gagandeep S Rana S Roy-Chowdhury N Tanka KE Vikram B Roy-Chowdhury J Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation.Cancer Res. 1999; 59: 5871-5874PubMed Google Scholar rat models. An intriguing aspect that has received little attention so far is that most, if not all of these model systems capable of sustaining liver repopulation are also associated with an increased risk of cancer development in the liver (Table 1).12Laconi S Laconi E Principles of hepatocyte transplantation.Semin Cell Dev Biol. 2002; 13: 433-438Crossref PubMed Scopus (40) Google Scholar, 13Laconi E Differential growth: from carcinogenesis to liver repopulation.Am J Pathol. 2000; 156: 389-392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Such increased risk is inherent to these model systems, ie, it is independent of cell transplantation. Furthermore, the human diseases related to some of these animals models, including hypertyrosinemia (modeled by the Fah-null mouse) and familial intrahepatic cholestasis (modeled by the mdr-2 knockout mouse), are also burdened with an increased risk of hepatocellular carcinoma, developing at childhood age.14Mieles LA Esquivel CO Van Thiel DH Konery B Makowka L Tzakis AG Starzl TE Liver transplantation for tyrosinemia. A review of 10 cases from the University of Pittsburgh.Dig Dis Sci. 1990; 35: 153-157Crossref PubMed Scopus (73) Google Scholar, 15Knisely AS Strautnieks SS Meier Y Stieger B Byrne JA Portmann BC Bull LN Pawlikowska L Bilezikçi B Ozçay F László A Tiszlavicz L Moore L Raftos J Arnell H Fischler B Németh A Papadogiannakis N Cielecka-Kuszyk J Jankowska I Pawłowska J Melín-Aldana H Emerick KM Whitington PF Mieli-Vergani G Thompson RJ Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.Hepatology. 2006; 44: 478-486Crossref PubMed Scopus (320) Google Scholar Is this a pure chance phenomenon, or does it suggest the existence of a fundamental linkage between the two processes, two sides of the same coin per se? In this review, the evidence for this intriguing association will be examined, and its possible biological significance and clinical implications will be discussed.Table 1Animal Models of Liver Repopulation Associated with Increased Risk of Liver Cancer DevelopmentThe albumin-urokinase-plasminogen activator (uPA) trangenic mouse1Sandgren EP Palmiter RD Heckel JL Daugherty CC Brinster RL Degen JL Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256Abstract Full Text PDF PubMed Scopus (341) Google Scholar, 2Rhim JA Sandgren EP Degen JL Palmiter RD Brinster RL Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Crossref PubMed Scopus (525) Google Scholar, 17Sandgren EP Palmiter RD Heckel JL Brinster RL Degen JL DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.Proc Natl Acad Sci USA. 1992; 89: 11523-11527Crossref PubMed Scopus (39) Google ScholarThe fumaryl-acetoacetate hydrolase (Fah) null mouse3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar, 19Demers SI Russo P Lettre F Tanguay RM Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia.Hum Pathol. 2003; 34: 1313-1320Abstract Full Text Full Text PDF PubMed Scopus (49) Google ScholarThe mouse model of progressive familial intrahepatic cholestasis9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 22Overturf K al-Dhalimy M Ou CN Finegold M Grompe M Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.Am J Pathol. 1997; 151: 1273-1280PubMed Google ScholarThe retrorsine-based rat model for hepatocyte transplantation and liver repopulation4Laconi E Sarma DSR Pani P Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine.Carcinogenesis. 1995; 16: 139-142Crossref PubMed Scopus (49) Google Scholar, 5Laconi E Oren R Mukhopadhyay DK Hurston E Laconi S Pani P Dabeva MD Shafritz DA Long term, near total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine.Am J Pathol. 1998; 158: 319-329Abstract Full Text Full Text PDF Scopus (353) Google Scholar, 6Laconi S Pillai S Porcu PP Shafritz DA Pani P Laconi E Massive liver replacement by transplanted hepatocytes in the absence of exogenous growth stimuli in rats treated with retrorsine.Am J Pathol. 2001; 158: 771-777Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 23Kvittingen EA Rootwelt H Berger R Brandtzaeg P Self-induced correction of the genetic defect of tyrosinemia type I.J Clin Invest. 1994; 94: 1657-1661Crossref PubMed Scopus (156) Google Scholar Open table in a new tab The uPA transgenic mouse model was the first to be associated with massive liver repopulation.1Sandgren EP Palmiter RD Heckel JL Daugherty CC Brinster RL Degen JL Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256Abstract Full Text PDF PubMed Scopus (341) Google Scholar, 2Rhim JA Sandgren EP Degen JL Palmiter RD Brinster RL Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Crossref PubMed Scopus (525) Google Scholar In this animal, targeted expression of uPA leads to chronic hepatocyte toxicity. However, it was observed that rare hepatocytes losing the transgene can selectively proliferate and regenerate the entire organ.1Sandgren EP Palmiter RD Heckel JL Daugherty CC Brinster RL Degen JL Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256Abstract Full Text PDF PubMed Scopus (341) Google Scholar Based on this finding, hepatocytes isolated from a congenic donor were then transplanted into the uPA mouse and tested for their ability to selectively proliferate in the host liver. Four to five weeks later, up to 80% of hepatocytes in the recipient liver were found to be of donor origin,2Rhim JA Sandgren EP Degen JL Palmiter RD Brinster RL Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Crossref PubMed Scopus (525) Google Scholar thereby confirming that the constitutive expression of the uPA transgene in resident hepatocytes generates a selective environment that favors the growth of cells with a normal (nontransgenic) phenotype. The uPA transgenic mouse is one of the most widely used systems for liver repopulation; in more recent years, human hepatocytes have been transplanted into a double mutant severe combined immune deficient/uPA transgenic mouse, leading to extensive replacement of the mouse liver by human cells.16Dandri M Burda MR Török E Pollok JM Iwanska A Sommer G Rogiers X Rogler CE Gupta S Will H Greten H Petersen J Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus.Hepatology. 2001; 33: 981-988Crossref PubMed Scopus (336) Google Scholar As early as 1992, Sandgren et al17Sandgren EP Palmiter RD Heckel JL Brinster RL Degen JL DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.Proc Natl Acad Sci USA. 1992; 89: 11523-11527Crossref PubMed Scopus (39) Google Scholar reported the development of liver cancer in the uPA transgenic mouse, with over 70% incidence of adenoma and carcinoma. Interestingly, all cancers were derived from endogenous hepatocytes that had lost the uPA transgene, thereby gaining a growth advantage compared with uPA-expressing neighboring cells. The authors proposed that extended segments of genomic DNA were probably lost in these cells together with the transgene, and this could explain both their growth advantage and their altered phenotype, causing their high propensity to progress to cancer.17Sandgren EP Palmiter RD Heckel JL Brinster RL Degen JL DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.Proc Natl Acad Sci USA. 1992; 89: 11523-11527Crossref PubMed Scopus (39) Google Scholar Furthermore, mitogenesis per se was excluded as a driving force for carcinogenesis in this system, in that several regenerative nodules with a normal phenotype were also observed in uPA-transgenic mice.17Sandgren EP Palmiter RD Heckel JL Brinster RL Degen JL DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.Proc Natl Acad Sci USA. 1992; 89: 11523-11527Crossref PubMed Scopus (39) Google Scholar Thus, at least two types of rare hepatocytes can be generated in the uPA transgenic livers following loss of the transgene: (1) hepatocytes that are seemingly normal and can participate in the process of liver repopulation, resulting in normal tissue architecture, and (2) phenotypically altered hepatocytes that can represent the site of origin of focal lesions, liver nodules and hepatocellular carcinoma. The important issue here is that both cell types and both processes (ie, liver repopulation with normal histology and cancer development) appear to be driven by the same basic mechanism: the selective emergence of hepatocytes that have lost the uPA transgene and that are stimulated to clonally expand because of the continuous death of uPA-expressing damaged hepatocytes. To our knowledge, no liver tumors have been reported arising from normal transplanted hepatocytes in this system; however, when mice carrying the uPA transgene and lacking recombination activation gene 2 knockout were transplanted with woodchuck hepatitis virus-infected hepatocytes, chronic viral infection and hepatocellular carcinoma were observed after several months18Petersen J Dandri M Gupta S Rogler CE Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma.Proc Natl Acad Sci USA. 1999; 95: 310-315Crossref Scopus (110) Google Scholar A general principle similar to the one discussed for the uPA transgenic mouse applies to the Fah-null mouse model of liver repopulation.3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar The Fah-deficient mouse serves as a model for hereditary tyrosinemia type I in humans. In both humans and mice, the lack of Fah enzyme, which is involved in the tyrosine catabolic pathway, leads to accumulation of its substrate, fumaryl-acetoacetate and its precursor maleyl-acetoacetate. Both fumaryl-acetoacetate and maleyl-acetoacetate are thought to be involved in liver toxicity, which is found in tyrosinemia type I patients and includes progressive liver failure and development of hepatocellular carcinoma (HCC) early in life.19Demers SI Russo P Lettre F Tanguay RM Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia.Hum Pathol. 2003; 34: 1313-1320Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Using the mouse model of Fah deficiency, Grompe and colleagues3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar demonstrated that normal hepatocytes transplanted in the these animals were able to replace >80% of host liver. However, if transplanted Fah-deficient mice were exposed to the drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, which limits the accumulation of toxic metabolites fumaryl-acetoacetate and maleyl-acetoacetate in host cells, no selective growth advantage for donor-derived hepatocytes was observed.3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar Nontreated Fah-deficient mice die within 6 weeks from fulminant hepatic failure. However, if the animals were either given 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione or transfected with an adenoviral vector carrying the Fah gene, they could survive for several months.20Grompe M Lindstedt S al-Dhalimy M Kennaway MG Papaconstantinou J Torres-Ramos CA Ou CN Finegold M Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.Nat Genet. 1995; 10: 453-460Crossref PubMed Scopus (270) Google Scholar, 21Grompe M Overturf K al-Dhalimy M Finegold M Therapeutic trials in the murine model of hereditary tyrosinaemia type I: a progress report.J Inherit Metab Dis. 1998; 21: 518-531Crossref PubMed Scopus (44) Google Scholar Interestingly, 50% (3 of 6) of surviving mice developed HCC, whereas no liver cancer was seen in 9 age-matched heterozygous controls,21Grompe M Overturf K al-Dhalimy M Finegold M Therapeutic trials in the murine model of hereditary tyrosinaemia type I: a progress report.J Inherit Metab Dis. 1998; 21: 518-531Crossref PubMed Scopus (44) Google Scholar indicating that the Fah-null background is conducive to neoplastic development in the liver. Similar to the u-PA transgenic mouse model, no evidence of neoplastic lesions arising from transplanted normal hepatocytes has been reported in the Fah-deficient mouse. In fact, serial transplantation studies conducted in this animal model revealed that up to six serial passages could be performed from donor to recipient, with preservation of repopulating capacity and in the absence of neoplastic transformation.22Overturf K al-Dhalimy M Ou CN Finegold M Grompe M Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.Am J Pathol. 1997; 151: 1273-1280PubMed Google Scholar The latter finding again points out that mitogenesis per se is not sufficient for cancer development. As already mentioned, the Fah-null mouse is a model for human hereditary tyrosinemia type I, and several analogies are present between the two systems. Patients with this disease survive to early childhood without treatment, but they develop chronic liver disease and liver cancer at a very young age.14Mieles LA Esquivel CO Van Thiel DH Konery B Makowka L Tzakis AG Starzl TE Liver transplantation for tyrosinemia. A review of 10 cases from the University of Pittsburgh.Dig Dis Sci. 1990; 35: 153-157Crossref PubMed Scopus (73) Google Scholar Interestingly, livers from some of these patients were also reported to harbor clones of seemingly normal hepatocytes expressing the Fah enzyme and resulting from self-induced correction of the genetic defect.23Kvittingen EA Rootwelt H Berger R Brandtzaeg P Self-induced correction of the genetic defect of tyrosinemia type I.J Clin Invest. 1994; 94: 1657-1661Crossref PubMed Scopus (156) Google Scholar Such clones gradually expand, display a normal histological appearance, and can replace up to 85% of the Fah-deficient human liver. Notably, the extent of repopulation by reverted, Fah-positive hepatocytes was reported to be inversely correlated with the clinical severity of the disease in these patients.19Demers SI Russo P Lettre F Tanguay RM Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia.Hum Pathol. 2003; 34: 1313-1320Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar In summary, the cytotoxic microenvironment of Fah-deficient livers sustains the selective growth of phenotypically normal hepatocytes, leading to extensive repopulation, both in human patients23Kvittingen EA Rootwelt H Berger R Brandtzaeg P Self-induced correction of the genetic defect of tyrosinemia type I.J Clin Invest. 1994; 94: 1657-1661Crossref PubMed Scopus (156) Google Scholar and in experimental animals3Overturf K Al-Dhalimy M Tanguay R Brantly M Ou C-N Finegold M Grompe M Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tryosinaemia type I.Nat Genet. 1996; 12: 266-273Crossref PubMed Scopus (501) Google Scholar; on the other hand, the same microenvironment can also foster the expansion of altered hepatocytes resistant to cytotoxicity, leading to the emergence of dysplastic nodules and the development of HCC in young patients,14Mieles LA Esquivel CO Van Thiel DH Konery B Makowka L Tzakis AG Starzl TE Liver transplantation for tyrosinemia. A review of 10 cases from the University of Pittsburgh.Dig Dis Sci. 1990; 35: 153-157Crossref PubMed Scopus (73) Google Scholar as well as in the corresponding experimental animal model.20Grompe M Lindstedt S al-Dhalimy M Kennaway MG Papaconstantinou J Torres-Ramos CA Ou CN Finegold M Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.Nat Genet. 1995; 10: 453-460Crossref PubMed Scopus (270) Google Scholar, 21Grompe M Overturf K al-Dhalimy M Finegold M Therapeutic trials in the murine model of hereditary tyrosinaemia type I: a progress report.J Inherit Metab Dis. 1998; 21: 518-531Crossref PubMed Scopus (44) Google Scholar An interesting variant to the basic paradigm described for the uPA-transgenic and the Fah-null mice is illustrated by the mouse model of human progressive familial intrahepatic cholestasis.9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar These animals lack the mdr 2 carrier protein and are therefore unable to secrete phospholipids into bile, leaving unopposed the cytotoxic detergent action of bile salts. Hepatocyte damage is confined to periportal areas, which are most active in bile salt uptake and metabolism. Elegant studies by De Vree et al9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar have indicated that the liver of mdr 2-deficient mice can be repopulated via transplantation of normal hepatocytes. However, repopulated areas are confined to periportal regions, where liver toxicity is expressed. The process of repopulation is self-limited and tightly controlled: if animals are fed bile salts in the diet, this causes an expansion in the areas of liver damage and a parallel increase in the extent of repopulation by transplanted, mdr 2-expressing normal cells. However, withdrawal of the bile salt-containing diet results in a relative decrease in repopulated areas.9De Vree JML Ottenhoff R Bosma PJ Smith AJ Aten J Oude-Elferink RPJ Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.Gastroenterology. 2000; 119: 1720-1730Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Relevant to the present discussion, nontransplanted mdr 2-deficient mouse liver is highly prone to developing hepatocellular carcinoma.24Mauad TH van Nieuwkerk CMJ Dingemans KP Smit JJM Schinkel AH Notenboom RGE van den Bergh Weerman MA Verkruisen RP Groen AK Oude Elferink RPJ van der Valk MA Borst P Offerhaus GJA Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.Am J Pathol. 1994; 145: 1237-1245PubMed Google Scholar Most importantly, children affected by progressive familial intrahepatic cholestasis also incur a high risk for the development of liver cancer.15Knisely AS Strautnieks SS Meier Y Stieger B Byrne JA Portmann BC Bull LN Pawlikowska L Bilezikçi B Ozçay F László A Tiszlavicz L Moore L Raftos J Arnell H Fischler B Németh A Papadogiannakis N Cielecka-Kuszyk J Jankowska I Pawłowska J Melín-Aldana H Emerick KM Whitington PF Mieli-Vergani G Thompson RJ Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.Hepatology. 2006; 44: 478-486Crossref PubMed Scopus (320) Google Scholar Thus, the analysis of this model system again reinforces the notion that endogenous conditions in the liver resulting in the selective growth of transplanted normal hepatocytes are also associated with an incr
Referência(s)