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H M Rabes

Publications and source records attributed to H M Rabes.

At least 37 records · Page 2Linked to original sources
PubMed1996

Proliferative heterogeneity of human renal cell carcinomas and prevalence of ras gene point mutations.

The variable prevalence and a possible stage-dependent increase of ras gene point mutations in human tumors might correspond to clonal growth advantages of ras-activated cells. Tumor areas with activated ras genes might thus differ in proliferative activity from those lacking ras gene activation. This hypothesis is studied in a series of human renal cell carcinomas that had been used previously for an analysis of proliferative compartments after post-operative vascular [3H]/[14C]thymidine perfusion [Rabes et al. (1979) Cancer 44: 799-813]. The growth fraction of different subcompartments of these tumors was studied by immunohistochemistry with mib1 antibody, recognizing a fixation- and embedding-resistant epitope of Ki-67 protein. Thirty subpopulations of 14 human renal cell carcinomas that exhibited a broad spectrum of proliferative activity were chosen for an analysis of the prevalence of K-ras point mutations in exon 1 by a mutation-enriching primer-mediated restriction-fragment-length-polymorphism analysis and/or direct sequencing of polymerase-chain-reaction-amplified material. The combined autoradiographic and immunohistochemical analysis confirmed the intra- and intertumoral proliferative heterogeneity. Compared to [3H]/[14C]thymidine labeling indices, mib1 labeling indices are higher. The ratio of mib1 to [3H]/[14C]thymidine labeling indices varies from 1.9 to 4.1 for the individual tumor subcompartments. However, neither in K-ras codons 12/13 nor in adjacent codons did we detect any mutations in the various tumor compartments. The results suggest that neither mode of proliferation nor type of differentiation is related to K-ras exon 1 point mutations in human renal cell carcinomas.

Adult↗
PubMed1996

Karyotype evolution of the clonal rat liver cell line CL 52 during progression in vitro and in vivo.

Liver cell line CL 52, derived from a diethylnitrosamine-treated rat at the stage of preneoplasia/early neoplasia, had an inconspicuous 2n karyotype when analyzed 6 months after in vitro propagation. Malignant progression was accompanied by cytogenetic alterations of chromosomes 1, 3, and 11. In addition, trisomy of chromosomes 4, 6, and 7 led to a significant reduction of the tumor latency period after retransplantation. During 4 years of cytogenetic observation, the once clonal 2n population showed a characteristic karyotype evolution: loss of diploidy, occurrence of polyploid sidelines, deletions followed by unbalanced rearrangements, clonal diversification, and selection of the in vitro most rapidly growing or in vivo most malignant cell type. The karyotype alterations in the four sublines of CL 52 are discussed with special reference to oncogenesis-related genes assigned to the involved rat chromosomes 1, 3, 11, 12, 4, 6, 7, 10. The observed karyotype evolution of this cell line exemplifies genetic/ chromosome instability of carcinogen-induced preneoplastic/early neoplastic liver cells and provides a tool for analyzing, under controlled conditions, stage-dependent sequences of molecular genetic alterations in liver carcinogenesis.

Animals↗
PubMed1996

What's new in ras genes? Physiological role of ras genes in signal transduction and significance of ras gene activation in tumorigenesis.

Ras gene mutations have been found with variable prevalence in different tumor types. While during the past decade a lot of information has been accumulated on the frequency of ras oncogene activation in tumors, the last two years brought considerable progress in elucidating molecular mechanisms of signal transduction for which cellular ras proteins are key elements. They transmit signals from upstream tyrosine kinases to downstream serine/threonine kinases ultimately leading to changes of gene expression cytoskeletal architecture, cell-to-cell interactions and metabolism. These signalling pathways are of interest for the physiological regulation of proliferation and differentiation in normal, as well as in cancer tissue. Mutational activation of cellular ras genes to transforming oncogenes is thought to promote cell growth even in the absence of extracellular stimuli, and may thereby contribute to the initiation and/or progression of tumors.

Animals↗
PubMed1995

High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident.

RET rearrangement was studied in papillary thyroid carcinomas (PTC) of children exposed to radioactive fallout in Belarus after the Chernobyl accident. To detect RET rearrangement in small tissue samples from thyroidectomy specimen (12 PTC of children; 2 PTC and 1 follicular carcinoma of adults; non-tumorous thyroid tissue of 4 children and 4 adults as controls), a RT-multiplex PCR was developed using primers suited to amplify fragments in different quantities depending on the presence or absence of RET rearrangements in the tissues. The type of rearrangement was determined by RT-PCR and direct sequencing using primers for ret/PTC1, 2 and 3. Two-thirds of the papillary thyroid carcinomas of the children revealed a RET rearrangement, with ret/PTC3 being more frequent by a factor of 3 than ret/PTC1. ret/PTC2 was not detected. All RET rearrangement-positive tumors had lymph node metastasis while half of the tumors with wild-type cRET had not. More than half of the cases with ret/PTC3 expressed not only the ELE/RET transcript as expected, but also the RET/ELE transcript. Intrachromosomal rearrangement involving RET and the adjacent H4 or ELE gene on chromosome no. 10 is a very frequent event in thyroid cancer of children of the Chernobyl-contaminated zone of Belarus.

Adult↗
PubMed1995

The DNA binding activity of the liver transcription factors LFB1 (HNF1) and HNF4 varies coordinately in rat hepatocellular carcinoma.

As renal cell carcinomas are characterized by the disappearance of the transcription factor LFB1, which is known to be primarily involved in gene regulation in the liver, we have measured the presence of LFB1 in rat hepatocellular carcinomas induced by diethylnitrosamine. The level of LFB1 binding activity in adenoid-cystic as well as trabecular tumours shows some variation and may either be lower or higher than in the non-tumorous tissue. The amount of LFB1 binding activity correlates with the binding activity of HNF4, a transcription factor reported to stimulate LFB1 expression. As the levels of LFB1 and HNF4 binding activity differ extensively in various hepatocellular carcinomas, it is unlikely that these transcription factors play a general role in hepatocarcinogenesis. This is in contrast to renal carcinogenesis where a dramatic loss of LFB1 is a consistent feature.

Albumins↗
PubMed1995

[Control of liver proliferation: structural, functional and molecular aspects].

After a period of active growth during embryonic and postnatal development, the liver attains a steady-state. In the adult organ, cell proliferation occurs after cell loss only or upon increased functional demand. It is triggered by an altered balance between growth inhibitory and stimulatory factors. The cell cycle of hepatocytes is controlled at various restriction points from G(0) to mitosis by cyclins which regulate cyclin-dependent kinases (cdk). Kinases or cyclin-cdk complexes are antagonized by a variety of inhibitory proteins. Actual commitment for proliferation is dependent on microenvironment, intralobular distribution as well as age and specific differentiation status and function, all of which play an important in modifying the actual mode of hepatocellular cell cycle transit. Major resection of liver parenchyma evokes a partially synchronized wave of systemic cell proliferation in a typical intralobular pattern. The size of the proliferative fraction appears limited by a priority to serve for the required specific function. It is altered by toxic or inflammatory processes or by changes of function. Multicellular organ-specific growth regulation and response is in contrast to monocellular escape from growth control in the clonal development of neoplasia. Genetic alterations during hepatocarcinogenesis, among many others constitutive expression of c-myc, mutations of p53, or amplification of cyclins, provide insight in the control of liver cell proliferation and their aberrant function in malignancy.

Aging↗
PubMed1994

Identification of tumor-associated protein variants during rat hepatocarcinogenesis. Aldose reductase.

Tumor-associated protein variants were detected by two-dimensional gel electrophoresis (2-DE) in soluble proteins from chemically induced rat hepatomas and transformed rat liver cell lines. Among them, a series of 8 protein variants was found localized at similar sites in 2-DE gels (33-35 kDa, with different pI values). We characterized four of them. In situ peptide mapping with limited proteolysis disclosed a significant relationship between these four individual protein spots. Their different position in 2-DE gels might be due to posttranslational modifications: one of the variants was phosphorylated, three others were modified by glycosylation. The most prominent tumor-associated protein variant of this series (spot 17) was further studied by amino acid analysis and internal amino acid microsequencing. It became evident that this variant is identical to aldose reductase (EC 1.1.1.21). This enzyme of the sorbitol pathway is expressed in the liver during embryogenesis, but is absent in adult rat liver. Our results suggest that it is reexpressed and functionally active during liver carcinogenesis.

Aldehyde Reductase↗
PubMed1994

Rat tumor cytogenetics: a critical evaluation of the literature.

Cancer cytogenetics is a valuable tool for the analysis of cellular and molecular aberrations during malignant transformation and tumor progression. The rat has served as an important experimental model to investigate various steps in oncogenesis. An attempt was made to compile data on rat tumor cytogenetics from previously published data in order to provide a basis for further research, especially when combining classic and molecular cytogenetics, a yet underdeveloped area of research in rat tumorigenesis. The wealth of data presented here provides a contrast to its impact on biological specificity. Because of the different experimental procedures involved with tumor induction and the application of carcinogens at relatively high dosages, as well as occasional less than careful histological documentation, a delineation of unambiguous chromosome alterations, critical in the process of carcinogenesis, is rare in the rat. Future studies should be performed with spontaneously arising rat tumors and/or tumors after low, single-dose carcinogen exposure in order to reduce unspecific karyotype alterations not intrinsically related to tumor initiation and progression. Short-term culture or early passages in vitro should be methods of choice, especially for solid tumors, to avoid erroneous karyotype analyses because of contaminating normal cells. The combined karyological and molecular genetic approach to an analysis of tumor-specific changes, still hindered by an almost complete lack of cell type-, chromosome-, or gene-specific molecular probes for the rat, should become a focus of research in order to continue having the advantages this species offers for stage-specific analysis of tumorigenesis.

Animals↗
PubMed1993

Cell proliferation and prevalence of ras gene mutations in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors.

Exposure of female inbred Sprague-Dawley Curl rats to intragastric 7,12-dimethylbenz(a)anthracene (DMBA) resulted in a variety of benign and malignant mammary tumors exhibiting a wide spectrum of proliferative activity as measured by [3H]-thymidine autoradiography. On the basis of earlier observations of 21% H-ras codon 61 mutations in DMBA-induced rat mammary tumors reported by Zarbl et al., the prevalence of this type of ras gene mutation was studied in relation to the rate of proliferation in individual benign and malignant tumors. In a series of 50 mammary tumors exhibiting highly different proliferation activities we did not detect any H-ras codon 61 mutations after allele-specific dot blot hybridization of PCR-amplified material obtained from paraffin sections. Neither mode of proliferation nor type of differentiation appears related to H-ras codon 61 mutations. The relevance of activated ras genes for rat mammary carcinogenesis appears restricted to model systems using N-methyl-N-nitro-sourea (MNU) as initiating carcinogen.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Excessive basement membrane material production by epithelial tumors induced by dimethylnitrosamine in rat kidneys.

In an experimental series of preneoplastic lesions and neoplasms induced in the rat kidney by dimethylnitrosamine, four of the 54 tumors showed particular morphological features that allowed them to be grouped separately. The leading characteristic of these lesions was an abundant PAS-positive matrix in which the tumor cells were embedded. The demonstration of variable amounts of laminin, heparan sulfate proteoglycan, collagen types IV and V in the tumor matrix provided circumstantial evidence that it consisted of basement membrane material. Since the tumor cells were in intimate contact with the matrix and no fibroblasts were present, it was assumed that the matrix was a product of the tumor cells. Until now, no similar renal tumors have been described in laboratory animals and no human equivalent is known.

Animals↗
PubMed1992

K-ras point mutations in human colorectal carcinomas: relation to aneuploidy and metastasis.

Material from paraffin sections of 109 human colorectal carcinomas, mostly obtained at autopsy, was analyzed for the presence of K-ras point mutations at codon 12, position 2. Mutations at this position were found in 23 cases (21.1%). Aneuploid colorectal carcinomas showed a significantly higher prevalence of K-ras point mutations than diploid tumors, suggesting an involvement of ras mutations in the development of aneuploidy. No differences in the prevalence of K-ras mutations were observed with respect to the patients' age, sex and tumor type. In metastases, the type of ras gene mutation was always identical to that of the respective primary tumor. Mutations were not found in metastases from primary tumors devoid of ras mutations. This renders a clonal selection of K-ras mutated cells from a wild-type primary tumor during the metastatic process unlikely. However, nearly twice as many ras gene mutations were seen in metastatic than in non-metastatic primary tumors.

Aneuploidy↗
PubMed1992

Morphology and proliferation kinetics of early tumor stages induced by dimethylnitrosamine in rat kidneys.

A total of 49 dimethylnitrosamine (DMN)-induced rat renal cell tumors were analyzed and classified cytomorphologically at an early stage of development. Of these, 17 were basophilic-tubular tumors, two of which showed a direct transition to proximal tubules of the P3-segment; 21 lesions were vacuolated and contained glycogen; these were defined cytomorphologically as a separate tumor type the histogenetic derivation of which from the collecting duct system was established by documentation of a direct transition. Morphological similarities point to the lipid-storing variant of the basophilic tumor, but a carcinoma of the ducts of Bellini is another possible human equivalent of this tumor type. Another seven lesions were clear and granular cell tumors. In two of these a direct transition from the collecting duct system was found, thus confirming that this only recently established origin of experimentally induced rat renal clear cell tumors also applies to lesions induced by DMN. The proliferation kinetics of DMN-induced lesions were studied in autoradiograms after pulse-labeling with tritiated thymidine. The basal proliferation of these early tumor stages displayed a marked proliferative advantage over the normal parenchyma. The lesions were still subject to physiological growth stimulation as determined by 3H-TdR-continuous-labeling with osmotic mini-pumps following unilateral nephrectomy. However, compared with normal kidney parenchyma, the 3H-TdR-labeling index of the lesions was even higher indicating a response modification during early neoplasia.

Animals↗
PubMed1992

Variant protein patterns in hepatomas and transformed liver cell lines as determined by high resolution two-dimensional gel electrophoresis (2DE).

Deviations in the pattern of soluble proteins from chemically induced primary rat hepatomas and from transformed, tumorigenic liver cell lines were determined by high resolution two-dimensional gel electrophoresis (2DE). As compared with the protein pattern of normal rat liver with approximately 1300 protein spots visible in silver-stained gels, quantitative and qualitative alterations were found in hepatomas including neoexpression of glutathione-S-transferase P, as described earlier. After correction for proliferation-related changes by comparison with gels of cells from regenerating rat liver, 30 protein variants remained, which were identically up- (n = 6) or down-regulated (n = 18) or were detected as new spots (n = 6) in primary hepatomas and transformed tumorigenic liver cell lines which are devoid of contaminating nonparenchymal cells. Seven of these variants showed a reduced expression in short-term cultured liver cells indicating dedifferentiation processes in the transformed state. Several hepatoma- and transformation-associated variants were found in clusters of similar mol. wt and/or pI, among them a complex of eight protein variants at approximately 33-35.5 kDa and a pI of approximately 6.6-7.4. Spots of this cluster show considerable changes between the investigated experimental groups and might be suited for being studied at the level of posttranslational modification during carcinogenesis.

Animals↗
PubMed1992

Ras gene mutation-independent tumours in the intestine of the rat by a single dose of N-methyl-N-nitrosourea.

Aiming at a sequential analysis of the role of ras gene point mutations during intestinal carcinogenesis, we established an experimental rat tumour model using N-methyl-N-nitrosourea (MNU) as an initiating agent as this carcinogen has been found to induce rat mammary carcinomas with a high prevalence of ras gene mutations. MNU treatment of a total of 249 rats (25 or 50 mg/kg i.p.) in various combinations with partial hepatectomy, hydroxyurea infusion and/or phenobarbital exposure resulted in a high incidence of intestinal adenomas and carcinomas of different histological types, besides liver, soft tissue and auditory sebaceous gland tumours. With PCR-amplified DNA the prevalence of mutations of codon 12 and 61 of H-, K- and N-ras was determined in dot blots by hybridization with 32P-labelled allele-specific oligonucleotides. Ras gene point mutations were not observed in any of the 41 intestinal rat tumours randomly selected from various experimental groups. Considering the high prevalence of ras mutations in MNU-induced mammary carcinomas of the rat the observed complete lack of ras mutations in intestinal tumours induced in the rat by the same carcinogen suggests that organ-specific intraspecies differences in the mechanism of malignant transformation exist even for a heterolytically decomposing, direct acting carcinogen like MNU.

Animals↗
PubMed1991

Carcinogen-induced liver tumours of Wistar rats: absence of activated ras genes and of N-rasC.

We examined mutational activation of ras genes in rat liver preneoplasias and tumours induced by diethylnitrosamine and N-methyl-N-nitrosourea (NMU). In accordance with previous reports on H- and K-ras genes, no mutations were detected in the investigated hepatic tumours and prestages suggesting that neither mutations at codons 12, 13 and 61 of H- and N-ras nor a mutation in the last intron of the H-ras gene are involved in initiation and progression of rat hepatocellular carcinomas. In the course of this investigation we found two N-ras genes (N-rasA, N-rasB). Surprisingly N-rasC, which is present in the germ line of Fischer rats, is missing in Wistar rats. This suggests different numbers of germline N-ras genes in members of one species. Two out of eight NMU-induced liver tumours exhibited additional N-ras-related sequences of unknown origin.

Animals↗
PubMed1989

Amplification, rearrangements, and enhanced expression of c-myc in chemically induced rat liver tumors in vivo and in vitro.

c-myc expression, amplification, and rearrangement were studied in neoplastic hepatic nodules of rats after diethylnitrosamine treatment, in hepatocellular carcinomas induced by N-methyl-N-nitrosourea, and in tumorigenic liver cell lines derived from rat hepatocytes transformed by diethylnitrosamine in vivo. Steady-state levels of c-myc transcripts, as measured by Northern blot hybridization, were slightly increased in neoplastic hepatic nodules and showed high levels in some hepatocellular carcinomas and some tumorigenic liver cell lines. DNA of the samples was analyzed after restriction nuclease treatment by Southern blot hybridization, using different probes specific for the three exons of the c-myc gene. The results suggest rearrangements of the complete gene and/or amplification in some cases. Rearrangements include the 5'-part of the first exon and a stretch upstream c-myc supposed to contain control elements of c-myc expression. Aberrations of this kind are most pronounced in advanced metastasizing hepatocellular carcinomas and highly tumorigenic, metastasizing liver cell lines. Heterogenicity of genomic alterations and c-myc transcript levels were found among different samples of the same hepatocellular carcinoma indicating subclonal diversification.

Animals↗