Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a serum-free medium we have established two new human breast carcinoma cell lines from a single primary tumor. Cultures were maintained on chemically defined medium CDM3 or on minor modifications of this medium, Dulbecco's modified Eagle medium-Ham's F12 supplemented with epidermal growth factor, insulin, transferrin, estradiol, hydrocortisone, triiodothyronine, cyclic AMP, phosphoethanolamine, ethanolamine, fibronectin, fetuin, ascorbic acid, bovine serum albumin, and trace element salts including selenite (Petersen and van Deurs, Cancer Res., 47: 856-866, 1987). Primary cultures comprised both NADPH-neotetrazolium reductase-positive carcinoma cells and NADPH-neotetrazolium reductase-negative cells of stromal appearance, as well as normal epithelial cells (Petersen and van Deurs, Cancer Res., 46: 2013-2020, 1986). In subsequent passages the cells were monitored exclusively using the tumorigenicity assay on nude mice. Two cell lines, one nontumorigenic, HMT-3909S1, and one tumorigenic, HMT-3909S8, were selected from the primary cultures. Selection of S8 through subline S4 required transient supplementation of CDM3 with fetal calf serum. Permanent lines S1 and S8 were maintained on serum-free medium. Further characterization of the two cell lines in terms of normal breast gland differentiation (Petersen and van Deurs, Differentiation, 39: 197-215, 1988) was carried out using immunocytochemistry, immunochemistry, electron microscopy, and cytogenetics. S8 appeared to be identical with the NADPH-neotetrazolium reductase-positive carcinoma cells of the primary cultures, with a particular subpopulation of carcinoma cells in the tumor of origin, and with the tumorigenic cells of the nude mice. This subline was aneuploid, typically epithelial in morphology, and expressed keratins K8 and K18 and the glycoprotein MAM-6, typical of luminal epithelial cells in the normal breast gland. Subline S1 appeared more like the elongated cells in the primary cultures and like a second subpopulation of cells in the carcinoma of origin. However, S1 cells were in fact epithelial, since they expressed keratins. Also, S1 cells seemed to be a triploidation of a cell with close resemblance to S4, while only few cytogenetic differences were found between S4 and S8, suggesting an origin of S1 and S8 via S4 from a single hypothetical stem cell.
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PMID:Differential tumorigenicity of two autologous human breast carcinoma cell lines, HMT-3909S1 and HMT-3909S8, established in serum-free medium. 215 55

Previous studies indicated that autotransplanted 7, 12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors were hormone-dependent and, if derived from a single primary tumor, many of their metabolic parameters varied little. Therefore, these tumors transplanted in multiple sites provided an opportunity for serial sampling of individual tumors for repeated biochemical evaluations. In the present study, primary mammary tumors induced by DMBA in female noninbred Sprague-Dawley rats were autotransplanted at six sites. When these grafts grew to an average size of 6 cm, the hosts were ovariectomized. Eighteen days later when all tumors were apparently regressing, a silastic tubing 2 cm long containing crystalline estradiol was implanted sc into each host for 14 days. Individual tumors were serially removed from each host before ovariectomy, after ovariectomy, and after estrogen replacement. Levels of cyclic AMP (cAMP) and cyclic GMP (cGMP) in these tumors were measured by radioimmunoassay. Results indicated that tumor regression was associated with an elevation of cAMP levels and that tumor growth was accompanied by a decline in cAMP. The level of cGMP did not correlate with either tumor growth or regression. Therefore, the concept that cAMP is a biologic regulator for tissue proliferation and regression may be applied to the present model of autotransplanted, DMBA-induced rat mammary tumors.
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PMID:Levels of cyclic nucleotides in autotransplanted 7, 12-dimethylbenz[a]anthracene-induced rat mammary tumors during their growth and regression. 625 5

The in vivo relationship was studied between these biochemical parameters which previous studies have separately implicated in the regression of hormone-dependent rat mammary tumors. Upon depletion of estrogen and suppression of prolactin levels by ovariectomy, there was a marked increase in the production of prostaglandin E2 (PGE2)(fourfold) and in the cyclic AMP (cAMP) content (twofold) in the regressing 7,12-dimethylbenz[a]anthracene-induced primary tumors. These two parameters appeared to be coupled since, in addition to this correlation, PGE2 stimulated adenylate cyclase and raised cAMP levels in both this primary tumor system and in another hormone-dependent transplantable rat mammary tumor (MTW9-A). Furthermore both the sensitivity of the adenylate cyclase system to PGE2 and the number of membrane binding sites for PGE2 increased upon induction of regression in these tumors. Under conditions where PGE2 and cAMP were elevated, (i.e., in regressing, but not growing, hormone-dependent mammary tumors), there was significant phosphorylation in the intact tissue of a 75,000-dalton nuclear protein, which appeared to be identical to the regression-associated protein shown by Cho-Chung and co-workers to undergo increased phosphorylation in response to elevated cAMP levels.
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PMID:Concurrent changes in growth-related biochemical parameters during regression of hormone-dependent rat mammary tumors. 631 51

Activation of the RET protooncogene tyrosine kinase (tk) by fusion with other genes is a frequent finding in papillary thyroid carcinoma. The tk domain of proto-RET can be fused either with the D10S170 gene generating the RET/PTC1 transforming sequence or with sequences belonging to the gene encoding the regulatory subunit RIA of c-AMP-dependent protein kinase A, thus forming the RET/PTC2 oncogene. We have previously shown that an inversion of chromosome 10, inv(10)(q11.2q21), is responsible for the generation of the RET/PTC1. Here we report that a chromosomal translocation, t(10;17)(q11.2;q23), juxta-poses the tk domain of the RET protooncogene, which resides on chromosome 10, to a 5' portion of the RIA gene on chromosome 17, leading to the formation of the chimeric transforming gene RET/PTC2. The finding of the transforming protein in primary tumor cell extracts supports the conclusion that RET/PTC2 activation plays a role in papillary thyroid tumorigenesis.
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PMID:A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. 751 46

Tissue specimens from the primary tumor and metastasis (histological examination: cystadenocarcinoma) of two postmenopausal women were cut into pieces and were incubated or superfused for 3- to 4-hr periods. The incubation and superfusion procedures were performed in the absence and presence of human chorionic gonadotropin (hCG, 10 IU/ml). After incubation, the medium concentrations of progesterone (P), testosterone (T), androstendione, and 17beta-estradiol (E2) were determined by radioimmunoassay, while after superfusion the medium concentrations of cyclic AMP (cAMP), P, T, and E2 were analyzed. HCG stimulated the production of cAMP in the superfused tissue of the first case and in the second case the addition of hCG to the incubation medium caused a significant drop in testosterone release by the primary tumor and in androstendione release by the metastasis. These results suggest that tissues from primary tumor and metastasis were capable of releasing steroids into the media, supporting the contention that tissue from epithelial ovarian cancers can produce and/or release steroids in its own right.
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PMID:Steroid release from two human epithelial ovarian tumors: evidence for an intrinsic production in vitro. 899 55

Chimeric proteins resulting from characteristic chromosomal translocations are believed to play a key role in the development of neoplasia. The consistent chromosomal translocation t(12;22) found in Clear Cell sarcoma (CCS) fuses the genes for Ewing's sarcoma protein (EWS) and activating transcription factor 1 (ATF1). Contribution of the chimeric EWS/ATF1 protein to maintenance of the tumor phenotype was investigated using intracellular expression of an inhibitory anti-ATF1 single chain antibody fragment (scFv4). Transfection of scFv4 into a cell line (SU-CCS-1) derived from CCS resulted in a 90% reduction in cyclic AMP response element-driven reporter activity. The delivery of scFv4 into SU-CCS-1 cells by a Moloney sarcoma retroviral vector (SRalpha-Fv4) significantly reduced viability and induced apoptosis as measured by terminal deoxynucleotidetransferase-mediated dUTP-biotin nick end labeling and flow cytometry. Conversely, scFv4 had no effect on viability of HeLa cells. The level of EWS/ATF1 expression was found to be significantly higher in primary tumor tissue than in SU-CCS-1 cells or in 293T cells following introduction of an EWS/ATF1 expression vector. These studies demonstrate a direct role for the EWS/ATF1 fusion protein in maintaining tumor cell viability of Clear Cell sarcoma and indicate that intracellular antibodies may be used to achieve a phenotypic knockout of tumor-related proteins as a method to explore their function.
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PMID:Tumor cell viability in clear cell sarcoma requires DNA binding activity of the EWS/ATF1 fusion protein. 1057 52

Clear cell sarcoma of soft tissue (CCSST), also known as malignant melanoma of soft parts, represents a rare lesion of the musculoskeletal system usually affecting adolescents and young adults. CCSST is typified by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion between the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1), of which the activity in nontransformed cells is regulated by cyclic AMP. Our aim was to identify critical differentially expressed genes in CCSST tumor cells in comparison with other solid tumors affecting children and young adults to better understand signaling pathways regulating specific features of the development and progression of this tumor entity. We applied Affymetrix Human Genome U95Av2 oligonucleotide microarrays representing approximately 12,000 genes to generate the expression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing tumor, and 6 osteosarcoma cell lines. Subsequent hierarchical clustering of microarray data clearly separated all four of the tumor types from each other and identified differentially expressed transcripts, which are characteristically up-regulated in CCSST. Statistical analysis revealed a group of 331 probe sets, representing approximately 300 significant (P < 0.001) differentially regulated genes, which clearly discriminated between the CCSST and other tumor samples. Besides genes that were already known to be highly expressed in CCSST, like S100A11 (S100 protein) or MITF (microphthalmia-associated transcription factor), this group shows an obvious portion of genes that are involved in cyclic AMP response or regulation, in pigmentation processes, or in neuronal structure and signaling. Comparison with other expression profile analyses on neuroectodermal childhood tumors confirms the high robustness of this strategy to characterize tumor entities based on their gene expression. We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST. Quantitative real-time PCR and Northern blot analysis verified the mRNA abundance and confirmed the absence of the inhibitory transcript variant of this gene. The protein product of the member of the epidermal growth factor receptor family ERBB3 could be shown to be highly present in all of the CCSST cell lines investigated, as well as in 18 of 20 primary tumor biopsies. In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker.
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PMID:Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. 1515 91

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) display unique characteristics that discriminate cHL from other B-cell lymphomas and normal B cells. Therefore, comparative gene expression profiling of Hodgkin and non-Hodgkin B cells could lead to the identification of candidate genes that are critical for the pathogenesis of cHL. We performed microarray analysis of Hodgkin and non-Hodgkin cell lines and identified activating transcription factor 3 (ATF3), a member of the cyclic AMP response element binding protein (CREB)/ATF family, as a differentially expressed candidate gene. Extensive analysis of a large panel of cell lines, primary tumor samples, and normal tissues revealed that high expression of ATF3 is found in nearly all cases of cHL and is almost exclusively restricted to it. Selective knock-down of ATF3 by RNA interference suppressed proliferation and strongly reduced viability of Hodgkin cells. Thus, overexpression of ATF3 is a molecular hallmark of cHL that contributes to the malignant growth of HRS cells.
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PMID:Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells. 1626 88

To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary human tissues. From this approach, we have found that maternal embryonic leucine zipper kinase (Melk), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. In situ hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the ApcMin and Apc1638N murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference-mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth in vitro as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.
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PMID:Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. 1626 96

Methylthioadenosine phosphorylase (MTAP) is an important enzyme in the salvage pathway of adenosine and methionine synthesis. MTAP is ubiquitously present in all normal cells and tissues, but deficient in a variety of malignant tumors. The enzyme deficiency is caused by either MTAP gene deletion or promoter hypermethylation. We investigated MTAP expression, MTAP gene deletion and promoter abnormality in 40 primary tumor samples from Japanese osteosarcoma patients and determined the frequency of the enzyme deficiency. We also tested whether or not the enzyme deficiency can be exploited for tumor-specific chemotherapy using osteosarcoma cell lines. For MTAP expression, immunohistochemistry (IHC) and Western blotting were used. Real-time quantitative PCR assay was used for the analysis of MTAP gene deletion in fifteen osteosarcoma samples. MTAP promoter abnormality was analyzed by methylation-specific PCR. Then, the relationship between MTAP expression and sensitivity to the inhibitors of de novo AMP synthesis was confirmed in an MTAP-negative and -positive osteosarcoma cell line. The MTAP protein was negative in 11 of 40 samples (27.5%) by IHC and in 4 of 6 osteosarcoma cell lines (66.7%) by Western blot analysis. Among 40 samples, 15 were subjected to quantitative real-time PCR and promoter methylation analysis. Of 6 samples that were negative by IHC, the MTAP gene was deleted in 3 and the MTAP promoter was methylated in 2. These results indicated that MTAP deficiency was caused by MTAP gene deletion or promoter methylation in all MTAP-negative samples except one that was negative with IHC although no deletion or promoter methylation was detected. In in vitro experiments using transfectoma along with the MTAP-negative parental cell line, the MTAP-negative parental cell line was more chemosensitive to the inhibitors of de novo AMP synthesis than MTAP-positive transfectoma. MTAP deficiency frequently found in osteosarcoma can be exploited for selective chemotherapy in MTAP-negative osteosarcoma patients with the inhibitors of de novo purine synthesis.
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PMID:Methylthioadenosine phosphorylase deficiency in Japanese osteosarcoma patients. 1791 32


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