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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the Ki-ras oncogene by specific point mutations at codon 12 occurs at a remarkably high frequency in pancreatic ductal adenocarcinoma and is likely to be an important event in the pathogenesis of this cancer. To determine whether ras activation also occurs in noninvasive proliferative lesions of the pancreas, a series of cases of ductal papillary hyperplasia, intraductal papillary neoplasia, and intraduct extensions of ductal adenocarcinoma were examined for activating mutations of Ki-ras at codons 12, 13, and 61 using polymerase chain reaction amplification. Specific mutations at Ki-ras codon 12 were found in 5 of 6 cases (83%) of intraduct extensions of carcinomas and in 12 of 16 (75%) invasive carcinomas. In cases with both intraductal and invasive components, the same mutation was identified in each. No mutations were found in 5 intraductal papillary neoplasms and 9 cases of ductal papillary hyperplasia. The authors conclude that Ki-ras activation at codon 12 is important in the tumorigenesis of ductal adenocarcinoma of the pancreas but is not required in the pathogenesis of ductal papillary hyperplasia or intraductal papillary neoplasm.
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PMID:Ki-ras oncogene activation in preinvasive pancreatic cancer. 130 58

Three types of transformants derived from rat embryonal fibroblasts (REFs) corresponding to the different progressional stages were obtained: TF1 (human papillomavirus type 16 E7 (HPV16 E7) transfection alone) and TF2 (E7 plus adenovirus type 12(Ad12) E1b were immortalized, TF3 (E7 plus adenovirus type 5 (Ad5) E1B) was anchorage-independent but not tumorigenic, and TF4 (E7 plus EJ-ras) was tumorigenic. Cytogenetic investigations revealed that the cells carrying specific chromosomal abnormalities expanded clonally in three of the five TF4 tumorigenic clones, in contrast to the TF1-TF3 non-tumorigenic clones, which showed a normal karyotype. By the inoculation of TF4 into syngeneic rats, 8 tumor-derived clones were obtained. Clonal expansion of cells carrying specific chromosome changes was also remarkable in these tumor-derived clones. However, the type of rearrangements and the chromosomes involved in the abnormalities were not identical. In addition, it was shown that chromosome constitutions of the parental TF4 transformants were apparently inconsistent with those of their tumor-derived clones. However, the clonal nature of abnormalities observed in the parental and the tumor-derived clones suggested that these genetic events of cellular genomes corresponded with and possibly contributed to the progression of malignant phenotypes of cells.
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PMID:Chromosome alterations contribute to neoplastic progression of transformed rat embryonal fibroblasts. 130 85

Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1.
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PMID:Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals. 130 92

The biological effects of expression of mutant ras at different stages of human uroepithelial cell (HUC) tumorigenesis were tested after transfection of EJ/ras into nonestablished HUC and three isogeneic cell lines representing different steps in HUC transformation in vitro. Transfection with EJ/ras failed to immortalize diploid HUC and also failed to cause tumorigenic conversion of a near-diploid SV40-immortalized HUC line (SV-HUC) except at one of six nude mouse inoculation sites. In contrast, EJ/ras-transfected aneuploid low-grade squamous cell carcinoma cells formed undifferentiated, invasive carcinomas at four of six inoculation sites. Furthermore, EJ/ras accelerated tumor growth in MC-ppT11-HA2, an aneuploid high-grade transitional cell carcinoma line, as determined by decreased tumor latent periods and doubling times. These results suggest that EJ/ras contributes to progression, possibly by accelerating tumor growth, but does not in itself cause tumorigenic transformation of uroepithelial cells. To test whether chromosome losses accompanied EJ/ras transformation of SV-HUC, the karyotype of the one SV-HUC tumorigenic transformant obtained (above) was examined. This tumor cell line showed losses of chromosome arms 3p, 10p, 11p, and 18, all of which have been hypothesized to contain genes that suppress cancer development. Therefore, these results also provide new evidence suggesting that genetic losses may be required for mutant ras to contribute to HUC tumorigenic progression.
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PMID:Neoplastic progression by EJ/ras at different steps of transformation in vitro of human uroepithelial cells. 131 69

The cellular basis for pituitary neoplasia is poorly understood. Mutations that activate the ras protooncogenes have been identified in a number of different types of human cancers and potentially represent one of the genetic alterations that occur in pituitary tumors. In this study we examined 19 pituitary tumors for the occurrence of ras mutations. The tumor types included 11 nonfunctioning adenomas, 6 somatotroph adenomas, and 2 prolactinomas. Each of the three ras genes (K-ras, N-ras, and H-ras) was amplified from pituitary tumor DNA using the polymerase chain reaction. Oligonucleotide-specific hybridization was used to screen for mutations that inhibit GTPase activity and cause activation of the ras oncogene. No ras mutations were observed in 18 of the pituitary adenomas. However, a mutation was identified in codon 12 of the H-ras gene (Gly to Val) in a recurrent prolactinoma that was highly invasive and ultimately proved to be fatal. We conclude that ras mutations are uncommon in pituitary adenomas, but may provide a marker for highly invasive tumors.
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PMID:Ras mutations in human pituitary tumors. 131 42

The E7 gene of human papillomavirus type 16 encodes a multifunctional nuclear phosphoprotein that is functionally and structurally similar to the adenovirus (Ad) E1A proteins and the T antigens of other papovaviruses. E7 can cooperate with an activated ras oncogene to transform primary rodent cells, trans activate the Ad E2 promoter, and abrogate transforming growth factor beta-mediated repression of c-myc. Recent studies suggest that these functions may in part be a consequence of the ability of E7 to associate with the product of the retinoblastoma tumor suppressor gene (pRB). In this study, a series of site-specific mutations of the human papillomavirus type 16 E7 gene product were constructed and assessed for their effects on intracellular protein stability, ras cooperativity, transcriptional trans activation, pRB association, and phosphorylation. The results of these studies indicate that the transforming and trans-activating domains extensively overlap within a region of the protein analogous to conserved region 2 of Ad E1A, suggesting that pRB binding is necessary for both activities. Deletion of sequences in conserved region 1 abrogates cellular transformation but has only a marginal effect on trans activation. These data suggest that E7 trans activation and cellular transformation are interrelated but separable functions.
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PMID:Structure-function analysis of the human papillomavirus type 16 E7 oncoprotein. 131 37

An expression vector was constructed in which TGF-beta 1 was placed under the control of the metallothionein promoter. Cys223 and Cys225 in the TGF-beta 1 propeptide were converted to serines, mutations which result in dissociation of the pro-peptide and secretion of bioactive TGF-beta 1 [Brunner, A.M., Marquardt, H., Malacko, A.R., Lioubin, M.N. and Purchio, A.F. (1989) J. Biol. Chem., 264, 13660-13664]. A fibrosarcoma was transfected with this plasmid and a clone (17.18) was selected in which TGF-beta 1 mRNA was able to be induced six-fold following zinc sulphate treatment. These cells increased the secretion of bioactive TGF-beta 1 14-fold and exhibited a coincidental increase in jun-B mRNA expression, suggesting that secreted TGF-beta 1 was acting to induce this early response gene by autocrine activation. Following zinc sulphate induction, the tumor cells became progressively more motile and able to invade collagen gels. In contrast to parental tumor not bearing the TGF-beta 1 expression vector, zinc sulphate stimulation of clone 17.18 enhanced collagenase IV and procathepsin L mRNA levels and enhanced the secretion of many collagenolytic proteases into the medium. Since the action of TGF-beta generally decreases proteolysis by suppression of protease transcription, we compared the response of normal parental fibroblasts to ras-transformed fibrosarcomas and confirmed that TGF-beta could greatly enhance collagenase IV and procathepsin L mRNA levels while having little effect on non-transformed fibroblasts. These experiments indicate that induction of TGF-beta secretion can enhance motility and protease production through autocrine activation, thus increasing the invasion potential of fibrosarcomas.
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PMID:Autocrine induction of tumor protease production and invasion by a metallothionein-regulated TGF-beta 1 (Ser223, 225). 131 70

The development of colon carcinomas is associated with allelic deletions on chromosomes 5q, 17p, and 18q. The DCC gene located on chromosome 18q21.3 codes for a potential tumor suppressor gene related to cellular adhesion receptors. We investigated the expression of this gene in several pancreatic carcinoma cell lines and in patients with ductal adenocarcinomas of the pancreas. In 8 of 11 cell lines and in 4 of 8 primary tumors a complete extinction of DCC gene expression was observed, whereas the c-Ki-ras gene was mutated at codon 12 in 7 of 8 tumors. A highly reduced or absent expression of DCC was found in all low or undifferentiated pancreatic tumor cell lines, whereas in the more differentiated ones DCC expression was conserved. These data suggest that loss of DCC gene expression is an important factor in the development or progress of pancreatic adenocarcinoma and may be linked to the differentiated phenotype of the pancreatic tumor cell.
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PMID:Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. 131

Tumorigenic transformation of SV40-immortalized human uroepithelial cells (SV-HUC) after transfection with EJ/ras was previously reported to be a rare event. To test the hypothesis that ras transformation requires loss of suppressor genes, somatic cell hybrids were generated between a rare tumorigenic transformant and an isogeneic nontumorigenic EJ/ras transfectant obtained in the same experiment. Both parental cell lines, as well as all hybrid progeny, expressed mutant p21 ras protein, but injections of three such independent hybrids into athymic nude mice at passage (P) 4 demonstrated that tumorigenicity was suppressed at 20 of 22 sites. Two tumors developed, after a relatively long 17-week latent period, as compared with a 4-week latent period for the tumorigenic parent. All three hybrids produced tumors at P8, but these showed different latent periods (3-14 weeks). Revertant hybrid tumors were high-grade carcinomas. Cell lines derived from these tumors expressed mutant p21 ras and retained at least 1 EJ/ras integration site. Karyotypic analysis of six independent hybrid tumor revertants showed that each had a unique clonal karyotype. Losses of two or more homologues of 1p, 3p, 4, 8, 10p, 11p, 13q, and 18 were identified in one or more tumorigenic revertants. Losses of all these chromosomes were previously associated with transformation of SV-HUC by EJ/ras, but were also associated with chemical transformation of SV-HUC in tumors that did not express mutant ras. Genetic losses involving most of these chromosomes have also been identified in clinical bladder cancers (i.e., 1p, 3p, 8, 11p, 13 and 18q). These data show that expression of EJ/ras does not negate or significantly alter requirements for multiple genetic losses in HUC tumorigenesis.
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PMID:Chromosome losses in tumorigenic revertants of EJ/ras-expressing somatic cell hybrids. 131 24

8-Bromo-cAMP and substances elevating cAMP levels within cells, such as forskolin, cholera toxin, and Bordetella pertussis-invasive adenylate cyclase (BPAC), suppress the growth of cultured granulosa cells cotransfected by simian virus-40 (SV40) DNA and Ha-ras oncogene concomitantly with the induction of steroidogenesis and without affecting oncogene expression. We, therefore, tested the hypothesis that cAMP can modulate tumorigenesis and metastatic spread of these cells in vivo. The cotransfected cells induced rapid development of tumors when injected sc in nude mice. Tumor development was faster in less differentiated cotransfected cells originating from preantral ovarian follicles than in those obtained from highly differentiated transformed cells originating from preovulatory follicles. Cells transfected by SV40 DNA alone produced only slow-growing small tumors. Metastatic lesions of cotransfected cells were most abundant in lung and less frequent in ovaries, kidney, and spleen. No metastatic lesions were found in the liver. However, metastatic spread was dramatically suppressed when cotransfected cells injected into nude mice were pretreated with the invasive BPAC. In contrast, no suppression of metastases was observed when the cells were pretreated with 8-bromo-cAMP, forskolin, or cholera toxin. Removal of forskolin in cultured cotransfected cells yielded a rapid decrease in cAMP levels. In contrast, high levels of cAMP persist in cell cultures even several hours after 1-h pretreatment and subsequent removal of BPAC from the medium of culture cotransfected cells. It is suggested that the inhibitory effect of BPAC on the metastatic spread of these cells is due to prolonged elevation of cAMP in vivo. The newly established granulosa cell lines transformed by SV40 and the Ha-ras oncogene can serve as a model for further studies of cAMP modulation of carcinogenesis in ovarian malignancies.
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PMID:Adenosine 3',5'-monophosphate suppresses metastatic spread in nude mice of steroidogenic rat granulosa cells transformed by simian virus-40 and Ha-ras oncogene. 131 28


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