Showing papers on "Tumour heterogeneity published in 1997"

Multistep carcinogenesis of breast cancer and tumour heterogeneity.

Abstract: Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.

p53 mutations in childhood thyroid tumors from Belarus and in theyroid tumors without radiation history

Abstract: Mutations in the p53 tumour-suppressor gene (exons 5–8) were investigated in 31 Belarussian childhood thyroid tumours (24 cases of papillary thyroid carcinoma, 3 benign tumours and 2 cases each of thyroiditis and goiter); 33 thyroid tumours from juveniles and adults without radiation exposures (25 carcinomas of various histological types, including 11 papillary carcinomas and 8 adenomas) and 6 tumours from adults (4 papillary carcinomas, 1 adenoma, 1 goiter) served as controls. The mutational spectrum of p53 differed greatly between the childhood thyroid carcinomas from Belarus and the control groups. In the control groups of 29 malignant thyroid tumours, 7 different mutations were detected on exons 5–8, none of which occurred among the 15 papillary carcinomas in this group. Five mutations were found in tissue samples of the 24 childhood papillary carcinomas, and they were all the same p53 point mutation (CGA |iO CGG) on codon 213 of exon 6. To determine whether this mutation is simply a polymorphism or whether it is specific to the tumour cells, laser-assisted microdissection was applied to collect various areas of tumorous and non-tumorous cells (10–20 cells per sample) from each paraffin-embedded tissue section of 8 of the papillary thyroid carcinomas. Using PCR-SSCP and sequence analysis on these cells, the very same p53 mutation on codon 213 was detected in various microdissected tumour samples of 2 cases, but it was not found in any microdissected non-tumorous sample. The exclusive occurrence of this p53 mutation in selective microdissected samples of tumour cells, even as homozygous mutation in 1 case, reflects a distinct tumour heterogeneity within papillary childhood thyroid carcinomas. Int. J. Cancer 73:802–807, 1997. © 1997 Wiley-Liss, Inc.

The effects on growth and survival of IL-6 can be dissociated in the U-266-1970/U-266-1984 and HL407E/HL407L human multiple myeloma cell lines

Abstract: Several studies have documented IL-6-dependent growth promotion of murine and human neoplastic plasma cells. However, it is well known that human multiple myeloma (MM) cells in vitro show a considerable degree of heterogeneity concerning growth and survival requirements. This heterogeneity, which probably reflects overlapping effects of feeder cells, interleukin 6 (IL-6) and components of fetal calf serum (FCS) as well as tumour heterogeneity in vivo, has hampered the elucidation of molecular mechanisms underlying the effects of IL-6. In an attempt to dissociate growth and survival promotion of IL-6, we have studied two pairs of human MM cell lines, HL407E/HL407L and U-266-1970/U-266-1984, selected to represent different stages of in vitro tumour progression and dependence of feeder cells and exogenous IL-6. We demonstrated that exogenous IL-6, in the presence of FCS, conveyed: (a) a strong growth stimulatory effect with weak or no survival promotion in HL407L and U-266-1970 cells; (b) promotion of survival with no effects on growth in HL407E cells; (c) no growth or survival promotion to U-266-1984. Moreover, our results suggested that IL-6 may enhance apoptosis in U-266-1970/U-266-1984 cells, and that FCS may interfere with IL-6 in its growth stimulatory effect. The relative dissociation of growth, survival and apoptotic effects of IL-6 leads to the conclusion that the HL407E/HL407L and U-266-1970/U-266-1984 pairs of cell lines provide a useful human model system to study molecular mechanisms underlying these separate events.

Heterogeneity of DNA distribution pattern in renal tumours

Abstract: The presence of intratumoural heterogeneity in DNA distribution patterns has been accepted. However, most previous studies have not taken this fact into consideration. The value of DNA cytometry depends on its reproducibility. This could be influenced by heterogeneity failure. The aim of the present study is to evaluate intratumoural heterogeneity in renal cell cancer. A sample of 22 tumours of the kidney was investigated by means of static DNA cytometry: 21 tumours were carcinomas, one was an angiomyolipoma. Probes from seven different locations of each tumour were Feulgen-stained and measured. The variability of DNA features was determined and correlated with histological grade and type and with tumour size. There was considerable intratumoural heterogeneity with respect to DNA distribution pattern in 45% of the tumours. Additional non-diploid tumour-stemlines and deviation of computed DNA features could be found in several cases by measuring more than one slide per tumour. A correlation between tumour heterogeneity, grading or typing, and tumour size could not be found. Because these DNA parameters could serve as the foundation of a risk-adapted treatment, tumour heterogeneity could have clinical consequences. Based on the results of this study we suggest measuring at least three slides per tumour to avoid misinterpretation of DNA measurements in renal cell cancer.