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Background: Although some cancer therapies have overt and/or subclinical cardiotoxic effects that increase subsequent cardiovascular risk in breast cancer patients, we have recently shown that the breast tumor itself can also induce cardiac hypertrophy through the activation of the endothelin system to contribute to cardiovascular risk. However, the extent to which the suppression of the activation of the endothelin system could improve cardiac remodeling in breast cancer patients has yet to be investigated. Objectives: We aimed to retrospectively assess the cardiac morphology/function in patients with breast cancer before receiving cancer chemotherapy and to investigate if the suppression of the activation of the endothelin system improves cardiac remodeling in a mouse model of breast cancer. Methods: Our study involved 28 previously studied women with breast cancer (including 24 after tumor resection) before receiving adjuvant therapy and 17 control healthy women. In addition, we explored how the endothelin system contributed to breast cancer-induced cardiac remodeling using a mouse model of breast cancer. Results: Our results indicate that before chemotherapy, breast cancer patients already exhibit relative cardiac remodeling and subclinical cardiac dysfunction, which was associated with the activation of the endothelin system. Importantly, our mouse data also show that the endothelin receptor blocker atrasentan significantly lessened cardiac remodeling and improved cardiac function in a preclinical model of breast cancer. Conclusions: Although our findings should be further examined in other preclinical/clinical models, our data suggest that endothelin receptor blockers may play a role in cardiac health in individuals with breast cancer. (Understanding and Treating Heart Failure With Preserved Ejection Fraction: Novel Mechanisms, Diagnostics and Potential Therapeutics [Alberta HEART]; NCT02052804 and Multidisciplinary Team Intervention in Cardio-Oncology [TITAN]; NCT01621659).
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Indolent systemic mastocytosis (ISM) represents the most common form of SM, typically following a slow clinical course. While anaphylactic reactions may come up in the life course of an ISM patient, these are often moderate and do not pose a threat to patient's health. Here, we present an undiagnosed case of ISM with recurrent severe anaphylactic episodes following consumption of food and emotional stress. One of these episodes led to anaphylactic shock, necessitating temporary mechanical ventilation and intensive care unit (ICU) support. Besides hypotension, a diffuse, itchy, red rash was the only notable clinical finding. Upon recovery, we found abnormally high baseline serum tryptase level as well as 10% bone marrow (BM) infiltration by multifocal, dense clusters of CD117+/mast cell tryptase+/CD25+ mast cells (MCs), consolidating the diagnosis of ISM. Prophylactic treatment with a histamine receptor antagonist was initiated, resulting in milder episodes thereafter. Diagnosis of ISM requires a high level of suspicion; its prompt recognition and treatment are important in preventing potentially life-threatening anaphylactic episodes.
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Anafilaxia , Mastocitosis Sistémica , Humanos , Persona de Mediana Edad , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitos , Médula Ósea , Triptasas , Anafilaxia/etiologíaRESUMEN
Metastasis is the primary cause of cancer patient death and the elevation of SLC2A5 gene expression is often observed in metastatic cancer cells. Here we evaluated the importance of SLC2A5 in cancer cell motility by silencing its gene. We discovered that CRISPR/Cas9-mediated inactivation of the SLC2A5 gene inhibited cancer cell proliferation and migration in vitro as well as metastases in vivo in several animal models. Moreover, SLC2A5-attenuated cancer cells exhibited dramatic alterations in mitochondrial architecture and localization, uncovering the importance of SLC2A5 in directing mitochondrial function for cancer cell motility and migration. The direct association of increased abundance of SLC2A5 in cancer cells with metastatic risk in several types of cancers identifies SLC2A5 as an important therapeutic target to reduce or prevent cancer metastasis.
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An epithelial-to-mesenchymal transition (EMT) phenotype with cancer stem cell-like properties is a critical feature of aggressive/metastatic tumors, but the mechanism(s) that promote it and its relation to metabolic stress remain unknown. Here we show that Collapsin Response Mediator Protein 2A (CRMP2A) is unexpectedly and reversibly induced in cancer cells in response to multiple metabolic stresses, including low glucose and hypoxia, and inhibits EMT/stemness. Loss of CRMP2A, when metabolic stress decreases (e.g., around blood vessels in vivo) or by gene deletion, induces extensive microtubule remodeling, increased glutamine utilization toward pyrimidine synthesis, and an EMT/stemness phenotype with increased migration, chemoresistance, tumor initiation capacity/growth, and metastatic potential. In a cohort of 27 prostate cancer patients with biopsies from primary tumors and distant metastases, CRMP2A expression decreases in the metastatic versus primary tumors. CRMP2A is an endogenous molecular brake on cancer EMT/stemness and its loss increases the aggressiveness and metastatic potential of tumors.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias de la Próstata , Semaforina-3A , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Humanos , Masculino , Células Madre Neoplásicas/metabolismo , Neoplasias de la Próstata/patología , Semaforina-3A/metabolismo , Estrés FisiológicoRESUMEN
The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers have opened up the possibility of a broader use of immunotherapy in less immunogenic but genetically heterogeneous tumours. Regarding metastatic colorectal cancer (mCRC), in first-line setting, pembrolizumab has been approved as preferred option and nivolumab, alone or in combination with ipilimumab as alternative option for patients with mismatch-repair-deficient and microsatellite instability-high (dMMR/MSI-H) disease, independently of their eligibility for intensive chemotherapy. In subsequent lines, both these immunotherapeutic regimens (e.g., pembrolizumab and nivolumab+/-ipilimumab) as well as dostarlimab-gxly are currently recommended for patients with dMMR/MSI-H chemo-resistant mCRC who have not previously received an ICI. Beginning from the rationale behind the immune-mediated interplay in the dMMR/MSI-H bowel microenvironment, we provide here an update on the evolution status of all available, approved or not, ICIs in mCRC, describing their efficacy and toxicity profile with an emphasis on the pivotal trials supporting current colorectal indications. For each ICI agent, the results from combinations under investigation, particularly for those being upgraded in clinical phasing, the perspectives but also the limitations of main ongoing trials are thoroughly discussed. In the close future, upcoming data are expected to confirm the clinical benefit of ICIs and to further expand their role in mCRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Anticuerpos Monoclonales Humanizados , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Inestabilidad de Microsatélites , Nivolumab/uso terapéutico , Microambiente TumoralRESUMEN
The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points. A decrease in nuclear MFN2 levels decreases mitochondria tethering and nPDC levels. Mitochondrial PDC crosses the NE and interacts with lamin A, forming a ring below the NE before crossing through the lamin layer into the nucleoplasm, in areas away from NPCs. Effective blockage of NPC trafficking does not decrease nPDC levels. The PDC-lamin interaction is maintained during cell division, when lamin depolymerizes and disassembles before reforming daughter nuclear envelopes, providing another pathway for nPDC entry during mitosis. Our work provides a different angle to understanding mitochondria-to-nucleus communication and nuclear metabolism.
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Núcleo Celular , Complejo Piruvato Deshidrogenasa , Acetilcoenzima A/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Laminas/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Membrana Nuclear/metabolismo , Complejo Piruvato Deshidrogenasa/genética , Complejo Piruvato Deshidrogenasa/metabolismoRESUMEN
Background Isolated loss-of-function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10-year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose-dependent manner), along with insulin resistance, compared with wild-type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild-type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.
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Diabetes Mellitus Tipo 2 , Polimorfismo de Nucleótido Simple , Hipertensión Arterial Pulmonar , Sirtuina 3 , Proteína Desacopladora 2 , Animales , Diabetes Mellitus Tipo 2/genética , Modelos Animales de Enfermedad , Humanos , Resistencia a la Insulina/genética , Ratones , Estudios Prospectivos , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/terapia , Índice de Severidad de la Enfermedad , Sirtuina 3/genética , Resultado del Tratamiento , Proteína Desacopladora 2/genéticaAsunto(s)
Antibióticos Antineoplásicos/efectos adversos , Receptores de Apelina/metabolismo , Doxorrubicina/efectos adversos , Miocardio/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Animales , Cardiotoxicidad , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Corazón/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The von Hippel-Lindau (VHL) protein binds and degrades hypoxia-inducible factors (HIF) hydroxylated by prolyl-hydroxylases under normoxia. Although originally described as a tumor suppressor, there is growing evidence that VHL may paradoxically promote tumor growth. The significance of its described interactions with many other proteins remains unclear. We found that VHL interacts with p53, preventing its tetramerization, promoter binding and expression of its target genes p21, PUMA, and Bax. VHL limited the decrease in proliferation and increase in apoptosis caused by p53 activation, independent of prolyl-hydroxylation and HIF activity, and its presence in tumors caused a resistance to p53-inducing chemotherapy in vivo. We propose that VHL has both anti-tumor function, via HIF degradation, and a new pro-tumor function via p53 target (p21, PUMA, Bax) inhibition. Because p53 plays a critical role in tumor biology, is activated by many chemotherapies, and because VHL levels vary among different tumors and its function can even be lost by mutations in some tumors, our results have important clinical applications. KEY MESSAGES: VHL and p53 physically interact and VHL inhibits p53 activity by limiting the formation of p53 tetramers. VHL attenuates the expression of p53 target genes in response to p53 stimuli. The inhibition of p53 by VHL is independent of HIF and prolyl-hydroxylation.
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Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Susceptibilidad a Enfermedades , Humanos , Neoplasias/etiología , Neoplasias/patología , Unión Proteica , Multimerización de Proteína , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal. Here, we propose that differences in oxygen tension between the myocardium and the tumor could provide a platform for redox-dependent tissue-specific therapies. We show by coimmunoprecipitation and mass spectrometry that the redox-regulated pyruvate kinase muscle 2 (PKM2) directly binds with p53 and that the redox status of cysteine-423 of tetrameric (but not monomeric) PKM2 is critical for the differential regulation of p53 transcriptional activity. Tetrameric PKM2 suppresses p53 transcriptional activity and apoptosis in a high oxidation state but enhances them in a low oxidation one. We show that the oxidation state (along with cysteine-423 oxidation) is higher in the heart compared to the tumor of the same animal. Treatment with TEPP-46 (a compound that stabilizes tetrameric PKM2) suppressed doxorubicin-induced cardiomyocyte apoptosis, preventing cardiac dysfunction, but enhanced cancer cell apoptosis and tumor regression in the same animals in lung cancer models. Thus, our work suggests that redox-dependent differences in common proteins expressed in the myocardium and tumor can be exploited therapeutically for tissue selectivity in CIC.
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Antraciclinas/efectos adversos , Cardiotoxicidad/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Especificidad de Órganos , Hormonas Tiroideas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Cardiotoxicidad/patología , Cardiotoxicidad/fisiopatología , Línea Celular Tumoral , Doxorrubicina/efectos adversos , Estabilidad de Enzimas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Oxidación-Reducción , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Transcripción Genética , Proteínas de Unión a Hormona TiroideRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
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Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Hipertensión Pulmonar Primaria Familiar/enzimología , Hipertensión Pulmonar Primaria Familiar/genética , Predisposición Genética a la Enfermedad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Biomarcadores/metabolismo , Ácido Dicloroacético/administración & dosificación , Ácido Dicloroacético/sangre , Ácido Dicloroacético/farmacología , Ácido Dicloroacético/uso terapéutico , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Masculino , Persona de Mediana Edad , Perfusión , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/enzimología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Sirtuina 3/metabolismo , Proteína Desacopladora 2/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Adulto JovenRESUMEN
During evolution, cells acquired the ability to sense and adapt to varying environmental conditions, particularly in terms of fuel supply. Adaptation to fuel availability is crucial for major cell decisions and requires metabolic alterations and differential gene expression that are often epigenetically driven. A new mechanistic link between metabolic flux and regulation of gene expression is through moonlighting of metabolic enzymes in the nucleus. This facilitates delivery of membrane-impermeable or unstable metabolites to the nucleus, including key substrates for epigenetic mechanisms such as acetyl-CoA which is used in histone acetylation. This metabolism-epigenetics axis facilitates adaptation to a changing environment in normal (e.g., development, stem cell differentiation) and disease states (e.g., cancer), providing a potential novel therapeutic target.
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Núcleo Celular/enzimología , Núcleo Celular/genética , Regulación de la Expresión Génica , L-Lactato Deshidrogenasa/metabolismo , Transcripción Genética , HumanosRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide with only few therapeutic options for patients with advanced disease. There is growing evidence indicating that activation of the PI3K/Akt/mTOR pathway plays an important role in HCC and therefore represents a promising target for novel therapeutic approaches. The aim of this study was to evaluate and compare the antitumour activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in vitro and in vivo. EXPERIMENTAL DESIGN: The antitumour effects of RAD001, BEZ235 and BKM120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5-Flourouracil in vitro and in xenografts. Cell-cycle progression, apoptosis, and autophagy were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed. RESULTS: Treatment with RAD001, BEZ235 and BKM120 markedly reduced tumour cell viability. Combination of PI3K inhibitors with chemotherapy was most effective. RAD001, BEZ235 and BKM120 reduced tumour growth mainly by inhibiting cell-cycle progression rather than by inducing apoptosis. Interestingly, the antitumour effects were strongly associated with a reduction of mitochondrial respiration. BKM120, which exhibited the strongest antiproliferative effect, most strongly impaired oxidative phosphorylation compared with the other drugs. CONCLUSIONS: In this study, BKM120 showed the strongest antitumour activity. Our findings suggest impairment of mitochondrial function as a relevant mechanism of BKM120. Moreover, combination of PI3K and mTOR inhibitors with cytotoxic agents could be promising option for non-cirrhotic HCC patients.
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Aminopiridinas/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Imidazoles/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinolinas/farmacología , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular , Respiración de la Célula/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Everolimus , Humanos , Immunoblotting , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Irinotecán , Sirolimus/farmacologíaRESUMEN
UNLABELLED: Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin-dependent kinase inhibitor p21 is an important transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21-deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling. CONCLUSION: The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21-signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury.