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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutional chromosome abnormalities have been associated with retinoblastoma, Wilm's tumor, and a familial form of renal carcinoma. For each tumor type, the particular chromosome segment involved in the observed rearrangements is different: in retinoblastoma, that segment is band q14 on chromosome #13. We now present evidence that in retinoblastoma, structural abnormalities involving the particular chromosome segment identified in the constitutional cases can also occur in the tumors of individuals with normal constitutional karyotypes. Six cases with retinoblastoma in one or both eyes were analyzed; deletions/rearrangements involving 13q14 were found in the tumor cell karyotypes of five of the six. These observations suggest that changes in a gene or genes at a common site (13q14) play a role in tumorigenesis in all forms of retinoblastoma, sporadic as well as heritable.
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PMID:Abnormalities of chromosome #13 in retinoblastomas from individuals with normal constitutional karyotypes. 711 19

Specific constitutional chromosome rearrangements have been described in a small number of individuals with two solid childhood tumors, retinoblastoma and Wilms' tumor. On the basis of these observations, a causal relationship between these chromosome abnormalities and tumorigenesis has been postulated. Though a specific constitutional chromosome abnormality has yet to be reported in association with neuroblastoma, another childhood tumor, we now confirm the involvement of a particular chromosome segment in structural abnormalities in cells from this tumor. Deletions or rearrangements of chromosome 1p were found in preparations from four of six neuroblastomas from individuals with normal constitutional karyotypes and in three of four permanent neuroblastoma cell lines. Structural abnormalities resulting in the loss or rearrangement of material from 1p (with the most frequent break point being 1p32 and with all rearrangements involving the apparent loss or rearrangement of material distal to 1p31, always including 1p34 to 1pter), represent the single most common class of chromosome aberrations in neuroblastoma. This suggests that the distal portion of 1p contains at least one gene involved in the development of neuroblastoma.
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PMID:Abnormalities of chromosome 1p in human neuroblastoma tumors and cell lines. 713 92

Altered expression of the retinoblastoma (RB) tumour-suppressor gene product (pRB) has been detected in sporadic bone and soft-tissue sarcomas. Earlier studies, analysing small cohorts of sarcoma patients, have suggested that these alterations are more commonly associated with high-grade tumours, metastatic lesions and poorer survival. This study was designed to re-examine the prevalence and clinical significance of altered pRB expression in a large and selected group of soft-tissue sarcomas from 174 adult patients. Representative tissue sections from these sarcomas were analysed by immunohistochemistry using a well-characterised anti-pRB monoclonal antibody. Tumours were considered to have a positive pRB phenotype only when pure nuclear staining was demonstrated, and cases were segregated into one of three groups. Group 1 (n = 36) were patients whose tumours have minimal or undetectable pRB nuclear staining (< 20% of tumour cells) and were considered pRB negative. Patients with tumours staining in a heterogeneous pattern (20-79% of tumour cells) were classified as group 2 (n = 99). The staining of group 3 (n = 39) was strongly positive with a homogeneous pRB nuclear immunoreactivity (80-100% of tumour cells). pRB alterations were frequently observed in both low- and high-grade lesions. Altered pRB expression did not correlate with known predictors of survival and was not itself an independent predictor of outcome in the long-term follow-up. These findings support earlier observations that alterations of pRB expression are common events in soft-tissue sarcomas; nevertheless, long-term follow-up results indicate that altered patterns of pRB expression do not influence clinical outcome of patients affected with soft-tissue sarcomas. It is postulated that RB alterations are primary events in human sarcomas and may be involved in tumorigenesis or early phases of tumour progression in these neoplasias.
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PMID:Altered patterns of retinoblastoma gene product expression in adult soft-tissue sarcomas. 754 54

Dysregulation of cyclin expression has been reported for several human malignancies, including breast cancer. To further investigate the role of cyclin genes in mammary tumorigenesis we analyzed the expression of cyclins D1, E and A and other cell cycle-related proteins in a series of nine N-methyl-N-nitrosourea-induced primary rat mammary tumors. Western blot analysis revealed a 10- to 15-fold increase in the level of cyclin D1 protein in most (7/9) of the tumors, when compared with normal rat mammary gland. The two tumors that did not show this increase also displayed negligible levels of the retinoblastoma protein. A moderate increase, 1.5- to 2-fold, in the level of cyclin E was observed in four tumors and three tumors displayed abnormal low molecular weight cyclin E-related proteins. None of the tumors showed amplification of the cyclin D1 or E genes when studied by Southern blot analysis. All nine tumors showed a 2- to 6-fold increase in the level of cyclin A protein. Most of the tumors also displayed a marked increase in levels of the CDK2 and CDK4 proteins. These changes did not appear to be simply a consequence of increased cell proliferation, as assessed by proliferating cell nuclear antigen analysis. Thus, aberrant expression of cyclins and other cyclin-related genes occurs frequently in mammary tumorigenesis in both rodents and humans.
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PMID:Deregulated expression of cyclin D1 and other cell cycle-related genes in carcinogen-induced rat mammary tumors. 755 74

The p16INK4/CDKN2, D-type cyclins, their partner cyclin-dependent kinases, and retinoblastoma protein constitute a G1 regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnormalities of p16INK4/CDKN2 occur concomitantly in two-thirds of cancer cell lines harboring aberrations of cyclin D1. Gene and protein transfer experiments demonstrated that concurrent alterations of cyclin D1 and p16 levels cooperate to (de)regulate G1 control in diploid fibroblasts, and that both events influence growth of retinoblastoma (RB)-positive, but not RB-deficient cancer cells. These results show that biological consequences of deregulating individual components along the pathway are unequal, reflecting their hierarchical roles in the G1 checkpoint control. Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16INK4/CDKN2, can cooperate in multistep tumorigenesis.
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PMID:Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control. 758 13

Aberrant cyclin expression has been implicated in oncogenesis in a number of human cancers. Since altered function of regulators of cyclin-dependent kinase (CDK) activity other than cyclins, in particular CDK inhibitors, might play a similar role in oncogenesis, we examined the expression and regulation of the CDK inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer cell lines. Both the INK4 and INK4B genes were homozygously deleted in 3 cell lines, while INK4 alone was deleted in 2 cell lines. A further 2 cell lines displayed loss of an allele at this locus, and in 1 of these the remaining allele contained a mis-sense mutation within the coding region of the p16INK4 protein. The majority of cell lines examined, including 2 normal mammary epithelial cell strains, expressed low levels of INK4 mRNA and low or undetectable levels of INK4B mRNA. However, INK4 mRNA was expressed at high levels in 5 cell lines, and this was associated with deletion or inactivation of the retinoblastoma susceptibility gene product pRB but not with mutation of TP53. No deletions of the WAF1/CIP1 gene were observed, but WAF1/CIP1 mRNA levels were reduced in cell lines with TP53 mutation. Transfection of a p16INK4 expression vector into MDA-MB-231 cells lacking the INK4 gene failed to produce any p16INK4-expressing cell lines, suggesting that such cells were selected against in continuous culture. Despite the frequent deletion of INK4 in breast cancer cell lines, no evidence was obtained for INK4 deletions in DNA from 45 primary breast carcinomas. Thus, homozygous deletion of the INK4 gene appears to be a rare event in primary breast cancer.
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PMID:Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. 759 Dec 70

Cyclin D1 plays a critical role in the timing of the initiation of DNA synthesis in the normal cell cycle of mammalian cells. Deregulated expression of this protein has been seen in a variety of tumours either as a result of gene amplification or chromosomal translocation, in breast cancer and B cell malignancies respectively. In order to determine the role this putative oncoprotein plays in breast cancer, we have applied a new monoclonal antibody, recently produced in our laboratory, in an immunohistochemical study of 93 primary breast carcinomas. We show that approximately 28% of the cases displayed enhanced expression of the cyclin D1 protein. Furthermore, either cyclin D1, cyclin D3, or both, were expressed in 69% of cases, suggesting that overexpression of any one member of this family may relieve cancer cells of their mitogenic stimulatory requirement. In addition, we show that those patients whose breast cancers co-express cyclin D1 with either epidermal growth factor receptor (EGFR) or the retinoblastoma protein (pRB) have a significantly poorer prognosis in comparison to those expressing cyclin D1 alone. Our observations indicate that, in a subset of breast cancers, aberrant cyclin D1 expression is a contributory factor to tumorigenesis and in association with EGFR or pRB expression, identify those tumours which may require more aggressive therapy.
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PMID:Determination of the prognostic value of cyclin D1 overexpression in breast cancer. 767 47

Retinoblastoma is a malignant tumor of the eye that affects about one in 20,000 young children and occurs as hereditary and non-hereditary (sporadic) forms. It results from successive loss or inactivation of the two alleles of the Rb1 gene, located in 13q14. A chromosomal deletion in 13q14 is revealed by cytogenetic investigation in about 5% of affected patients. Molecular studies have confirmed that inactivation of both alleles of the Rb1 gene, even by point mutation, is required for tumorigenesis, leading to the concept of antioncogenes or tumor suppressor genes. The protein (p110RB) produced by the Rb1 gene is involved in cell cycle regulation. Absence or abnormal forms of the protein may result in deregulation of the cell cycle and subsequent cell proliferation. Association of p110RB with viral oncoproteins may be a step in tumorigenesis. Differences in penetrance and expressivity among families, could be explained by balanced insertional translocation and by defects of the Rb1 gene, which codes for a shortened Rb protein with partial oncosuppressor function. Techniques allowing analysis of Rb1 mutations can be successfully used to predict or exclude the development of retinoblastoma in newborn infants.
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PMID:The genetics of retinoblastoma. 771 Feb 51

The D-type cyclins are growth factor-regulated delayed early functions which peak at the G1/S transition, are thought to regulate entry into S phase and have been implicated in tumorigenesis. Here, we show that cyclin D2 can co-operate with Ha-Ras to impose a novel transformed state on rat embryo fibroblasts (REF). While clonal cyclin D2/Ha-Ras REF transformants exhibit a characteristic transformed phenotype in high serum, in low serum they arrest cell proliferation and display profound morphological and cytological changes indicating loss of control of cell mass and deregulation of the G1/S transition. Notably, in low serum, despite re-establishment of actin cables and arrest of proliferation, cell mass continues to increase, creating giant cells up to 10 x normal size. Also, during low-serum culture the cells make a very gradual but progressive entry into S phase, reaching a 2.4N DNA content after 6 days. PCNA is expressed and 2N and 4N cells are largely absent, and thus the cells undergo a novel S phase arrest. While transfer to low serum induced the retinoblastoma protein to enter its dephosphorylated state, and cyclin A, cyclin B and cdc2 levels to decrease, all as normal, cyclin E, cdk4, cdk2 and the exogenous cyclin D2 persisted at high levels. These results indicate that cyclin D2 and Ha-Ras can transform cells when mitogenic signals from growth factors are provided. However, in low serum, co-operation of cyclin D2 and Ha-Ras provides only a subset of the progression signals and these are sufficient for G1-related cell mass increase and S phase entry, but are insufficient for full cell cycling.
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PMID:Cyclin D2 and Ha-Ras transformed rat embryo fibroblasts exhibit a novel deregulation of cell size control and early S phase arrest in low serum. 774 96

The IE2 gene product of human cytomegalovirus (HCMV) is one of a few viral regulatory proteins expressed immediately upon infection of the host cell. It is a potent transcriptional activator of many viral and cellular promoters. We found that the retinoblastoma susceptibility gene product (Rb) dramatically suppressed this IE2 transactivation of various promoters. However, unlike another tumor suppressor protein, p53, Rb did not have any significant effect on basal levels of transcription, suggesting that Rb specifically interacts with IE2 rather than other cellular factors involved in the general transcription machinery. We found by protein-affinity chromatography that Rb in nuclear extracts or produced by in vitro translation directly bound to IE2. Our results suggest that Rb may regulate the life cycle of HCMV, which is endemic in the human population. Furthermore, these data may provide new insights into the slow rate of HCMV DNA replication in cells and the possible involvement of HCMV in tumorigenesis.
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PMID:The retinoblastoma gene product negatively regulates transcriptional activation mediated by the human cytomegalovirus IE2 protein. 774 17


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