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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the possibility of collaboration between telomeric deletion on the short arm of chromosome 1 and genetic amplification similar to that described in human neuroblastoma, 122 human primary breast tumors were examined by restriction fragment length polymorphism analysis for loss of heterozygosity on 1p32-pter and for the three most frequently amplified genetic regions in breast carcinomas (MYC and ERBB2 protooncogenes and the chromosomal region 11q13). Allelic losses at one or more loci on the telomeric part of the short arm of chromosome 1 was observed in 57 (47%) of 122 informative tumors. MYC, ERBB2, and the 11q13 region were amplified in 23, 20, and 21% of breast tumors, respectively. A correlation was found between loss of heterozygosity on chromosome 1p32-pter and amplification of the MYC (formerly c-myc) protooncogene (P = 0.003), suggesting that these two genetic events may collaborate during tumor progression in human breast cancer. These results, together with those obtained in human neuroblastoma, suggest that the distal part of the short arm of chromosome 1 harbors an unidentified tumor suppressor gene(s), whose inactivation may be involved in MYC family gene amplification (an example of genetic instability) in tumors of various cellular origins.
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PMID:A tumor suppressor gene on chromosome 1p32-pter controls the amplification of MYC family genes in breast cancer. 791 73

To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes. The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.
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PMID:Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. 805 51

Activation of the c-myc protooncogene, resulting in deregulated, over-expression of the c-Myc protein, can induce both cell proliferation and programmed cell death (apoptosis) in nontransformed cells. Yet, c-myc activation is commonly tolerated in many tumors. This apparent paradox can be resolved if activation of c-myc in transformed cells is associated with loss of Myc-induced apoptosis. To examine this hypothesis, we characterized both the mechanisms of c-myc activation and programmed cell death in the tumorigenic L929 cell line. We showed that activation of c-myc in the L929 cell line involves several distinct mechanisms, including dysfunction of the Myc autosuppression pathway and alteration of c-Myc protein expression. In addition, we demonstrated that L929 cells do not undergo Myc-induced apoptosis. Analysis of somatic cell hybrids revealed that this abrogation of programmed cell death can be partially restored and is likely due to one or more genetic lesions. Our results support the hypothesis that the dysfunction of the Myc-induced apoptosis mechanism can accompany c-myc activation and provide an in vivo example illustrating two cooperative events which can contribute to tumor progression.
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PMID:Dysfunction of the Myc-induced apoptosis mechanism accompanies c-myc activation in the tumorigenic L929 cell line. 808 39

Transitions between the small cell lung cancer and the non-small cell lung cancer phenotype occur during clinical tumor progression in small cell lung cancer. We have previously developed a culture model which mimics these transitions. In our model, the insertion of the v-Ha-ras oncogene into c-myc overexpressing NCI-H82 small cell lung cancer cells induces features characteristic of non-small cell lung cancer. We now report that treatment of NCI-H82 cells with 1 microM all-trans-retinoic acid resulted in decreased cellular growth, decreased c-myc mRNA levels, and increased L-myc mRNA levels. Retinoic acid treatment prior to v-Ha-ras insertion also inhibited the typical ras-induced phenotypic transition seen in untreated NCI-H82 cells. In contrast, retinoic acid treatment of NCI-H82 ras cells after ras-induced transition to the non-small cell lung cancer phenotype did not affect cellular phenotype, nor c-myc or L-myc gene expression. These data show that all-trans-retinoic acid, a clinically relevant compound, inhibits small cell lung cancer progression in our in vitro model and alters the expression of the c-myc and L-myc oncogenes. These findings suggest mechanisms for the biological effects of retinoic acid in small cell lung cancer.
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PMID:All-trans-retinoic acid alters myc gene expression and inhibits in vitro progression in small cell lung cancer. 812 93

Proliferation and proto-oncogene expression in 19 meningiomas of typical and atypical histology were analyzed in an attempt to understand the mechanism of growth that characterizes the neoplastic process in these tumors. Proliferation was estimated as the proliferative index by the enumeration of S-phase cells in imprints of tumor tissue exposed to bromodeoxyuridine in vitro, and the gene expression of c-myc, c-fos, c-src, c-H-ras, N-myc, acidic and basic fibroblast growth factor, insulin-like growth factors I and II, platelet-derived growth factor-alpha, and epidermal growth factor was quantified by messenger ribonucleic acid dot-blot hybridization assay. Atypical and malignant tumors had significantly higher proliferative indexes than did their nonmalignant counterparts. Levels of c-myc and c-fos messenger ribonucleic acid were elevated more than fivefold in 72 and 78% of the tumors, respectively, relative to the lowest levels detected in the series. Levels of growth factor messenger ribonucleic acid were sporadically elevated; 37 to 44% of tumors had more than fivefold enhanced levels of acidic and basic fibroblast growth factor. Positive correlations between proliferation and proto-oncogene/growth factor expression were found for c-myc in atypical/malignant tumors and for epidermal growth factor in fibroblastic meningiomas. Deregulated expression of c-myc and c-fos common to both typical and atypical tumors suggests that these are early events in the meningioma tumor process that may disturb the control of cell differentiation and together with fibroblast growth factors are likely to endow the transformed cell with a selective growth advantage by reducing the requirement for exogenous mitogens and by providing a niche for the growth of the tumor clone. Positive correlation of c-myc levels with proliferation in atypical/malignant meningiomas implies that this is a feature of malignancy and indicates continued disruption of the negative regulation of proto-oncogene expression, perhaps by tumor suppressor gene losses, during the course of tumor progression.
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PMID:Correlation of proto-oncogene expression and proliferation and meningiomas. 813 92

Tumor progression is a complex process involving many alternative molecular pathways that are often tissue and/or species specific. The c-myc oncogene has been implicated in malignant progression in a variety of human tumors. In many instances, amplification and/or elevated expression of the c-myc gene have been associated with poor prognosis or decreased survival; in other cases, correlations have been demonstrated between c-myc activation and specific parameters of advanced neoplastic stage such as hormone independence, transplantability, invasiveness, etc. The tumor types exhibiting c-myc as a "progressor" gene include breast, colon, small cell lung carcinoma, as well as ovarian cancer, lymphomas, and squamous cell carcinomas. The c-myc oncogene has been implicated in a number of experimental animal tumor models, especially rat liver. Several studies have found that c-myc often functions in rodent tumor progression. For example, rat skin carcinomas induced by ionizing radiation show c-myc amplification to be related directly to tumor size and age.
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PMID:The c-myc oncogene in tumor progression. 835 42

To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.
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PMID:Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. 841 34

Proto-oncogenes are the genes which are most frequently found amplified in human tumor cells. Acquisition of a drug-resistant phenotype by gene amplification is frequent for in-vitro cultured cells but is very rare in human tumors. Proto-oncogenes amplified in human tumors belong essentially to one of three families (erbB, ras, myc) or to the 11q13 locus. Amplification is always specific for the tumor cells and is not found in constitutional DNA of the patient, indicating that amplification of the gene is selected for during tumor growth. For genes of the first three families, amplification results in overexpression in most of the cases. These are strong arguments in favor of a role of this amplification in tumor progression. The gene whose overexpression is the driving force for the selection of the amplification of the 11q13 locus is not known. The prad1 gene is presently a good candidate. Amplification of one type of proto-oncogene is generally not restricted to one tumor type. However, the N-myc gene is amplified mainly in tumors of neuronal or neuroendocrine origin and L-myc amplification is restricted to lung carcinomas. To understand the role of proto-oncogene amplification and overexpression in tumor progression it is necessary to know the function of the corresponding protein in the cell. erbB proteins are transmembrane receptors for growth factors. ras genes encode small GTP-binding proteins which are possibly involved in signal transduction. The myc proteins are transcription factors. The expression of the c-myc gene is induced a few hours after cells of various types have been induced to proliferate. The genes of these three families therefore encode proteins which appear to be involved in signal transduction. It is possible that overexpression of one of them, as a result of gene amplification, makes the cell a better responder to low levels of growth stimuli. For several genes which are found amplified in human tumors, it was shown that overexpression of the normal protein could confer a transformed or tumorigenic phenotype to in-vitro cultured cells. In addition, several studies on animal and human tumor-derived cell lines with an amplified proto-oncogene have established a relationship between proto-oncogene amplification and the tumorigenic phenotype. In neuroblastomas, it was proposed that down-modulation of MHC Class I antigens is a consequence of N-myc amplification and that this could be important in the progression toward a metastatic phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Gene amplification and tumor progression. 850 29

Cyclophosphamide is one of the most active agents in the treatment of medulloblastoma. However, development of resistance to this alkylator frequently occurs and is the harbinger of tumor progression and death. In order to understand the biochemical basis of this resistance, we generated a panel of medulloblastoma cell lines in our laboratory that were resistant to 4-hydroperoxycyclophosphamide (4-HC). Previously, we have shown that elevated levels of aldehyde dehydrogenase and glutathione mediate cellular resistance to 4-HC. The present study was conducted to identify the third unknown mechanism mediating the resistance of cell line D283 Med (4-HCR) to 4-HC, testing the hypothesis that this resistance is mediated by an increased repair of DNA interstrand crosslinks (ICLs). The doses of 4-HC that produced a one- and two-log cell kill of D283 Med cells were 25 and 50 microM, respectively, compared with values of 125 and 165 microM in D283 Med (4-HCR), the resistant cell line. The formation and disappearance of 4-HC-induced DNA ICLs at the c-myc gene were subsequently studied by DNA denaturing/renaturing gel electrophoresis and Southern blot analysis. 4-HC-induced DNA ICLs in the c-myc gene exhibited a dose-dependent relationship. The percentage of the c-myc gene that was crosslinked was approximately 1-3% at a dose of 100 microM. More than 50% of the DNA crosslinking in D283 Med (4-HCR) cells was removed by 6 h after drug treatment, whereas, in D283 Med cells, more than 90% of the DNA crosslinking was still present at 6 h. These findings suggest that the increased repair of DNA ICLs in D283 Med (4-HCR) may contribute significantly to its resistance to 4-HC.
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PMID:Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand crosslinking in the c-myc gene in 4-hydroperoxycyclophosphamide-sensitive and -resistant medulloblastoma cell lines. 852 84

c-Myc and Mad each form heterodimers with Max that bind the same E-box related DNA sequences. Whereas Myc:Max complexes activate transcription and promote cell proliferation and transformation, Mad:Max complexes repress transcription and block c-Myc-mediated cell transformation. Here we examine these antagonistic transcription factors during epithelial differentiation and neoplastic progression. During differentiation of primary human keratinocytes, Mad is rapidly induced and c-Myc is downregulated, resulting in a switch from c-Myc:Max to Mad:Max heterodimers. In normal epidermis and colonic mucosa c-myc expression is restricted to proliferating cell layers, while mad expression is restricted to differentiating cell layers. Using HPV18 transformed keratinocytes that vary in their ability to differentiate in organotypic cultures, we find that Mad induction occurs only in those cells that retain a differentiation response. In the epidermis of transgenic mice in which expression of the HPV16 E6 and E7 oncogenes are targeted to basal keratinocytes, neoplastic progression occurs and is marked by an expansion of c-myc expressing basal-like cells. Expression of mad is found only in growth-arrested differentiating cells on the outer edges of preneoplastic lesions. The squamous cell carcinomas that arise evidence a variable number of sites within the tumor masses where mad expression and morphological differentiation coincide; increasing malignancy correlates with loss of both mad and capability to differentiate. These results indicate that c-Myc and Mad expression are tightly coupled to the transition from proliferation to differentiation of epithelial cells and that restriction of Mad expression may be associated with loss of normal differentiation capability and with tumorigenesis.
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PMID:Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis. 854 5


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