RESUMEN
Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. However, the relationship between the vascularity of HCC and the expression of angiogenic factors has not been investigated. In addition, no detailed studies have examined the possible involvement of angiogenic factors in the grade of malignancy of HCC. The aim of this study was to determine which angiogenic factors regulate tumor angiogenesis and contribute to the invasive ability of liver tumors, especially of HCC. Northern blot analysis was used to examine the transcriptional expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and acidic FGF in resected surgical specimens (20 HCC and 9 metastatic liver tumors). Correlations between messenger RNA (mRNA) expression and arteriographic findings, as well as histopathological findings, were evaluated. Immunohistochemistry was performed to identify the localization of cells expressing VEGF in HCC. Higher levels of VEGF mRNA were observed in 12 of 20 HCC and 2 of 9 metastatic liver tumors than in corresponding nontumorous tissues. The degree of VEGF mRNA expression was significantly correlated with the intensity of tumor staining in angiograms (P<.01). On immunohistochemical observation, VEGF protein was intensely detected in HCC cells. Furthermore, basic FGF mRNA was detected in 9 of 20 HCC and was related to the capsular infiltration of cancer cells (P<.05). In contrast, no significant difference was observed in the very low levels of acidic FGF mRNA found in the tumorous and nontumorous portions of the liver. In conclusion, these results suggest that VEGF contributes to angiogenesis of liver tumors, whereas basic FGF may be involved in the invasion of HCC into the surrounding tissues.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Factores de Crecimiento Endotelial/genética , Factor 2 de Crecimiento de Fibroblastos/genética , Expresión Génica , Neoplasias Hepáticas/metabolismo , Linfocinas/genética , Anciano , Secuencia de Bases , Northern Blotting , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/patología , Factores de Crecimiento Endotelial/metabolismo , Femenino , Factor 1 de Crecimiento de Fibroblastos/genética , Humanos , Inmunohistoquímica , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/patología , Linfocinas/metabolismo , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neovascularización Patológica , ARN Mensajero/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
We cloned five cDNAs encoding putative protein tyrosine phosphatases (PTPs; protein-tyrosine-phosphatase phosphohydrolase, EC 3.1.3.48) from the murine testis by using degenerate primers and the polymerase chain reaction cloning technique. Two of them were identical to the mouse cytoplasmic PTP and PTP-1B. The remaining three were likely to represent the murine counterparts of human PTP delta, human PTP epsilon, and rat striatum-enriched PTP. The cells expressing these genes were determined either by in situ hybridization histochemistry or by Northern blot hybridization. Moreover, Northern blot hybridization revealed that the transcripts of PTP-1B, mouse cytoplasmic PTP and the murine homologue of human PTP delta were quantitatively and/or structurally regulated during germ cell development, suggesting their roles in spermatogenesis.
Asunto(s)
Proteínas Tirosina Fosfatasas/biosíntesis , Espermatozoides/enzimología , Testículo/enzimología , Secuencia de Aminoácidos , Animales , Clonación Molecular , Secuencia Conservada , Cuerpo Estriado/enzimología , Cartilla de ADN , ADN Complementario/aislamiento & purificación , Humanos , Hibridación in Situ , Isoenzimas/biosíntesis , Isoenzimas/química , Masculino , Ratones , Ratones Mutantes , Reacción en Cadena de la Polimerasa , Proteínas Tirosina Fosfatasas/química , Ratas , Homología de Secuencia de Aminoácido , Maduración Sexual , Espermátides/enzimología , Espermatocitos/enzimología , Testículo/crecimiento & desarrolloRESUMEN
We analyzed PGE2 production in primary-cultured human hepatic macrophages (HHM phi) and peripheral monocytes (MO) from patients with and without liver cirrhosis, and correlated PGE2 production with the patients' liver function. Serum choline esterase (ChE) levels were used as an indicator of liver function. PGE2 production in both HHM phi and MO from cirrhotic patients was significantly lower than in HHM phi and MO from non-cirrhotic patients. PGE2 production in cirrhotic HHM phi was inversely correlated with ChE levels, whereas PGE2 production in cirrhotic MO showed no obvious correlation. In conclusion, both HHM phi and MO might contribute to the pathophysiology of liver cirrhosis via attenuated PGE2 production. Furthermore, HHM phi activity appears to be more strongly affected by the chronic pathological changes observed in the cirrhotic liver.
Asunto(s)
Cirrosis Hepática/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Prostaglandinas E/biosíntesis , Células Cultivadas , Humanos , Cirrosis Hepática/patología , Hepatopatías/metabolismoRESUMEN
The effect of biological response modifiers, such as interleukin-2 (IL-2) and streptococcal preparation OK432, on the functions of hepatic macrophages was investigated. The macrophages, even with no exogenous stimulation, produced superoxide anion (O2-) and tumor necrosis factor (TNF), displayed cytotoxicity against K562 cells and cytostasis against P815 cells and expressed immune-region-associated antigen (Ia). IL-2 administered in vitro or in vivo enhanced O2- production by hepatic macrophages and the intravenous injection of OK432 also enhanced O2 production. Furthermore, IL-2 added to the culture medium of hepatic macrophages isolated from OK432-injected rats augmented O2- production even more. The TNF production and Ia expression of the macrophages were also increased by the intravenous injection of OK432. As with O2- production, the cytotoxicity of the cells was enhanced by OK432 injection or by IL-2 added to the culture medium and the combination of OK432 and IL-2 augmented their cytotoxicity even more. Thus, the present study suggested that IL-2 and OK432 induce the augmentation of the antitumor activity of hepatic macrophages, partly as a result of the increase in production of O2- and TNF and Ia expression.
Asunto(s)
Antígenos de Histocompatibilidad Clase II/fisiología , Interleucina-2/farmacología , Hígado/citología , Macrófagos/efectos de los fármacos , Neoplasias Experimentales/terapia , Picibanil/farmacología , Animales , Autorradiografía , Radioisótopos de Carbono , Adhesión Celular/fisiología , Citotoxicidad Inmunológica , Humanos , Factores Inmunológicos/farmacología , Hígado/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/fisiología , Masculino , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Picibanil/farmacocinética , Ratas , Ratas Endogámicas , Superóxidos/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
In order to learn more about how human hepatic macrophages function, we analyzed the effect of exogenous PGE2 on the amounts of interleukin-1 (IL-1) and superoxide (O2-) released from primary-cultured human hepatic macrophages (HHM phi). When endogenous PGE2 production was blocked by indomethacin, exogenous PGE2 reduced IL-1 release from HHM phi in a dose-dependent manner, whereas it tended to increase O2- release from HHM phi. These results may suggest the probable contribution of PGE2 in regulating HHM phi mediator release in vivo.