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M Muleris

Publications and source records attributed to M Muleris.

At least 55 records · Page 3Linked to original sources
PubMed1993

Karyotypic and phenotypic variations between cell lines established from a primary colorectal tumour and two corresponding metastases from one patient.

In an attempt to characterise the mode of dissemination of colorectal carcinoma cells in host tissues, we established in vitro 3 human cancer cell lines isolated from a single patient: ALT-I from a primary colorectal tumour, ALT-F from the corresponding hepatic metastasis, and ALT-G from the lymphatic metastasis. The three cell lines exhibit variations in morphology, karyotype, antigens expression, anchorage-independent cell growth and tumorigenicity in nude mice related to their origin. Studies of the biological properties of these cell lines showed that the ALT tumour cells maintain, in vitro, some biochemical expressions, morphological properties and cytogenetic characteristics largely described for colon carcinoma in vivo. Significant increases of carcinoembryonic and CA19.9 antigens expressions were noted in the primary tumour cells as well as in the comparative metastatic ones. The karyotypes shared structural rearrangements and chromosome losses frequently described in fresh colorectal cancers, and revealed increasing alterations from the primary to the hepatic and lymph node tumours. Although the metastatic potential of the ALT cell lines was not demonstrated in the present paper, significant differences in the tumorigenic properties between the primary and the corresponding metastatic tumour cells were evident using in vitro and in vivo investigations. The present data support the hypothesis that, in our model, the hepatic metastasis might occur before or independently of the proximal lymph node metastasis originating from the colorectal carcinoma.

Animals↗
PubMed1992

Constitutional balanced translocations in patients with solid tumors.

In a sample of 329 patients with a solid tumor (colon and breast adenocarcinoma, cervical carcinoma, and meningioma), four balanced constitutional translocations were observed. Two were t(13q14q), and two were reciprocal translocations. Comparison with surveys of newborns showed a significant excess of translocations in our sample.

Adenocarcinoma↗
PubMed1992

Survival and acquired genetic alterations in colorectal cancer.

To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations: histological staging (P less than 0.00001), preoperative serum carcinoembryonic antigen concentration (P less than 0.002), DNA content (P less than 0.009), and allelic loss on the short arm of chromosome 17 (P less than 0.002) and 1 (P less than 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P less than 0.0001 and P less than 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered.

Aged↗
PubMed1992

[Genetic abnormalities in "sporadic" colorectal cancers].

There are many genetic abnormalities in colorectal cancers, and they can schematically be studied according to 3 approaches. 1. The quantitative abnormalities of the DNA content of the nucleus and the cell cycle are studied with flow cytometry. 2. Karyotypic abnormalities relating to the loss and/or gain of chromosomes or structural abnormalities are studied by cytogenetics. 3. Oncogene or anti-oncogene mutations carried out by these chromosomal segments are studied by molecular biology. When compared to the clinical data, some of these abnormalities have a prognostic value. They allow an insight into the fundamental mechanisms of colorectal carcinogenesis. Finally, they may allow predicting and assessing the efficacy of some adjunctive therapies, especially that of medication.

Chromosome Aberrations↗
PubMed1991

Adaptation to 5-fluorouracil of the heterogeneous human colon tumor cell line HT-29 results in the selection of cells committed to differentiation.

The HT-29 cell line contains a small proportion of differentiated polarized, enterocytic and mucus-secreting cell types (less than 95%) which can be selected under various pressure conditions, e.g., glucose deprivation or methotrexate. The purpose of the present work was to investigate whether this also applies to 5-fluorouracil (FUra). Stepwise adaptation of exponentially growing cells to 1, 5, 10 and 20 microM FUra results, after a phase of high mortality, in the emergence of adapted sub-populations with stable growth rates and curves, and IC50 6, 18, 37, and 110 times higher than in untreated cells respectively. FUra-adapted cells are all differentiated, according to 2 phenotypes: (I) polarized dome-forming cells which express carcinoembryonic antigen at their apical surface and (2) goblet cells which secrete a mucus of colonic immunoreactivity. These phenotypes are present in the parental population and are different from those selected e.g., by glucose deprivation or methotrexate. This differentiation pattern is maintained when the cells are subcultured in drug-free medium. Resistance to FUra is acquired through gene amplification as substantiated by a 4- to 6-fold increase of thymidylate synthase gene copies in cells stably adapted to the drug. Whether the same mechanism or others are responsible for the first steps of resistance to FUra remains to be elucidated. Altogether, these results support the hypothesis that some of the cells which are present in the parental line and are committed to differentiation possess advantages which allow them to immediately resist and secondarily adapt to FUra. Comparison of the differentiation characteristics of FUra-adapted cells with those from cells selected under other pressure conditions suggests that resistance and adaptation to either type of pressure may depend on the differentiated phenotype to which the cells are committed.

Blotting, Northern↗
PubMed1991

Relationships between UMPK and PGD activities and deletions of chromosome 1p in colorectal cancers.

A deletion involving a large segment of the short arm of chromosome 1(1p-) occurs in about 50% of colorectal cancers. It was previously noticed that, in these tumors, many deletions affect genes encoding for enzymes of the de novo pathway of nucleotide synthesis. The gene for uridine monophosphate kinase (UMPK), mapped on 1p32, is generally involved in del(1p). The activity of the corresponding enzyme was measured and compared to that of 6-phosphogluconate dehydrogenase (PGD), encoded by a gene also mapped on chromosome 1p and frequently deleted, but involved in another metabolism. It was found that a clear relationship exists between activity and the number of chromosome 1p for PGD but not for UMPK, both on primary tumors (PTs) and on tumors grafted into nude mice (GTs). By comparison to corresponding normal mucosae, the activity of PGD was high in PTs and GTs, but this increase was reduced in case of del(1p). The activity of UMPK being increased in PTs but not in GTs, it is assumed that the increase in PTs is due to non-cancerous cells, which are missing in GTs. The fact that no gene dosage effect exists, although the tendency for del(1p) coexists with the relative decrease of UMPK activity in cancerous by comparison to non-cancerous cells, suggests that either mutation or disregulation of UMPK gene occurred early.

Adult↗
PubMed1991

Activity of thymidylate synthetase, thymidine kinase and galactokinase in primary and xenografted human colorectal cancers in relation to their chromosomal patterns.

The relationship between chromosome anomalies and metabolic modifications in human colorectal cancers grafted into nude mice was studied. Two distinct chromosomal patterns have been demonstrated i.e., monosomic type (MT) characterized by multiple chromosome losses or deletions always involving chromosome 18, and trisomic type (TT) characterized by progressive gains of chromosomes. Grafted tumors conserve original karyotypes observed on corresponding primary tumors. Most changes involve the loss of chromosomes carrying genes encoding for enzymes of the de novo pathways and the gain of chromosomes carrying genes encoding for enzymes of the salvage pathways of nucleotide synthesis. In MT tumors the long arm (q) of chromosome 17 is frequently duplicated in association with a deletion of the short arm, forming an isochromosome 17q. The activities of 3 enzymes, thymidylate synthetase (TS) mapped on chromosome 18, thymidine kinase (TK) and galactokinase (GalK), both mapped on chromosome 17q, were studied. TS is a de novo enzyme and TK and GalK are salvage enzymes. A clear correlation could be demonstrated between tumor types and enzyme activities: MT tumors had lower TS and higher TK and GalK activities than TT tumors. These differences were too large to result from a gene dosage effect only. These data suggest that serial studies on grafted colorectal cancers give a better representation of metabolic disturbances than studies on fresh tumor samples, usually contaminated by non-cancerous cells.

Adult↗
PubMed1990

Sex chromosomes in a series of 79 colorectal cancers: replication pattern, numerical, and structural changes.

The cytogenetic study of a series of 79 colorectal cancers was performed with special attention to sex chromosome behavior. It was found that apart from other chromosomal changes, the early-replicating X chromosome (Xe) was frequently duplicated in tumors from both males and females. This contrasted with a frequent loss of either the late-replicating X (XI) in tumors from females or of the Y chromosome in tumors from males. All the detected unbalanced rearrangements resulted in a gain of the long, but not the short, arm of the X chromosome. The replication pattern of Xe chromosomes was similar to that of control tissues, whereas that of XI chromosomes was unusual. Its main characteristic was that the two major R bands of the short arm, Xp11 and Xp22, replicated too early.

Aneuploidy↗
PubMed1990

Cytogenetics of colorectal adenocarcinomas.

The occurrence of nonrandom chromosomal anomalies in colorectal adenocarcinomas could be demonstrated from the cytogenetic study of 100 cases. The most frequent changes are a rearrangement of chromosome 17, leading to the loss of its short arm and a loss of one chromosome 18. Three types of tumors with abnormal karyotypes can be defined. First are the monosomic-type near-diploid tumors (MD), characterized by a monosomy of both 17p and chromosome 18 mostly associated with other recurrent monosomies. In two of three cases, one or several minor derived polyploid subclones are also observed. Second are the monosomic-type polyploid tumors (MP), which have a pattern of chromosome imbalance very similar to that of MD tumors. They derive from MD tumors by endoreduplication followed by complete disappearance of the original MD clone. Third are the trisomic-type tumors (TT), which lose either 17p or chromosome 18 or none, most of the anomalies being gains of entire chromosomes. These TT tumors never undergo endoreduplication. In addition, seven tumors with normal karyotypes were found and may constitute another category (NT). A nonrandom distribution of these tumor types in relation to tumor site was observed, since in the distal colon, TT and NT tumors are underrepresented and endoreduplications are significantly more frequent. The level of chromosomal mutagenesis is two- to threefold higher in MD and MP than in TT tumors. More than 95% of the rearrangements are unbalanced, and most of them result from breakpoints located in juxtacentromeric heterochromatin. A good correlation is found between our results and the available molecular data on allelic losses. The involvement of recessive tumor suppressor genes in colorectal tumorigenesis and the possible relationship between chromosomal imbalances and deviations in metabolic pathways is described.

Adenocarcinoma↗
PubMed1990

Cytogenetic and molecular approaches of polyploidization in colorectal adenocarcinomas.

We present the cytogenetic analysis of 23 cases of polyploid colorectal adenocarcinomas. We took advantage of the high intratumoral heterogeneity of the karyotypes to identify clones, subclones, and cell-to-cell variations. This allowed us to reconstruct the chromosomal evolution of each tumor and to propose a schema of the chromosomal changes in relation to the endoreduplication process. All but one case were characterized by a relative deficiency of chromosomes 17p and 18. Other deficiencies affecting the late-replicating X, and to a lesser degree, 1p, 5q, 14, 15, 8p, 10, 21, and 4, and excesses affecting the early-replicating X, 8q, 13, 16, 17q, and 11 were frequently associated. This pattern of imbalances is very similar to that of the monosomic type previously described in near-diploid tumors. The pattern of the 23rd tumor corresponded to those of the trisomic type tumors. These data largely confirm the existence of two distinct processes of chromosomal evolution in colorectal adenocarcinomas, with a strong tendency to undergo endoreduplication for the monosomic type near-diploid tumors. To correlate cytogenetic and molecular data, allelic losses analyses were investigated for probes of chromosomes 17p and 18. In all 12 informative tumors, a loss of heterozygosity for probes of the short arm of chromosome 17 indicated the occurrence of a rearrangement of chromosome 17 before the endoreduplication. The same was true for allelic losses for probes of chromosome 18 found in 11 of 12 informative tumors. The correlation between cytogenetic and molecular data is thus excellent and indicates that losses of 17p and 18 are early events in the tumor process.

Adenocarcinoma↗
PubMed1989

Preservation of chromosome and DNA characteristics of human colorectal adenocarcinomas after passage in nude mice.

Twenty-seven human colorectal adenocarcinomas were implanted s.c. into nude mice. A comparative study of chromosomes and DNA between fresh tumor (FT) and xenografted tumor cells (XT) could be performed in 9 cases. Losses or deletions were consistently found in FTs as well as in XTs, particularly on chromosomes 17 and/or 18. This was correlated with loss of heterozygosity for these chromosomes. Comparison between corresponding FT and XT karyotypes showed great similarities. However, the tendency toward polyploidization, which exists in FTs, appeared to be more pronounced in XTs. Passage in nude mice makes it possible to repeat cytogenetic analyses in order to obtained interpretable metaphases. Xenografting not only increases the number of tumorigenic cells, but also eliminates human normal stromal or blood cells and gives unambiguous data on allelic loss.

Adenocarcinoma↗
PubMed1989

Detection of 1q polysomy in interphase nuclei of human solid tumors with a biotinylated probe.

A biotinylated probe (L23-21) specific for the 1q12 band of human karyotype was used to detect the 1q segment in interphase nuclei of breast and colon carcinomas. This probe was selected because trisomy or polysomy 1q is the most frequent chromosomal change observed in solid tumors. This method enables cancerous cells, including near-diploid ones carrying an unbalanced rearrangement of 1q, to be easily identified.

Biotin↗
PubMed1989

Cytogenetic characterization of a colon adenocarcinoma from a familial polyposis coli patient.

We report on the cytogenetic findings in a fresh biopsy of a colorectal adenocarcinoma in a patient with familial polyposis coli (FAP). The stemline had 45 chromosomes with several clonal chromosome aberrations including a der(17)t(17;?), and -18, which are the two most recurrent aberrations in sporadic colorectal carcinomas. This finding is discussed in relation to the chromosomal changes described in sporadic colorectal carcinomas and in FAP cell lines.

Adenocarcinoma↗
PubMed1988

DNA content and genetic evolution of human colorectal adenocarcinoma. A study by flow cytometry and cytogenetic analysis.

We have conducted in parallel DNA flow cytometry (FCM) and cytogenetic (CG) analysis of a series of surgical specimens from 35 human colorectal adenocarcinomas. An excellent quantitative correlation was observed (r = 0.99) between modal peak values of FCM histograms and chromosome counts. This observation confirms that aneuploidy, as defined by FCM, accurately reflects the deviation from diploidy of the genomic DNA. FCM-derived DNA patterns have been analyzed in the context of the clonal chromosomal evolution determined by CG analysis. In the metaphases of a given tumor, even if karyotypes of different ploidy exist, the presence of identical marker chromosomes suggests a common origin for the multiple populations observed by FCM. Thus, heterogeneity in DNA content within a tumor, including the polyploidization step, would be indicative of genetic evolution.

Adenocarcinoma↗
PubMed1988

Loss of alleles on chromosome 18 and on the short arm of chromosome 17 in polyploid colorectal carcinomas.

The zygosity of 19 colorectal carcinomas (either near-diploid or polyploid) from patients known to be heterozygous for RFLPs located on chromosome 18 or on the short arm of chromosome 17 has been examined. In most cases, at least one allele was significantly under-represented. The reason for the absence of complete loss of heterozygosity was investigated for 5 polyploid tumors. It was shown that the diploid component which, in these tumors, is essentially composed of non-neoplastic cells, remains heterozygous as the polyploid component invariably loses heterozygosity. The results strongly suggest that many colorectal carcinomas originate from a single cell which had lost at least part of either chromosome 18 or of one short arm of chromosome 17, or both.

Adult↗
PubMed1988

Existence of two distinct processes of chromosomal evolution in near-diploid colorectal tumors.

The comparison of all the karyotypes established in each of 18 near-diploid colorectal tumors made it possible to reconstruct a clonal evolution and to distinguish between early and late chromosomal aberrations. Because no abnormalities were observed in all tumors, and as even the most frequent changes, i.e., monosomy 17p and monosomy 18, may be present in mosaic, no chromosomal change can be regarded as a common primary event in the carcinogenetic process. However, the repeated occurrence of several changes favors the hypothesis of two karyotypic evolutionary processes. In most tumors, monosomy 17p and 18 were found, and the karyotypic evolution involved mainly several additional monosomies due to unbalanced rearrangements or losses that affect, by order of decreasing frequency, chromosomes 1p, 4, 14, 5q, 6q, 2p, and 11q, as well as gains of chromosomes 20, 8q, 13, 17q, and X. In this group of tumors, the mean number of chromosomes remains close to 46. In the other tumors, either only a monosomy 17p or a monosomy 18 was found and the karyotypic evolution involved essentially trisomies, resulting from gains with, by order of decreasing frequency, a preferential involvement of chromosomes 7, 8q, 13, 17q, 20, X, 2p, 5, and 16, the only additional recurrent deletion affecting chromosome 1p. In these tumors, the mean chromosome number is close to 51. Ten out of 11 polyploid sidelines emerged from monosomic-type tumors.

Chromosome Aberrations↗