Biomedical subjects

G Horvath

Publications and source records attributed to G Horvath.

99 records · Page 6Linked to original sources

PubMedDate not supplied

Protein expression of p53 and Rb suppressor genes during the first passages of human endometrial adenocarcinomas heterotransplanted into nude mice.

Five human endometrial adenocarcinomas were heterotransplanted into nude mice to study changes in p53 and Rb protein expression and loss of heterozygosity of these genes during the first nude mice passages. Three of five heterotransplanted tumours were established and measured. In one tumour over-expression of p53 protein was found in passage 1 and subsequently, whereas the original tumour did not over-express the protein. We concluded that the heterotransplantation, i.e. the new host environment, may lead to mutations in the p53 gene. Two tumours from patients and also during nude mice passages expressed p53 protein in two bands, which were probably the result of allele polymorphism. Both p53 and Rb protein expression were increased after growth in estradiol-treated animals. Our results suggest that several changes in the function of these suppressor genes, including mutations, occur during the first passages in nude mice. Consequently, the growth regulation of established tumours may differ from that in their original counterparts in the patients.

Animals↗

PubMedDate not supplied

Tumor volume growth and cell proliferation in an estradiol resistant human endometrial adenocarcinoma growing in nude mice.

Ten human endometrial adenocarcinoma grafts were subsequently transplanted from an original tumour growing in nude mice for several years and nine were investigated for cell proliferation, tumour volume growth, allele imbalance and protein products of Rb and p53 suppressor genes to study a possible inherited connection between these factors. We did not find faster tumour volume growth in tumours with increased cell proliferation, in contrast to melanomas and breast cancers growing in nude mice. We concluded that a probably existing link between mechanisms regulating cell proliferation and cell loss in these two tumours does not operate in endometrial carcinoma as measured by us. The tumour progression may be one important factor which influences mechanisms regulating cell proliferation and cell loss.

Adenocarcinoma↗

PubMedDate not supplied

Effect of estradiol on tumor growth, cell kinetics and p53 oncoprotein expression in human endometrial adenocarcinoma heterotransplanted into nude mice.

To study the importance of estradiol concentrations in which tumors are growing to progression of tumor growth and cell kinetics, we have used a human tumor-nude mice model. In this model a human endometrial adenocarcinoma with estradiol independent but estradiol-responsive growth phenotype (i.e. the tumor was capable of growing in absence of estradiol but its growth could be stimulated by estradiol at the start of preparation phase) was examined. In the preparation phase pieces from this tumor were transplanted into nude mice, randomly divided into two groups, one with and one without estradiol treatment. After 18 months growth in these different hormone conditions the tumors were measured for p53 protein expression and pieces from both these groups were again transplanted into oophorectomized nude mice, each group being randomly allocated to two subgroups, one with and one without estradiol treatment (experimental phase). Tumor growth was measured during the experimental phase, whereas cell kinetic parameters and steroid receptor concentrations were analyzed after the experimental phase. Our findings indicate that progression of the growth phenotype is independent of estradiol conditions in which human endometrial adenocarcinomas are grown. Long-term growth in estradiol-poor conditions results in estradiol resistance of the cell cycle, probably accompanied by overexpression of the p53 protein. Tumor growth in estradiol-rich conditions, however, may protect, at least to some extent, the same tumor, which retains higher sensitivity of cell proliferation to estradiol and normal production of the p53 protein despite progressive changes in growth regulation.

Animals↗

PubMedDate not supplied

Growth interaction between different tumor populations in human endometrial adenocarcinoma growing in nude mice.

In these studies of tumor cell growth interaction we have used two tumors differing from each other in sensitivity to estradiol, transplanted to opposite sites of the same nude mice. In the first experiment we found that the growth of an estradiol-sensitive tumor may be delayed by the presence of an estradiol-resistant tumor in the same animal. Although the growth pattern was changed, proliferative activity, as reflected in the S-phase fraction measured by flow cytometry, and the steroid receptor concentrations were unchanged. Increase of circulating estradiol, however, protects the estradiol-sensitive population from this down-regulation of growth. Findings in a second experiment suggest that this growth delay is probably caused by changes such as decrease in labelling index, increase of non BrdU-incorporating cells in the S-phase, and cell loss in estradiol-sensitive tumors. We concluded that the estradiol-resistant tumor population may secrete some factor(s) acting as endocrine product(s) which may delay the growth of estradiol-sensitive cell populations when the tumors are grown in an estradiol-poor environment. If our model also represents interactions between tumor subpopulations within a single tumor, these findings may have implications for our understanding of the biology of tumor progression in some hormone-related human tumors.

Adenocarcinoma↗

PubMedDate not supplied

Estradiol influences p53 expression in a human endometrial adenocarcinoma heterotransplanted into nude mice.

The influence of different estradiol concentrations on the expression of the p53 suppressor gene and on cell kinetics was examined by semiquantitative analysis of protein and bromodeoxyuridine labelling in a human endometrial adenocarcinoma grown in nude mice. We found that increasing the circulating estradiol increases (p = 0.001), and decreasing the hormone value decreases (p = 0.001) the expression of p53 in this tumor. The number of cells in the G1/G0 phase of the cell cycle was significantly higher (p = 0.03), and the number of cells in the G2/M phase was significantly lower (p = 0.01) in tumors grown in estradiol-treated mice than in tumors obtained from the nontreated group. Changes in p53 expression may possibly be explained by either altered transcription activity of the gene or increased half-life of the protein. Our results suggest an important role of estradiol in the progression of estrogen receptor (ER) positive human endometrial adenocarcinomas.

Adenocarcinoma↗

PubMedDate not supplied

Estradiol regulates tumor growth by influencing p53 and bcl-2 expression in human endometrial adenocarcinomas grown in nude mice.

This study analyzes the effects of estradiol on p53 and bcl-2 expression, tumor growth and cell kinetic parameters in three human endometrial adenocarcinomas grown in nude mice. The tumors used were estradiol receptor (ER) positive but differed in receptor concentration and hormone sensitivity. All three tumors expressed wild-type p53 protein. Using a tumor with an estradiol independent but responsive (inhibited) growth phenotype, we found that an increase in the circulating estradiol concentration led to increases in p53 expression and a decrease in bcl-2 levels, resulting in increased cell loss (CL) measured as delayed tumor growth. In another tumor which demonstrated estradiol independent and resistant growth, we observed an estradiol dose-related increase in p53 expression but no changes in bcl-2 expression or cell kinetic parameters. The ER mechanism of these cells was at least partly intact, as evidenced by maintained PgR induction. The third tumor showed an estradiol independent and resistant growth phenotype and a non-functional ER mechanism, lacking PgR induction. After estradiol treatment of the tumor-bearing animals no changes were observed in p53 or bcl-2 expression or in cell kinetics. We conclude that estradiol may regulate tumor growth in some ER positive human endometrial adenocarcinomas through regulation of p53 expression, which in turn regulates the bcl-2 protein concentration. Furthermore, this regulation of p53 expression is estradiol dose dependent. These growth regulating functions appear to be strongly influenced by ER mechanisms and do not seem to operate synchronously in tumors with an estradiol resistant growth phenotype.

Animals↗

PubMedDate not supplied

Characterisation of a human endometrial adenocarcinoma established in vivo and in vitro.

A moderately differentiated human endometrial adenocarcinoma was heterotransplanted into nude mice and later established as a continuous in vitro cell line. Western blot analysis showed an accumulation of p53 protein in the cell line compared to the original tumour and heterotransplants. Sequential analysis of the p53 gene revealed point mutations in codons 175 and 248 in the cell line while no mutations were found prior to in vitro establishment. Immunohistochemistry confirmed the epithelial origin of the heterotransplants and of retransplants of the cell line. The intraperitoneal retransplants remained moderately differentiated, whereas subcutaneous retransplants became less differentiated. Heterotransplants were estrogen receptor (ER) positive and progesterone receptor (PgR) negative, indicating preservation of normal steroid receptor status. The ER could not be detected in the in vitro cell line using an enzyme immunoassay, but was detected with Western blot using a polyclonal antibody toward the carboxy terminus. After estradiol treatment, the in vitro cell line became weakly positive for the PgR, suggesting the ER mechanism was at least partly intact. Tumour growth in vivo was independent of endogenous estrogen but was inhibited when the tumour-bearing animals were treated with estradiol. Analysis of cell growth kinetics by flow cytometry (FCM) after bromodeoxyuridine (BrdU)-labelling revealed no difference in S-phase fraction (SPF) or labelling index (LI) between the treated and control groups. Cell loss (CL) was significantly increased from 42% to 89%, resulting in increased tumour volume doubling time (TVDT). Under in vitro conditions estradiol treatment resulted in an increase in cell doubling time and this growth retardation was accompanied by a significant decrease in SPF and LI. The estrogen responsive (inhibited) phenotype was thus preserved in the in vitro cell line but was probably mediated through another mechanism. This cell line thus appears to represent the development of a more malignant clone with divergent receptor function and growth behaviour, and provides us with an interesting new tool for the study of tumorigenesis in the human endometrium.

Adenocarcinoma↗

PubMedDate not supplied

Increased concentrations of neopterin in plasma, ascites and ovarian cyst fluid in malignant tumours compared with benign ovarian tumours.

Neopterin is a marker of the activation of cell-mediated immunity. The aim was to determine whether the concentrations of neopterin differ in plasma, ascites and ovarian cyst fluid between patients with ovarian cancer and patients with benign ovarian tumours. Neopterin was measured in 29 patients with cystic ovarian tumours of unknown histology. 14 ovarian cancers and 15 benign ovarian tumours were diagnosed histologically. Patient age and tumour size did not differ significantly between the groups. Neopterin levels were determined in plasma, and in ascites and cyst fluid by ELISA. The neopterin concentration in plasma, ascites and ovarian cyst fluid was significantly higher in patients with ovarian cancer compared with patients with benign ovarian tumours of the same size. The study shows that activation of cell-mediated immunity, defined as increased formation of neopterin, was increased in patients with ovarian cancer compared with patients with benign ovarian tumours.

Aged↗

PubMedDate not supplied

Estradiol induces DNA fragmentation in a human endometrial adenocarcinoma with estradiol-inhibited growth phenotype.

A moderately differentiated human endometrial adenocarcinoma heterotransplanted into nude mice was investigated for morphological and molecular changes in the tumours after treating the animals with estradiol. The tumour growth was previously characterised as estradiol-independent but responsive (inhibited) without any changes in cell proliferation. In response to hormonal treatment rather the cell loss factor increased. In this experiment tumours influenced by estradiol were investigated at different time-points after treatment by an in situ labelling technique to detect cells undergoing DNA fragmentation as a sign of apoptosis. Expression of the apoptosis related protein bcl-2 was evaluated by Western blotting. Tumours from animals treated with estradiol showed an increase in tumour volume doubling time from 5.4 days to 16 days compared to control tumours. Histologically, tumours influenced by estradiol were better differentiated than control tumours and showed a significant increase in cells staining positively with the in situ apoptosis detection technique. A parallel time dependent decreased expression of bcl-2 protein was observed. These results confirm our previous findings where estradiol influenced the cell loss factor without changes in the growth fraction, indicating increased apoptotic activity in response to hormonal treatment.

Adenocarcinoma↗