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

Increasing numbers of alterations have been found in protooncogenes (e.g., ras, myc), as well as tumor suppressor genes (e.g., p53, Rb) in various types of tumors. The multiple mutations cannot be explained by the spontaneous mutation rate. It has been suggested that mutator phenotypes leading to the accumulation of these mutations may be required in the early stages of tumorigenesis. To test this hypothesis, the entire coding region of DNA polymerase beta, a repair enzyme, mRNA from colorectal tumors, and corresponding normal mucosa were amplified by polymerase chain reaction, cloned, and sequenced. Mutations in the catalytic domain of DNA polymerase beta were detected in colorectal tumor specimens compared to the normal colorectal mucosa, placenta, and blood samples. Since these mutations changed the structure of polymerase beta, it is expected that the efficiency of the DNA repair system would be impaired and thus may account for the high mutation rate observed in colorectal carcinomas.
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PMID:DNA polymerase beta mutations in human colorectal cancer. 151 47

Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate, ultimately producing the neoplastic phenotype. A model was proposed to explain the genetic basis of colorectal neoplasia that included several salient features. First, colorectal tumors appear to occur as a result of the mutational activation of oncogenes coupled with the inactivation of tumor-suppressor genes. Second, mutations in at least four or five genes are required to produce a malignant tumor. Third, although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their chronologic order of appearance, is responsible for determining the tumor's biologic properties. Several different genetic alterations were identified that occur during colorectal tumorigenesis. Activational mutation of the ras oncogene was found in approximately 50% of colonic carcinomas and in a similar percentage of intermediate-stage and late-stage adenomas. Allelic deletions were discovered of specific portions of chromosomes 5, 17, and 18, which presumably harbor tumor-suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is mutated, not only in colonic cancer, but also in a large percentage of other human solid tumors. The gene dcc recently was identified; this candidate tumor-suppressor gene on chromosome 18 appears to be altered in colorectal carcinomas. The protein encoded by the dcc gene has significant sequence similarity to neural cell adhesion molecules and other related cell-surface glycoproteins. By mediating cell-cell and cell-substrate interactions, this class of molecules may have important functions in mediating cell growth and differentiation. Alterations of the dcc gene may interfere with maintenance of these controls and thus may play a role in the pathogenesis of colorectal neoplasia. Another candidate tumor-suppressor gene also was identified on chromosome 5, mcc (for mutated in colorectal cancers). The mcc genetic alterations include one tumor with somatic rearrangement of one mcc allele and several tumors with somatically acquired point mutations in the coding region. Studies currently are ongoing to (1) identify additional tumor-suppressor gene candidates, (2) increase our understanding of normal tumor-suppressor gene function, and (3) demonstrate the functional tumor-suppressor ability of these genes both in vivo and in vitro.
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PMID:Genetic alterations in the adenoma--carcinoma sequence. 151 27

During the past few decades medical science has accepted the concept that cancer is a fundamental disorder of cellular growth control. A disorder can originate in some cells through changes in genes (DNA level: gene amplification, mutation and rearrangement) or their expression (RNA and protein levels), and stimulates growth in contrast to surrounding cells. Over the last decade genes affected in the cancer cell have been identified as well as the nature of changes undergone. Only a few of the known oncogenes play a role in head and neck cancer. These are epidermal growth factor receptor, c-myc, the ras gene family, int-2, hst-1 and bcl-1. In some clinical disorders, such as childhood neuroblastoma and breast cancer, oncogenes have been shown to play an important role in tumor staging or as a prognostic parameter. The aim for future therapy is the effective application of oncogenes (or "gene therapy") in clinical practice.
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PMID:[Oncogenes and their significance for head and neck cancers]. 151 16

We established an androgen-sensitive cell line (BR31-5) from a ras + myc-induced mouse prostate carcinoma and used this cell line together with a previously reported transplantable androgen-independent mouse prostate carcinoma to investigate patterns of expression for apoptosis-related genes in an androgen-deprived environment. Single cell suspensions derived from the BR31-5 cell line were inoculated into the flank of intact or castrated adult male C57BL/6 mice and tumors were harvested 12 days post-inoculation for Northern blotting. A transplantable androgen-independent prostate cancer was also inoculated into intact or castrated mice and tumors harvested 21 days later. Tumor volume analyses showed that BR31-5 carcinomas were androgen-sensitive. Northern blotting showed that mRNA levels for two apoptosis-related genes, transforming growth factor-beta 1 and c-myc, were significantly elevated to a similar extent in carcinomas grown in castrated hosts compared to intact hosts for both the androgen-sensitive BR31-5 and androgen-independent carcinomas. Levels of mRNA for tissue type plasminogen activator, shown previously to be elevated in androgen-independent carcinomas following growth in castrates, were also increased in BR31-5 carcinomas under similar androgen-deprived conditions but to a lesser extent. Interestingly, testosterone repressed prostate mRNA No. 2 levels shown previously to be similar in both the intact and castrated groups for androgen-independent carcinomas were significantly increased in the castrated group compared to the intact group for BR31-5 carcinomas. Therefore, specific patterns of expression for apoptosis-related genes may be able to discriminate androgen-sensitive and androgen-independent prostate cancer under androgen-deprived conditions.
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PMID:Androgen sensitivity and gene expression in ras + myc-induced mouse prostate carcinomas. 152 69

Several genetic alterations that perturb normal cellular growth control mechanisms can cause cancers. These include point mutations, deletions, translocations, amplifications and gene rearrangements and occur primarily in two classes of interacting genes, oncogenes and tumor suppressor genes. While mutation or amplification of certain oncogenes can facilitate cell growth and tumor formation (Bishop, 1983, 1991; Hunter, 1991; Land, et al., 1983), loss or mutation of tumor suppressor genes, which normally inhibit these processes, can promote tumor formation (Knudson, 1985; Cavenee, et al., 1989; Marshall, 1991). Human skin tumors display multiple genetic alterations such as Ha-ras gene mutation and LOH, N-ras gene amplification, and mutations in p53 tumor suppressor gene. In most cases, the mutations in ras and p53 genes are localized to pyrimidine-rich sequences, particularly C-C sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. Since UV radiation in sunlight is an environmental carcinogen it is important to understand the molecular mechanisms by which UV radiation induces human skin cancers. In addition, suitable animals models are available for comparative studies and risk assessment. By comparing the various genetic alterations detected in sunlight-induced human skin tumors with those present in UV-induced murine skin tumors, it may be possible to identify the carcinogen-related events that are involved in the multi-step process of carcinogenesis. Studies addressing these issues should provide further insights into the molecular mechanisms of UV carcinogenesis.
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PMID:Molecular alterations in human skin tumors. 152 30

Following v-Ha-ras transfection of nonmetastatic dimethylbenz(( a ))anthracene-induced rat mammary cancer (RMC1) cells, occasional transfectants were isolated that acquired high metastatic ability. High metastatic ability is not a simple process regulated by v-Ha-ras p21 levels alone in these v-Ha-ras transfectants but involves the development of cytogenetic changes. If such cytogenetic changes involve only gain in gene expression, then all hybrids formed by fusing highly metastatic v-Ha-ras RMC1 transfectants with the parental nonmetastatic RMC1 should be highly metastatic. If loss of a metastatic suppressor gene(s) is also involved, then such hybrids should be nonmetastatic since chromosomes from the nonmetastatic parental cells should supply the suppressor function. To test this possibility, a highly metastatic cloned v-Ha-ras transfectant was fused with the nonmetastatic parental RMC1 cells. Five hybrid clones were isolated that conserved the chromosomes from their parental cells. When these hybrid clones were injected into animals, primary tumors developed with the same tumor-doubling time as that of the highly metastatic parental v-Ha-ras transfectant (i.e., approximately 2 days). High metastatic ability was, however, suppressed in these hybrid clones. All hybrid clones continued to express v-Ha-ras p21. Thus, suppression of metastatic ability in the hybrids can occur even in the presence of an elevated v-Ha-ras p21 level. This suggests that the acquisition of metastatic ability following v-Ha-ras transfection involves loss of metastasis suppressor gene function in rat mammary cancer cells.
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PMID:Genetic factors and suppression of metastatic ability of v-Ha-ras-transfected rat mammary cancer cells. 154 51

A clonal mouse prostate carcinoma was established by the introduction of the ras and myc oncogenes via the recombinant retrovirus Zipras/myc 9 using a mouse prostate reconstitution model system. A single-cell suspension derived from an early passage ras+myc-induced carcinoma was inoculated into the flanks of intact or castrated adult male C57BL/6 mice, and tumors were harvested 3 wk postinoculation for northern and Southern blotting. Tumor volume analysis showed that this carcinoma was not dependent on testicular androgens for growth. Southern blot analysis of virus-cell DNA junction fragments revealed that tumor cell populations recovered from both intact and castrated mice were progeny of the same virus-infected cell. Northern blotting showed that mRNA levels for the four growth-related genes transforming growth factor-beta 1 (TGF-beta 1), transforming growth factor-beta 3 (TGF-beta 3), tissue-type plasminogen activator (tPA), and c-myc were significantly elevated in clonal mouse prostate carcinomas grown in castrated hosts. In contrast, androgen receptor mRNA levels were significantly reduced under the same conditions. The response of TGF-beta 1, tPA, and c-myc mRNA levels in the carcinomas grown in castrated hosts was similar to that shown previously in normal rat ventral prostate. However, unlike normal rat ventral prostate after castration, increased numbers of apoptotic cells were not seen in the castrated group relative to the intact group at the time of analysis, indicating that the altered gene expression was not associated with cell death. In addition, testosterone-repressed prostate mRNA number 2 levels, shown previously to be elevated after castration in normal rat ventral prostate, were not increased in the androgen-deprived clonal mouse prostate carcinomas. Therefore, this early passage clonal ras+myc-induced prostate carcinoma demonstrates unique patterns of expression for a set of growth-related genes in an androgen-deprived environment.
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PMID:Alterations in mRNA levels for growth-related genes after transplantation into castrated hosts in oncogene-induced clonal mouse prostate carcinoma. 154 41

Lipotrope-deficient (methyl-deficient) diets cause fatty livers and increased liver-cell turnover and promote carcinogenesis in rodents. In rats prolonged intake of methyl-deficient diets results in liver tumor development. The mechanisms responsible for the cancer-promoting and carcinogenic properties of this deficiency remain unclear. The results of the experiments described here lend support to the hypothesis that intake of such a diet, by causing depletion of S-adenosylmethionine pools, results in DNA hypomethylation, which in turn leads to changes in expression of genes that may have key roles in regulation of growth. In livers of rats fed a severely methyl-deficient diet (MDD), lowered pools of S-adenosylmethionine and hypomethylated DNA were observed within 1 week. The extent of DNA hypomethylation increased when MDD was fed for longer periods. The decreases in overall levels of DNA methylation were accompanied by simultaneous alterations in gene expression, yielding patterns that closely resembled those reported to occur in livers of animals exposed to cancer-promoting chemicals and in hepatomas. Northern blot analysis of polyadenylated RNAs from livers of rats fed control or deficient diets showed that, after 1 week of MDD intake, there were large increases in levels of mRNAs for the c-myc and c-fos oncogenes, somewhat smaller increases in c-Ha-ras mRNA, and virtually no change in levels of c-Ki-ras mRNA. In contrast, mRNAs for epidermal growth factor receptor decreased significantly. The elevated levels of expression of the c-myc, c-fos, and c-Ha-ras genes were accompanied by selective changes in patterns of methylation within the sequences specifying these genes. Changes in DNA methylation and in gene expression induced in livers of rats fed MDD for 1 month were gradually reversed after restoration of an adequate diet. In hepatomas induced by prolonged dietary methyl deficiency, methylation patterns of c-Ki-ras and c-Ha-ras were abnormal. Although human diets are unlikely to be as severely methyl deficient as those used in these experiments, in some parts of the world intake of diets that are low in methionine and choline and contaminated with mycotoxins, such as aflatoxin, are common. Even in industrialized nations, deficiencies of folic acid and vitamin B12 are not uncommon and are exacerbated by some therapeutic agents and by substance abuse. Thus, it seems possible that interactions of diet and contaminants or drugs, by inducing changes in DNA methylation and aberrant gene expression, may contribute to cancer causation in humans.
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PMID:Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. 154 43

Ribonuclease/angiogenin inhibitor (RAI) is a tight-binding inhibitor of ribonucleolytic and angiogenic activities involved in tumor progression. It is translated from various mRNAs differing in their 5 regions and originating from a single gene locus. Recently, this gene (RNH) has been assigned to 11p15.5, the terminal part of the short arm of chromosome 11. The regional chromosomal localization was confirmed by somatic cell and in situ hybridization and further refined by long-range restriction mapping. The data place RNH within 90 kb of the Harvey-ras protooncogene (HRAS), so far the most telomeric gene on 11p, in a region involved in growth regulation and tumor development.
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PMID:The human ribonuclease/angiogenin inhibitor is encoded by a gene mapped to chromosome 11p15.5, within 90 kb of the HRAS protooncogene. 154 20

Translation initiation factor eIF-4E, which binds to the 5' cap structure of eukaryotic mRNAs, is believed to play an important role in the control of cell growth. Consistent with this, overexpression of eIF-4E in fibroblasts results in their malignant transformation. The activity of eIF-4E is thought to be regulated by phosphorylation on a single serine residue (Ser-53). Treatment of rat pheochromocytoma (PC12) cells with nerve growth factor (NGF) strongly curtails their growth and causes their differentiation into cells that resemble sympathetic neurons. The present study shows that eIF-4E is rapidly phosphorylated in PC12 cells upon NGF treatment, resulting in a significant increase in the steady-state levels of the phosphorylated protein. In contrast, epidermal growth factor, a factor which elicits a weak mitogenic response in PC12 cells, did not significantly enhance eIF-4E phosphorylation. We also show that although the mitogen and tumor promoter, phorbol 12-myristate-13-acetate, is able to induce phosphorylation of eIF-4E in PC12 cells, the NGF-mediated increase is primarily a protein kinase C-independent response. The NGF-induced enhancement of eIF-4E phosphorylation is abrogated in PC12 cells expressing a dominant inhibitory ras mutant (Ser-17 replaced by Asn), indicating that eIF-4E phosphorylation is dependent on a ras signalling pathway. As phosphorylation of eIF-4E effects translation initiation, these results suggest that NGF-mediated and ras-dependent eIF-4E phosphorylation may play a role in switching the pattern of gene expression during the differentiation of PC12 cells.
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PMID:Phosphorylation of translation initiation factor eIF-4E is induced in a ras-dependent manner during nerve growth factor-mediated PC12 cell differentiation. 154 5


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