Tenascin and type IV collagen expression in liver cell dysplasia and in hepatocellular carcinoma

The extracellular matrix (ECM) located in and around tumors is different from normal organ stroma, and there is evidence that it is critically involved in carcinogenesis and malignant growth. Whereas an abnormal composition of ECM in hepatocellular carcinomas (HCC's) has previously been demonstrated, not much is known so far with respect to putative HCC precursor lesions. We have, therefore, systematically analyzed the immunohistochemical reactivity for two major ECM components, tenascin and type IV collagen, in three types of liver cell dysplasia (LCD), and compared the findings with patterns observed in HCC's of different types and grades. Tenascin reactivity was generally stronger in HCC's than in cirrhosis. In cirrhotic nodules harboring areas of LCD, tenascin expression was significantly lower in small cell LCD than in large cell LCD. Type IV collagen reactivity in and around HCC's decreased as a function of a lower differentiation grade. In both groups of cirrhosis, ¡.e. with or without HCC, cirrhotic nodules occupied by the small cell variant of LCD exhibited a significantly lower type IV collagen reactivity than those with large cell LCD or simple regenerative cells. Taken together these findings suggest that, similar to adenomatous hyperplasia, small cell LCD is characterized by an abnormal tenascin and type IV collagen expression, thus reflecting the defective ECM pattern observed in HCC's

«Neuroendocrine» differentiation in hepatocellular carcinomas (HCCs): lmmunohistochemical reactivity is related to distinct tumor cell types, but not to tumor grade

We have analyzed neuroendocrine differentiation (ND) in hepatocellular carcinomas (HCCs) of fifty patients. It turned out that ND is frequent in HCCs, and that it is not restricted to fibrolamellar hepatocellular carcinoma (FL-HCC). Multiexpression is seen in a quarter of the cases, and marker coexpression may occur within the same tumor cell. ND predominates in trabecular and rnixed HCCs, but does not appear to be related to grade. Most positive cases showed a hepatocyte-like cell morphology, frequently associated with bile formation. It thus appears that the HCC cell type most likely to show ND is a hepatocyte-like one, i.e. differentiated cell, frequently polarized and producing bile, rather than a small and poorly-differentiated cell. Possible pathogenic mechanisms leading to ND in HCCs are briefly discussed

Hepatocyte apoptosis in hepatic iron overload diseases

In this retrospective study, we systematically analyzed hepatocyte apoptosis in three situations of hepatic iron overload (hereditary hemochromatosis; hepatic iron overload of unknown reason; iron overload due to hyperhemolysis or exogenous iron administration). Apoptosis was assessed by use of DNA nick end-labelling. The results suggest that hepatic iron overload is associated with an increased apoptotic rate of hepatocytes, and that iron-laden hepatocytes in hemochromatosis behave, with respect to apoptosis, differently from those in other states of iron overload. The hepatocyte apoptotic rate tended to increase as a function of the degree of iron storage. As in other pathological liver changes studied so far, an elevated apoptotic rate of hepatocytes predominated in the pericentral parts of liver acini in hemochromatosis, but not in the two other groups of hepatic iron overload. Possible mechanisms for this difference are discussed, particularly with respect to a participation of the Kupffer cell system

Copper zinc and manganese superoxide dismutases in alcoholic liver disease: immunohistochemical quantitation

Alcohol damage to the liver can, among other factors, be mediated through the action of toxic oxygen radicals generated by ethanol. Major antioxidants in the liver are copperlzinc and manganese superoxide dismutases (CuIZn- and Mn-SODS). In order to test whether SODS may be differentially expressed in alcoholic liver disease (ALD), biopsies from 45 patients with ALD were analyzed for qualitative and quantitative immunoreactivity of CuIZn- and Mn-SOD in hepatocytes. The overall amount of Cu/Zn-SOD reactivity was significantly lower in ALD than in control biopsies, whereas no difference was found for Mn-SOD. Staining for both enzymes was decreased in ballooned hepatocytes. Low Cu/Zn-SOD was correlated with advanced lattice-like perisinusoidal fibrosis. In hepatocytes forming cirrhotic nodules, SOD reactivity was similar to that of control cells. The results suggest that SODS may be differentially regulated in ALD, and that Mn-SOD, an inducible enzyme, may be involved in recovery and cell protection in ALD

Three types of liver cell dysplasia (LCD) in small cirrhotic nodules are distinguishable by karyometry and PCNA labelling, and their features resemble distinct grades of hepatocellular carcinoma

We have studied the occurrence and specific features of li\er cell dysplasia (LCD) in Chinese patients showing li\.er cirrhosis with or without hepatocellular carciiioina (HCC). Three types of LCD (SLCD, LLCDo. LLCDe) were rnorphologically defined. and these types were further analyzed using karyoinetry, estiniation of nucleic acid conteiit and deiisity, and PCNA iinmuiiostaiiiing. Features found for three types of LCD were coniparetl with those of normal hepatocytes (NLC). siinple regei~eratiiig hepatocytes (SRLC), and cells of HCCs covering different grades. The results show that 1 ) Aaryoinetry arid nucleic acid parameters allow an objecti\,e separation of LCD types both from NLC aiid SRLC; 2) karyometric features of LLCDe are most cloile to those of tiighly differentiated HCCs. whereas nuclear size nnd chroin~itinc omposition of SLCD closely 1-etlect those of poorly differentiated HCCs: 3) the frequency of LCD cluster.; was higher iii cirrhotic livers carrying HCC. being about douhle for al1 three LCD types: 4) the h i ~ h e sP~CN A labelling occurred in the small cell group of LCD (SLCD), still, however, beiiig smaller tlian that of simple i-egenerating hepatocytes. Based on these fiiidiiiys i t i \ suggested that, similar tu atypical adenoinatous hyperplasia, LCDs of distinct inorphotypes riiay represent precursor lesions for HCC, aiid soine cellular forms niay mimick cell types known to occur in experiinental carcinogenesis

Culture of normal and leukemic cells in diffusion chambers

Normal murine, caprine, and human bone marrow and peripheral blood cells can be grown in diffusion chambers. The irradiated host provides a stimulus to erythrocytic and granulocytic growth over what is seen in the DC's implanted in the nonirradiated host. The stimulus is most likely humoral and affects erythropoiesis, granulopoiesis, and megakaryocytopoiesis. It is suggested but not proved that the stimulus for erythropoiesis is an increased level of plasma erythropoietin. It is tempting to suggest that CSF and thrombopoietin are responsible for the stimulation of the other cell lines. Growth of normal human cells in irradiated mice shows a marked reduction of the transit time from the myelocyte to the segmented neutrophils. Growth does not follow steady conditions in terms of rates and transit times. Since all cells produced are retained in the DC's after the time they would normally be extruded into the blood, a nonsteady state system exists. Senescent death of non-proliferating cells occurs. Human leukemic and multiple myeloma cells grow in DC's as do blood cells from patients with myelofibrosis and myeloid metaplasia. Data are insufficient to characterize aberrations in growth. Pilot studies show that human eosinophils will grow, proliferate and mature. (auth

Spatially fractionated microirradiation of normal CNS and gliosarcomas of the rat with synchrotron photons: Cell and tissue lesions; Raeumlich fraktionierte Mikrobestrahlung von normalem ZNS und Gliosarkomen der Ratte mit Synchrotron-Photonen: Zell- und Gewebelaesionen

Rats were implanted intracerebrally with 9L gliosarcoma cells were used to experimentally determine the curative effectiveness of synchrotron radiation produced by the National Synchrotron Radiation Source. Radiation was delivered in beams with each ray 25 micrometers thick and arranged in an array of 4 mm corners. All experimental animals receiving the gliosarcoma cells and not treated died within four weeks. Treated animals surviving 113 days were sacrificed and their brains were examined histologically

Synchrotron X-ray microbeams: A promising tool for drug-resistant epilepsy treatment

International audienceEpilepsy is one of the most important neurological diseases. It concerns about 1% of the population worldwide. Despite the discovery of new molecules, one third of epileptic patients are resistant to anti-epileptic drugs and among them only a few can benefit from resective surgery. In this context, radiotherapy is an interesting alternative to the other treatments and several clinical devices exist (e.g., Gamma Knife®). The European Synchrotron Radiation Facility offers the possibility to develop new methods of radiosurgery and to study their antiepileptic effects. Here, we discuss several studies that we performed recently to test and try to understand the antiepileptic effects of X-ray synchrotron microbeams in different animal models of epilepsy. We showed a decrease of seizures after Interlaced Microbeam Radiotherapy (IntMRT) of the somatosensory cortex, known as the seizure generator, in a genetic model of absence epilepsy. These antiepileptic effects were stable over 4 months and with low tissular and functional side-effects. The irradiated pyramidal neurons still displayed their physiological activity but did not synchronize anymore. We also obtained a lasting suppression of seizures after IntMRT of the dorsal hippocampus in a mouse model of mesiotemporal lobe epilepsy. However, an important variability of antiepileptic efficiency was observed probably due to the small size of the targeted structure. Despite these encouraging proofs-of-concepts, there is now a need to adapt IntMRT to other models of epilepsy in rodents which are close to refractory forms of epilepsy in human patients and to implement this approach to non-human primates, before moving to clinical trials