Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumors derived from a Li-Fraumeni syndrome cancer-susceptible family were examined for expression of the retinoblastoma susceptibility gene (RB). Whereas RB expression was normal in a primary breast carcinoma and its metastases from one member of this family, overexpression of RB was found in an adrenocortical carcinoma from another family member. This was in contrast to normal RB expression in normal tissue of this patient, the adrenocortical adenocarcinoma cell line SW-13, and the fibroblast cell line MRC-5, and low level RB expression in normal adrenal tissue. The overexpression in the adrenocortical carcinoma resulted in increased synthesis of the RB-encoded protein and did not appear to be associated with RB amplification or rearrangement. This result is novel as it is usually the loss of expression or production of an altered RB transcript exhibiting deletions that is associated with carcinogenesis. In light of the recent discovery of p53 point mutations in the affected Li-Fraumeni syndrome family members tested, RB overexpression may constitute a secondary event in Li-Fraumeni syndrome tumorigenesis.
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PMID:Overexpression of the retinoblastoma gene in a familial adrenocortical carcinoma. 175 10

Inactivation of tumor suppressor genes is now believed to play an important role in various progression stages of human cancers. To clarify the possible involvement of tumor suppressor gene inactivation in the acquisition of metastatic potential in lung and colorectal carcinoma cells, we examined various genetic alterations in both primary tumors and metastases obtained from patients with lung and colorectal carcinomas. In lung carcinoma, loss of heterozygosity on chromosomes 3p, 13q, and 17p is a common genetic alteration, and both RB and p53 genes are inactivated as a result of chromosome 13q and 17p losses. In some cases, allelic loss on chromosome 11p and amplification of myc family oncogenes occur during tumor progression. In colorectal carcinoma, p53 and DCC alterations were detected in 100% of metastases, and sequential accumulation of allelic losses on chromosomes 13q, 14q, and 18q in the process of metastasis was observed. These results indicate that a subset of tumor suppressor genes is involved in metastasis of lung and colorectal carcinomas.
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PMID:Tumor suppressor genes involved in metastasis of lung and colorectal carcinomas. 184 53

Overexpression of the nuclear phosphoprotein p53 is one of the most common abnormalities in primary human cancer and appears to be due to point mutation within a highly conserved region of the p53 gene which then encodes for a mutant, more stable protein. In this study different stages of breast cancer progression were examined, from in situ to metastatic disease, to determine at what stage mutational activation occurs and whether it is maintained during tumor progression. Two (13%) of 15 pure intraductal tumors expressed high levels of p53 in all malignant epithelial cells. Sequencing of p53 mRNA from one of these tumors demonstrated a nucleotide substitution altering the amino acid composition of the protein. Six (17%) of 35 specimens which contained both in situ and invasive disease expressed high levels of p53. All malignant epithelial cells in these 6 cases stained positively and in no specimen did one component express different levels of the protein than the other growth phase. Sequence analysis of a tissue with significant amounts of both in situ and invasive disease revealed only a single point mutation, without evidence of wild-type nucleotide at the site of substitution, suggesting that p53 mRNA from each component of the tumor contained the same nucleotide substitution. Eleven (50%) of 22 pairs of primary tumors and their lymph node metastases expressed elevated levels of p53, and in each case, expression levels were identical in the primary and secondary sites. Identical mutations were found in the p53 mRNA from two paired primary and metastatic sites. Therefore, mutation within a highly conserved region of the p53 gene leading to overexpression of the protein product can occur in the earliest recognized phase of breast cancer and this alteration is maintained during progression from intraductal to infiltrating carcinoma. Mutations are also conserved during the process of metastatic spread.
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PMID:Maintenance of p53 alterations throughout breast cancer progression. 185 Jun 60

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.
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PMID:Relation between p53 overexpression and established prognostic factors in breast cancer. 185 36

Using a combination of polymerase chain reaction and single-strand conformation polymorphism techniques we analyzed 34 ovarian cancer samples (30 primary tumors and four matched metastases) for the presence of mutations in exons 5, 6, 7, 8 and 9 of the p53 gene. Mutations in this portion of the gene are known to lead to the loss of the oncosuppressive potential of p53. Thirty-six percent (11/30) of the ovarian carcinomas tested presented a mutated p53 allele. Mutations were clustered in exons 5 and 7 to the exclusion of the other exons screened. Most mutations (10/11) were point mutations, but no preferential pattern of nucleotide substitution could be observed. In three tumors the mutation of one allele was concomitant with the loss of the wild-type counterpart. Another sample presented both alleles independently mutated. These observations are in agreement with the recessive nature of the p53 mutation. However, analysis of tissue sections from two tumors showed that the portion composed of 100% cancer cells could hold both the mutated and the wild-type form. Moreover analysis of serial sections gave evidence of a heterogeneous cellular content in one of these tumors, suggesting that p53 mutations may, in some cases, occur late during ovarian cancer evolution. It is, moreover, noticeable that, in matched sets of primary tumors and metastases, the same mutation was observed in both tumor samples. Therefore, even as a late event, p53 mutation occurs before metastatic spread.
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PMID:p53 mutations in ovarian cancer: a late event? 192 32

Osteosarcoma is the most common malignant bone tumor in children and adolescents. The tumor, which is composed of malignant spindle cells that produce osteoid, typically occurs in the diaphyseal region of long bones; about half of all osteosarcomas arise in the distal femur or proximal tibia. Clinically detectable metastases are present in about 20% of patients at diagnosis, and most patients have subclinical metastases. Effective therapy with complete surgical resection of tumor and intensive multiagent chemotherapy results in the cure of over 50% of patients with osteosarcoma. Recent developments of importance include an improved understanding of the importance of the p53 gene in the pathogenesis of osteosarcoma, the description of preclinical models, the development of improved imaging techniques for determining tumor extent and responsiveness to chemotherapy, and refinements in therapy.
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PMID:Recent developments in genetic mechanisms, assessment, and treatment of osteosarcomas. 193 29

Structural alterations of the p53 gene were investigated in tissue specimens of gastric and cervical cancers and in cell lines of gastric, esophageal, and cervical cancers, by polymerase chain reaction-single-strand conformation polymorphism analysis. Two of the four gastric cancer metastases and four of the eight cell lines originally established from gastric cancer metastases were found to have p53 gene alterations in the exon 5 to 11 region; point mutations and amino acid replacements were detected in a liver and an ovary metastasis at exon 7, in the TMK1 and MKN1 cell lines at exon 5, and in the OKAJIMA cell line at exon 10. The normal allele was not found in these cell lines. In the KATO-III cell line, gross deletion and rearrangement of the p53 gene were noted. However, no p53 mutations were identified in 19 primary lesions of gastric cancer, suggesting that the p53 gene abnormality preferentially occurs in the advanced stages of gastric cancer. In contrast to the gastric cancer, none of the 13 esophageal cancer cell lines, including two cell lines established from metastases, and none of the four cervical cancer cell lines showed any aberration in exons 5 to 11 of the p53 gene. During the course of the study, a novel polymorphism in intron 7 of the p53 gene was found, which can be recognized by restriction enzyme digestions of the polymerase chain reaction product.
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PMID:p53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. 193 50

The p53 gene initially was thought to be an oncogene, but recent evidence suggests that wild-type p53 can function as a tumor suppressor gene in lung, colon, and breast cancer as well as less common malignancies. This study reports the first identification of intronic point mutations as a mechanism for inactivation of the p53 tumor suppressor gene. Abnormally sized p53 mRNAs found in a small cell and a non-small cell lung cancer cell line were characterized by sequence analysis of cDNA/PCR products, the RNase protection assay and immunoprecipitation. These mRNAs were found to represent aberrant splicing leading to the production of abnormal or no p53 protein. Sequence analysis of genomic DNA revealed that a point mutation at the splice acceptor site in the third intron or the splice donor site in the seventh intron accounts for the abnormal mRNA splicing. In one patient the same intronic point mutation was found in the tumor cell line derived from a bone marrow metastasis and in multiple liver metastases but not in normal DNA, indicating that it occurred as a somatic event before the development of these metastases. These findings further support the role of inactivation of the p53 gene in the pathogenesis of lung cancer and indicate the role of intronic point mutation in this process.
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PMID:Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. 216 47

A recently established model for local breast cancer recurrence using the 13762NF rat mammary adenocarcinoma was used to evaluate biologic and biochemical properties related to clinical outcome for this class of tumors. Sublines isolated from local tumor regrowths following surgical resection differed from each other and from the 'parental' cell lines for multiple phenotypes, including metastatic propensity. Local recurrence- and primary tumor-derived sublines were examined by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), lectin binding to electrophoretically separated proteins, and lactoperoxidase-catalyzed cell surface iodination; and differential protein patterns were compared to tumor progression and metastatic potential. 2D-PAGE revealed several quantitatively different spots which correlated with lung colonization potential. In particular, quantities of an apparently unique, non-cell-surface protein, P50.9 (Mr approximately 50,900, pI approximately 7.3) correlated inversely with metastatic propensity, suggesting that it may be associated with, among other possibilities, the negative regulation of the metastatic phenotype. P50.9 was unrelated to four similarly sized metastasis-associated proteins--tumor autocrine motility factor; the rat analog of tumor suppressor, p53; rat cytokeratin 14 or procathepsin D--as determined by amino acid analysis. A major wheat germ agglutinin binding sialoglycoprotein, gp93 (Mr approximately 93,000), was present in smaller amounts as cells were passaged in vivo and re-established as in vitro cultures [MTF7 greater than 'primary' tumor-derived lines (sc1, sc3) much greater than local recurrence-derived lines (LR1, LR1a, LR3, LR4, LR5, LR6)]. Besides cell surface glycoprotein losses, two of six local recurrence-derived sublines expressed a wheat germ agglutinin-binding sialoglycoprotein, gp110 (Mr approximately 110,000), previously undetected on any of the other cell lines including the parental populations. gp110 was found in LR3 and LR6 which were relatively highly metastatic; however, correlation with metastatic potential failed because gp110 was not present on the metastatic parental cell line, MTF7. These results demonstrate specific quantitative and qualitative protein differences associated with the selection of locally recurrent mammary tumors.
Clin Exp Metastasis
PMID:Tumor progression- and metastasis-associated proteins identified using a model of locally recurrent rat mammary adenocarcinomas. 222 68

Oncogenes encoding serine/threonine or tyrosine kinases were introduced into the established rodent fibroblast cell line NIH 3T3 and tested for tumorigenic and metastatic behavior in T cell-deficient nude mice. Transforming oncogenes of the ras family were capable of converting fibroblast cell lines to fully metastatic tumors. Cell lines transformed by the kinase oncogenes mos, raf, src, fes, and fms formed experimental metastases and (in some cases) these genes were more efficient at metastatic conversion than a mutant ras gene. In contrast, cells transformed by either of two nuclear oncogenes, myc or p53, were tumorigenic when injected subcutaneously but were virtually nonmetastatic after intravenous injection. These data demonstrate that, in addition to ras, a structurally divergent group of kinase oncogenes can induce the metastatic phenotype.
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PMID:Transformation by oncogenes encoding protein kinases induces the metastatic phenotype. 365 11


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