RESUMEN
Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
Asunto(s)
Plaquetas/metabolismo , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Animales , Plaquetas/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Gránulos Citoplasmáticos/efectos de los fármacos , Gránulos Citoplasmáticos/metabolismo , Endotelio/efectos de los fármacos , Endotelio/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones Transgénicos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Recuento de PlaquetasAsunto(s)
Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Tejido Linfoide/embriología , Linfotoxina-alfa/metabolismo , Organogénesis , Lesiones Precancerosas/metabolismo , Neoplasias de la Próstata/patología , Animales , Carcinoma Hepatocelular/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias Hepáticas/metabolismo , Tejido Linfoide/patología , Receptor beta de Linfotoxina/metabolismo , Masculino , Ratones , FN-kappa B , Lesiones Precancerosas/patología , Neoplasias de la Próstata/metabolismo , Transducción de SeñalRESUMEN
Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTßR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.
Asunto(s)
Activación Metabólica , Linfocitos T CD8-positivos/inmunología , Hígado Graso/inmunología , Hepatocitos/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Hepáticas/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
Asunto(s)
Neoplasias del Colon/metabolismo , Extravasación de Materiales Terapéuticos y Diagnósticos , Janus Quinasa 2/metabolismo , Receptores CCR2/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Quinasas Quinasa Quinasa PAM/fisiología , FN-kappa B/metabolismo , Animales , Apoptosis , Transformación Celular Neoplásica , Hiperplasia , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones Transgénicos , NecrosisRESUMEN
Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) alpha and beta and their receptor (LTbetaR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTalphabeta expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6(+) oval cells, depends on lymphocytes and IKappa B kinase beta expressed by hepatocytes but is independent of TNFR1. In vivo LTbetaR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTbetaR inhibition in LTalphabeta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.