Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of Bfl-1 gene, a novel Bcl-2 related gene, was determined by Northern blot analysis using a radiolabeled cDNA specific for Bfl-1 gene in 82 surgically resected tissue specimens of 28 gastric cancers, 15 colon cancers, nine breast cancers, eight bone and soft tissue sarcomas, five ovarian cancers, nine colon adenomas and eight gastric adenomas. A high rate of expression was observed in gastric and colon cancer, at 86 and 93%, respectively. In breast cancer, bone and soft tissue sarcoma and ovarian cancer, the expression rate was 33, 25 and 40%, respectively. In stomach cancer, the expression rate of Bfl-1 gene in metastatic lymph nodes was 82%, which was higher than 50% of the primary sites (p < 0.02). The intensity of RNA bands of the gastric cancer specimens was compared according to the stage, demonstrating that there was no difference in the expression levels of Bfl-1 gene between the stages in both primary sites and metastatic lymph nodes. Bfl-1 gene was expressed in three (33%) out of nine adenomas of the colon, while it was not detected in all eight gastric adenomas, We also examined the RNA expression of Bfl-1 gene in 22 human cancer cell lines consisting of five stomach cancer, four squamous cell carcinoma, three lung cancer, three cervical cancer, two colon cancer, two brain cancer, two leukemia and one osteosarcoma cell lines. Bfl-1 gene band was detected in one (5%) cervical cancer cell line, SiHa. The results of cancer tissue specimens indicate that Bfl-1 gene may play an important role in carcinogenesis of human cancers and may be involved in a relatively early phase of the adenoma-carcinoma sequence in colon cancer development. However, the mechanism responsible for the very low rate of expression in established cell lines is not clearly understood and further investigation is necessary to clarify the mechanism involved.
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PMID:Expression of a novel Bcl-2 related gene, Bfl-1, in various human cancers and cancer cell lines. 949 79

Oxidative stress has been frequently implicated in the initiation and promotion phases of carcinogenesis. Antioxidant enzymes, which can antagonize this process, are lowered in a number of malignancies even though different findings have been reported in the literature. It has been shown that tumors have less copper/zinc superoxide dismutase (Cu/Zn SOD) in comparison with the more metabolically active tissues, but there is a large overlap between normal and tumor tissue. In order to examine the relationship between osteosarcoma at different degrees of proliferation and differentiation and Cu/Zn SOD levels, four different human ostosarcoma cell lines: HOS, U-2 OS, MG63, Saos-2 were studied for their production and release of Cu/Zn SOD. A normal human stromal cell line was used as control. Osteosarcoma cells were stimulated with TNF alpha, a cytokine previously shown to have antiproliferative activity. The release of Cu/Zn SOD into the supernatant was higher for the HOS and U-2 OS lines when compared to the other cell lines evaluated both in basal condition and after incubation with TNF alpha. Elevated intracellular levels of Cu/Zn SOD were shown except for the HOS and U-2 OS which possess high concentrations of the enzyme at 24 hours declining during the other incubation periods. These concentrations were increased after TNF alpha treatment. The different behaviour of the four cell lines evaluated might be explained by their degree of differentiation.
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PMID:Copper/zinc superoxide dismutase expression by different human osteosarcoma cell lines. 961 84

Deoxyribonucleic acid (DNA) oncoviruses can induce neoplastic transformation by interfering with proliferative proteins. Simian virus 40 (SV40) has been shown to induce brain tumors, osteosarcoma, lymphoid tumors and malignant mesothelioma in hamsters and SV40-like DNA sequences corresponding to the Rb-pocket binding domain of SV40 T-antigen (Tag) have been detected in the same human tumors. Since only a small percentage of people exposed to asbestos fibers develop a malignant mesothelioma, SV40 has been suspected to co-operate with the fibers in the neoplastic transformation or even to itself induce the onset of malignant mesothelioma in patients without expositive history. The mechanism that seems to be involved in the SV40-induced carcinogenesis process is mediated by interaction of Tag, both with p53 and Rb proteins, leading to their functional inactivation that is responsible for the removal of their inhibitory cell cycle effect which determines the increase of the number of cells entering the G1-S phase. Up to now the source of SV40 human infections has not yet been completely identified even though administration from 1957-1965 of SV40 contaminated polio vaccines is highly suspected. Horizontal infection by sexual transmission has been also hypothesized. Due to the important public health implications further investigations are required in order to establish both the source and the carcinogenetic role of simian virus 40 in humans.
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PMID:Simian virus 40 and human cancer. 968 9

Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells. We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1alpha protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1alpha proteins accumulated following exposure to Ni. The induction of HIF-1alpha and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h. These results suggest that acute Ni treatment causes accumulation of HIF-1alpha protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis.
Carcinogenesis 1999 Sep
PMID:Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. 1046 29

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division, but the specific genes involved in progression of hormone-related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and prevention of hormonal carcinogenesis are discussed. This includes developing polygenic models of cancer predisposition and the further development of safe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizing that functionally relevant sequence variants in genes involved in steroid hormone metabolism and transport would act together, and also interact with well-known hormonally related risk factors, to define a high-risk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinically useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17alpha (CYP17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5alpha-reductase type II (SRD5A2), CYP17 and the 3beta hydroxysteroid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic cohort to support these models.
Carcinogenesis 2000 Mar
PMID:Hormonal carcinogenesis. 1123 97

A 34-year-old premenopausal woman developed asynchronous bilateral nonpalpable breast cancers at the age of 32 and 34 years. She had undergone amputation of her left lower leg because of osteosarcoma at the age of 16. Her mother had beendiagnosed with breast cancer at the age of 45. The clinicopathological features of the two breast tumors in this patient closely resembled each other; both were nonpalpable, and detectable only by helical CT scan. Histologically, they consisted mainly of an intraductal component with small grade 3 invasive foci. In addition, both tumors estrogen receptor (ER) status was negative, and both were positive for c-erbB-2 protein on immunohistochemical staining. A missense germ line mutation of BRCA2 (exon 25 codon 3118; Met3118Thr) was detected in this patient. These data may provide useful information on the carcinogenesis and biological behavior of breast cancers which develop in patients with BRCA2 germ line mutations.
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PMID:Bilateral Nonpalpable Breast Carcinomas in a Patient with BRCA2 Germ Line Mutation and Past History of Osteosarcoma. 1109 90

Aneuploidy is a characteristic of the majority of human cancers, and recent studies suggest that defects of mitotic checkpoints play a role in carcinogenesis. MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability. Rare mutations of this gene have been reported in colon and lung cancers. We examined a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast and glioblastoma) for alterations of MAD1L1 by RT-PCR-SSCP and nucleotide sequencing. Eight mutations consisting of missense, nonsense and frameshift mutations were found, together with a number of nucleotide polymorphisms. All the alterations in cell lines were heterozygous. Frequency of mutations was relatively high in prostate cancer (2/7 cell lines and 2/33 tumor specimens). We placed a mutant truncated MAD1L1, found in a lymphoma sample, into HOS, Ht161 and SJSA cell lines and found that it was less inhibitory than wild type MAD1L1 at decreasing cell proliferation. Co-expression experiments showed that the mutant form had a dominant-negative effect. Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in HOS cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent, nocodazole. Our results suggest a pathogenic role of MAD1L1 mutations in various types of human cancer.
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PMID:Mutations in the mitotic check point gene, MAD1L1, in human cancers. 1142 79

Limited data exist to permit an accurate assessment of risks for carcinogenesis and mutagenesis from embedded fragments or inhaled particulates of depleted uranium (DU). Ongoing studies have been designed to provide information about the carcinogenic potential of DU using in vitro and in vivo assessments of morphological transformation as well as cytogenetic, mutagenic, and oncogenic effects. For comparison, we also examined tungsten alloys used in military projectiles and the known carcinogen nickel. Quantitative and qualitative in vitro transformation studies were done to assess the carcinogenic potential of radiation and chemical hazards. Using a human osteosarcoma cell model, we demonstrated that soluble and insoluble DU compounds can transform cells to the tumorigenic phenotype, as characterized by morphological, biochemical, and oncogenic changes consistent with tumor cell behavior. Tungsten alloys and nickel were also shown to be neoplastic transforming agents, although at a frequency less than that of DU. Sister chromatid exchange, micronuclei, and alkaline filter elution assays showed DU and tungsten alloys were genotoxic. Exposure to a nontoxic, nontransforming dose of DU induced a small but statistically significant increase in the number of dicentrics formed in cells. These results suggest that long-term exposure to DU or tungsten alloys could be critical to the development of neoplastic disease in humans and that additional studies are needed.
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PMID:Potential late health effects of depleted uranium and tungsten used in armor-piercing munitions: comparison of neoplastic transformation and genotoxicity with the known carcinogen nickel. 1187 92

A two-mutation carcinogenesis model has been applied to model osteosarcoma incidence in two data sets of beagles injected with 226Ra. Taking age-specific retention into account, the following results have been obtained: (1) a consistent and well-fitting solution for all age and dose groups, (2) mutation rates that are linearly dependent on dose rate, with an exponential decrease for the second mutation at high dose rates, (3) a linear-quadratic dose-effect relationship, which indicates that care should be taken when extrapolating linearly, (4) highest cumulative incidences for injection at young adult age, and highest risks for injection doses of a few kBq kg(-1) at these ages, and (5) when scaled appropriately, the beagle model compares fairly well with a description for radium dial painters, suggesting that a consistent model description of bone cancer induction in beagles and humans may be possible.
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PMID:A consistent two-mutation model of bone cancer for two data sets of radium-injected beagles. 1240 Sep 50

Sodium fluoride is a white, crystalline, water-soluble powder used in municipal water fluoridation systems, in various dental products, and in a variety of industrial applications. Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting 14 days, 6 months, and 2 years. In addition, genetic toxicology studies were performed with Salmonella typhimurium, with mouse L5178Y cells, and with Chinese hamster ovary cells. 14-Day Studies: Rats and mice received sodium fluoride in drinking water at concentrations as high as 800 ppm. (Concentrations are expressed as sodium fluoride; fluoride ion is 45% of the sodium salt by weight.) In the high-dose groups, 5/5 male and 5/5 female rats and 2/5 male mice died; one female rat was given 400 ppm in the drinking water also died before the end of the studies. No gross lesions were attributed to sodium fluoride administration. 6-Month Studies: Rats received concentrations of sodium fluoride in drinking water as high as 300 ppm, and mice as high as 600 ppm. No rats died during the studies; however, among the mice, 4/9 high-dose males, 9/11 high-dose females, and 1/8 males in the 300 ppm group died before the end of the studies. Weight gains were less than those of controls for rats receiving 300 ppm and mice receiving 200 to 600 ppm. The teeth of rats and mice receiving the higher doses of sodium fluoride were chalky white and chipped or showed unusual wear patterns. Mice and male rats given the higher concentrations had microscopic focal degeneration of the enamel organ. Rats receiving 100 or 300 ppm sodium fluoride had minimal hyperplasia of the gastric mucosa of the stomach, and one high-dose rat of each sex had an ulcer. Acute nephrosis and/or lesions in the liver and myocardium were observed in mice that died early, and minimal alterations in bone growth/remodeling were observed in the long bones of mice receiving sodium fluoride at concentrations of 50 to 600 ppm. The sodium fluoride concentrations selected for the 2-year studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concentrations were selected based on the decreased weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6-month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2-year study. Body Weights and Survival in the 2-Year Studies: Mean body weights of dosed and control groups of rats and mice were similar throughout the 2-year studies. Survival of rats and mice was not affected by sodium fluoride administration. Survival rates after 2 years were: male rats-control, 42/80; 25 ppm, 25/51; 100 ppm, 23/50; 175 ppm, 42/80; female rats-59/80; 31/50; 34/50; 54/81; male mice-58/79; 39/50; 37/51; 65/80; female mice-53/80; 38/52; 34/50; 52/80. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The teeth of rats and mice has a dose-dependent whitish discoloration, and male rats had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. The teeth of male and, to a lesser degree, female rats had areas of microscopic dentine dysplasia and degeneration of ameloblasts. Dentine dysplasia occurred in both dosed and control groups of male and female mice; the incidence of this lesion was significantly greater in high-dose than in control male mice. Osteosclerosis of long bones was increased in female rats given drinking water containing 175 ppm sodium fluoride. No other significant nonneoplastic lesions in rats or mice appeared related to sodium fluoride administration. Osteosarcomas of bone were observed in 1/50 male rats in the 100 ppm group and in 3/80 male rats in the 175 ppm group. None were seen in the control or 25 ppm dose groups. One other 175 ppm male rat had an extraskeletal osteosarcoma arising in the subcutaneous tissue. Osteosarcomas occur in historical control male rats at an incian incidence of 0.5&percnt; (range 0-6&percnt;). The historical incidence is not directly comparable with the incidences observed in this study because examination of bone was more comprehensive in the sodium fluoride studies than in previous NTP studies of other chemicals, and the diet used in previous studies was not controlled for fluoride content. In the current study, although the pairwise comparison of the incidence in the 175 ppm group versus that in the controls was not statistically significant, osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between the occurrence of these neoplasms and the administration of sodium fluoride. No other neoplastic lesions in rats or mice were considered possibly related to chemical administration. Genetic Toxicology: Sodium fluoride was negative for gene mutation induction in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without S9. In two laboratories, sodium fluoride was tested for induction of trifluorothymidine resistance in mouse L5178Y lymphoma cells; results were positive both with and without S9. Sodium fluoride was tested for cytogenetic effects in Chinese hamster ovary (CHO) cells in two laboratories. In the first laboratory, the sister chromatid exchange (SCE) test was negative with and without S9, and the chromosomal aberration (Abs) test was positive in the absence of S9; in the second laboratory, the SCE test was positive with and without S9, but no induction of Abs was observed. The laboratory that reported a negative result for Abs tested at doses below that shown to be positive at the other laboratory. Similarly, the positive SCE result was obtained at a higher dose and longer harvest time than used by the laboratory reporting the negative SCE response. Conclusions: Under the conditions of these 2-year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. Dosed rats had lesions typical of fluorosis of the teeth and female rats receiving drinking water containing 175 ppm sodium fluoride had increased osteosclerosis of long bones.
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PMID:NTP Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No. 7681-49-4)in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1263 66


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