Biomedical subjects

W Bursch

Publications and source records attributed to W Bursch.

59 records · Page 4Linked to original sources

PubMed1983

The role of growth of normal and preneoplastic cell populations for tumor promotion in rat liver.

A number of different compounds, including phenobarbital, hypolipidemic drugs such as clofibrate and nafenopin, the sex steroids progesterone, cyproterone acetate, estradiol and mestranol, chlorinated hydrocarbons such as DDT, hexachlorocyclohexane, and TCDD and the antioxidant butylhydroxytoluene, appears to promote the development of liver tumors from previously induced initiated cells. The mechanisms of tumor promotion by several representative prototypes of these compounds were studied in rat liver in vivo. All liver tumor promoters mentioned above stimulate growth of normal liver. The growth response is due to cellular hypertrophy and/or increased rate of DNA (and cell) replication and/or decreased rate of cell death. Hepatocytes in foci or islands of altered cells (putatively preneoplastic) show higher rates of replication than normal liver cells; various different liver tumor promoters cause a further increase of proliferation of focal cells. The increased proliferative activity is found in different island phenotypes and thus seems to be a useful marker of the putative preneoplastic state. The focal cells respond to several factors limiting proliferation in normal liver, suggesting that they are not autonomous with respect to growth control. Early preneoplastic foci grow slowly without promotion, despite the relatively high rates of cell replication. Thus their cells seem to have a much shorter life-time than normal hepatocytes or to undergo reversion to the normal phenotype. Promoters seem to accelerate island enlargement by increasing cell replication and delaying cell death or remodeling. Thus, tumor promoters enhance the manifestation of the proliferation advantage of the putative initiated cell population. In addition, promoters cause increases in the number of detectable islands. This can partially be explained by enlargement of existing islands, but phenotypic changes that would enhance the probability of detection of remodelling islands and growth of dormant initiated cells, probably contribute to the apparent increase of island number. Putative preneoplastic foci of unknown origin are frequent in the liver of aged Wistar rats. They are morphologically and functionally very similar to those induced by carcinogens and are responsive to the mitogenic effect of tumor promoters. Promotion of these "spontaneous" foci may explain tumor appearance after long-term application of promoters.The findings may provide a basis for improved identification of initiated hepatocytes (and of initiating hepatocarcinogens) and for detection of tumor promoters. All suspected liver tumor promoters tested so far induced enhanced preneoplastic cell proliferation after single doses. The long-term carcinogenicity bioassay as currently performed does not discriminate between initiating and promoting properties of a test compound if the animals used develop spontaneous preneoplastic lesions in the organ affected.

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PubMed1983

Synchronization of hepatic DNA synthesis by scheduled feeding and lighting in mice treated with the chemical inducer of liver growth alpha-hexachlorocyclohexane.

A single dose of alpha-hexachlorocyclohexane (alpha-HCH) induces liver enlargement in adolescent mice. Concomitantly, the DNA content of the organ increases, and DNA synthesis is enhanced in parenchymal cells after a lag phase ('pre-replicative period') of 12-20 hr. DNA replication appears not to be followed by mitosis. Adaptation of the mice to a controlled feeding and lighting schedule provides synchronization of the hepatic DNA synthesis response to alpha-HCH. This appeared due to the provision, by the feeding and lighting schedule, of permissive signals which are required for stimulation of hepatic DNA synthesis in addition to alpha-HCH. One such signal is provided by food consumption before alpha-HCH administration, i.e. in the G0 phase. A second signal is provided after alpha-HCH administration in the late prereplicative period by feeding a protein-containing diet, and by other events, possibly related to the light-dark shift. Without this signal, the majority of hepatocytes stimulated to replicate DNA is arrested and accumulates at a stage a few hours before the start of DNA synthesis. The signal provides release from the block fairly synchronously. Both permissive signals seem also operative in the control of 'physiological' DNA synthesis in the liver of untreated mice. In conclusion, use of alpha-HCH and proper timing of feeding and lighting periods should provide an experimental model helpful for studying the interaction of growth stimuli with endogenous regulators of hepatic DNA replication.

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PubMedDate not supplied

Active cell death: role in hepatocarcinogenesis and subtypes.

Active cell death, the genetically programmed self-destruction of a cell, is now recognized to be a widespread phenomenon in biology that counterbalances mitosis to preserve tissue homeostasis. It is subject to the control of the growth regulatory networks in tissues. Close examination of the morphology of dying cells in liver and other tissues suggests that there are a number of morphological types of active cell death, ranging from forms dominated by nuclear changes and without signs of autophagy ("classical" apoptosis), e.g., in thymocytes and the liver, to those dominated by autophagic degradation of cytoplasm, e.g., in the mammary gland. The induction of gene expression in these diverse types of cell death is anticipated to be different. Here we review the data regarding the regulation of apoptosis in the liver by liver tumor promoter, transforming growth factor beta-1 and related peptides as well as nutrition. In the course of hepatocarcinogenesis, initiated cells as well as preneoplastic and neoplastic cell populations showed enhanced cell replication, but also enhanced apoptosis. Tumor promoter shift the balance between birth and death by increasing the rate of cell replication and by decreasing the rate of apoptosis. Thereby, liver tumor formation is accelerated. Food restriction exhibits the opposite effect and consequently, provides protection from carcinogenesis.

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PubMedDate not supplied

Kinetics of apoptosis and secondary necrosis in cultured rat thymocytes and S.49 mouse lymphoma and CEM human leukemia cells.

Cell culture systems are widely used to study metabolic changes during apoptosis. In cell culture, unlike in vivo, apoptotic cells are not phagocytosed and eventually lyse (secondary necrosis). This is of practical importance because metabolic changes seen in cultures may be due to the transition from apoptosis to necrosis, rather than to the induction of apoptosis itself. In the present study, we followed the kinetics of the occurrence of several indicators of cell death in rat thymocytes and mouse lymphoma (S.49), and human leukemia (CEM) cell cultures after dexamethasone treatment (10(-6) M). The presence of apoptosis and secondary necrosis was demonstrated by electron microscopy. Nuclear condensation and fragmentation, which are considered to reflect early stages of apoptosis, were visualized with Hoechst fluorescent dye H 33258 for quantitative determination by light microscopy. In S.49 and CEM cultures their incidence increased after glucocorticoid treatment, but remained at relatively low levels not exceeding 6-9% until 36 h (S.49) or 3-4% until 92 h (CEM). The trypan blue positive cells, however, increased steadily to about 60%. Furthermore, flow cytometry (single parameter DNA analysis after propidium iodide staining) revealed the occurrence of cells with reduced DNA fluorescence. Morphological and biochemical (internucleosomal DNA cleavage) analysis of FACS-sorted cells showed that early after dexamethasone the majority of them were apoptotic. In S.49 and CEM cell cultures no clear-cut time lag between increase in cells with reduced DNA fluorescence, chromatin condensation/fragmentation, and the uptake of trypan blue could be detected.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMedDate not supplied

Concepts of cell death and application to carcinogenesis.

The occurrence of cell death as a physiologic event in multicellular organisms has been known for more than 150 yr. In 1972, the term apoptosis was introduced on morphological grounds. The hypothesis that all kinds of cell death can be categorized as either "apoptotic" or "necrotic" is not generally confirmed. Cells seem to use different pathways for suicide, as reflected by different morphology: condensation-prominent, Type I or apoptosis; autophagy-prominent, Type II; and so forth. Type II cell death was found in mammary tissue and mammary tumor cells and in a variety of other organs. For unequivocal identification of the various types of cell death, morphological, biochemical, and functional criteria may be used in combination. During tumor development in various organs of animals and humans, not only rates of cell proliferation but also rates of cell death may increase with increasing malignancy. Morphological and functional criteria (antipromotion, withdrawal of survival factors) indicate that cell death in tumors frequently is of an active nature.

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