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)

Human endometrial adenocarcinoma cells (Ishikawa line) constitutively express c-erbB2 coded oncoprotein p185erbB2 (p185) which is believed to be an orphan receptor for an unknown growth factor. Since we have shown that expression of p185 in primary lesions of endometrial cancer correlates well with high frequency of lymph node++ metastases and that the metastatic cells in the nodes strongly expressed p185, the role of the oncoprotein in processes of metastases was studied. Culturing the cells in the presence of 15% FCS and with monoclonal antibody to the extracellular domain of p185 (CB-1) inhibited cell growth and attenuated p185 expression on Western blotting, whereas no change occurred with the control antibody. Cells cultured without FCS achieved only approximately 1/3 growth compared to cells with FCS, and further suppression of growth was observed after adding CB-1. When cells were cultured on human term amnion, basement membrane invasion with p185 expression was observed. In nude mice, intraperitoneal seeding resulted in implant formation which was also associated with positive p185 as well as cyclin immunohistochemistry. In the two experiments, treatment of cells with CB-1 inhibited invasion or implant formation. The present study suggests that a signal through p185 receptor molecules acts as a trigger for early proliferation, and interaction with the host may enhance up-regulation of p185.
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PMID:[Role of p185c-erbB2 in endometrial cancer growth in vitro]. 135 38

Mitogenic stimulation of normal cells initiates a sequence of events leading to activation of cyclin-dependent kinases, phosphorylation of Rb, and subsequent entry of the cell into the S phase. Evidence is accumulating that transforming growth factor-beta 1 (TGF beta 1) inhibits cell cycle progression by blocking a number of steps involved in cdk activation, thus preventing the massive phosphorylation of Rb in late G1. Many types of cancer have lost sensitivity to the growth-inhibitory actions of TGF beta 1, which is thought to be an important step in the process of oncogenic transformation. Recent findings suggest that in many cancers TGF beta 1 insensitivity may result from disregulated expression of cyclin, cdk, and cdk inhibitor genes. These alterations allow inappropriate cdk activation and Rb phosphorylation, resulting in inactivation of the growth suppressive functions of Rb and uninhibited S phase entry. Further work will be needed to clarify the mechanisms of cdk inhibition by TGF beta 1 and how these events are linked to TGF beta 1 receptor-ligand binding and signaling.
Invasion Metastasis
PMID:Mechanisms of transforming growth factor-beta 1-induced cell cycle arrest. 765 24

Alcohol- and formalin-fixed, paraffin-embedded samples of 71 brain tumors (35 gliomas, 22 metastatic carcinomas, 8 meningiomas and 6 other tumors) were investigated by immunocytochemistry with three different monoclonal antibodies against proliferating cell nuclear antigen (PCNA)/cyclin (19A2; 19F4; PC10). PC10 was found to work best; it is applicable to both alcohol- and formalin-fixed tumor samples. PCNA labeling indices (LIs) were compared in the same tumors with LIs obtained by Ki-67 immunostaining of frozen sections and by in vitro incubation with bromodeoxyuridine (BrdUrd); in the latter preparations, BrdUrd LIs could be compared with PCNA LIs in the very same areas of serial sections. In gliomas, PCNA LIs were 0.7-80.2% (mean 31.7%), in metastases 0-76.0% (mean 47.8%), and in meningiomas 0-53.0% (mean 19.3%). In general, PCNA LIs were highly significantly correlated with Ki-67 LIs (P = 0.0002) and BrdUrd LIs (P = 0.0001). However, when tumor subgroups are considered, only gliomas show a significant correlation with Ki-67 and BrdUrd LIs. Despite this statistical correlation, PCNA expression was out of proportion to proliferation indices as determined by both other methods in almost one third of all brain tumors. Immunocytochemistry for PCNA produces a broad spectrum of staining intensity of labeled nuclei, whose number is dependent upon the sensitivity of the immunocytochemical technique used. Thus, inter-observer and inter-laboratory variabilities in PCNA LI determination may occur. Overlapping of PCNA LIs between tumor subgroups of varying malignancy further limits the informational value for the individual case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunostaining for proliferating cell nuclear antigen: its role in determination of proliferation in routinely processed human brain tumor specimens. 790 72

The MTS1/CDK4I gene encodes a 16 kDa cyclin kinase inhibitor and maps to chromosome 9p21. Previous studies have suggested the presence of a major tumour suppressor gene at this locus which may be inactivated in head and neck squamous cell carcinoma (HNSCC). To determine the status of this gene in human primary and metastatic HNSCC, we examined the locus and its transcript for abnormalities by polymerase chain reaction (PCR). Out of 14 cell lines studied, four had lost only exon 1, one had lost only exon 2, three had lost both exons 1 and 2, and none of the remaining six lines expressed a normal p16 mRNA. These latter six cell lines expressed p16 transcripts that had suffered deletions ranging in size from 2-16 base pairs. In each case, deletions led to a change of reading frame. Furthermore, in two cases abnormalities in the MTS1/CDK4I gene were identical in cells derived from metastatic tumours as compared to cells derived independently from the corresponding primary tumour. The identical nature of mutations observed in primary tumours and metastases derived from the same patient provides strong evidence that inactivation of p16 function was an in vivo event.
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PMID:MTS1/CDK4I is altered in cell lines derived from primary and metastatic oral squamous cell carcinoma. 800 Dec 21

PRAD-1 is a putative oncogene localized on chromosome 11q13 which encodes cyclin D1, a novel cyclin involved in cell cycle regulation. Amplification of this gene has recently been reported in several human tumors including breast and head and neck carcinomas. In this study we have analyzed the presence of PRAD-1/cyclin D1 gene amplification and mRNA overexpression in a series of 46 matched normal mucosas and squamous cell carcinomas of the larynx. PRAD-1/cyclin D1 was found to be amplified 2- to 12-fold in 17 carcinomas (37%). DNA amplification correlated with advanced local invasion (P = 0.0015), presence of lymph node metastases (P = 0.0078), and stage IV of the tumors (P = 0.0021). mRNA overexpression was found in 15 of the 43 (35%) cases examined and it was also significantly associated with advanced local invasion (P = 0.0025) and stage IV carcinomas (P = 0.0032). A significant association was observed between gene amplification and mRNA overexpression (P < 0.0001) with only 3 discordant cases (2 amplifications with no overexpression and 1 overexpressed carcinoma with no gene amplification). Furthermore, the degree of DNA amplification correlated with the levels of mRNA expression (r = 0.6; P = 0.024). These findings suggest that the PRAD-1/cyclin D1 gene may be an important target of 11q13 amplifications in laryngeal carcinomas and the activation of this gene may be involved in the progression of these tumors. Its association with advanced-stage tumors indicates that PRAD-1/cyclin D1 gene amplification and overexpression may be of prognostic significance.
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PMID:PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. 806 83

Clinicopathological and immunohistochemical analyses were performed on ten samples of gastrointestinal carcinoids resected in Ishikawa Prefectural Central Hospital. All samples showed positive reaction to chromogranin A. Serotonin was detected in 8 samples, somatostatin in 4 samples, gastrin in 2 samples. Glucagon/Glicentin in 1 sample, and PYY production in 2 samples. CEA production was detected in 8 samples, and microvascular invasion was observed in 6 of these 8 patients. The PCNA/cyclin labeling index (L.I.) of the cases with metastases was significantly higher than those without metastases. In conclusion, the expression of CEA and the PCNA/cyclin L.I. may be useful markers of the malignant potential of carcinoid tumors.
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PMID:Immunohistochemical analysis of gastrointestinal carcinoids. 810 55

Tumor formation results from alterations in the control of normal cell proliferation. To further our understanding of the molecular mechanisms underlying the deregulation of cell proliferation much attention, over the past decade, has been focused on the function of proto-oncogenes. Cellular oncogenes are thought to be growth promoting. More recently, a class of genes known as tumor suppressors have come under intense study. Tumor suppressors are largely thought to restrain cell proliferation. The retinoblastoma protein (Rb) is one of a growing list of tumor suppressors. Concurrent with the study of tumor suppressor genes has been a rapid increase in our understanding of the cell cycle at the molecular level. Rb and a related protein p107 are involved in the processes of cell proliferation and differentiation. Each functionally interacts with and affects the activity of the transcription factor E2F as well as other transcription factors involved in cell proliferation and differentiation. Additionally, Rb and p107 are modified by, and/or form specific complexes with, several elements of the basic cell cycle machinery. Specifically, Rb and p107 interact with and are modified by various cyclins and cyclin dependent kinases (cdk), some of which have been shown to be essential for cell cycle progression and in some cases their deregulation has been implicated in the development of cancer. This review will attempt to convey our current functional and mechanistic understanding of the biological roles Rb and p107 play in proliferation, development and differentiation. A knowledge of the interplay between these positive and negative regulators of cell proliferation and differentiation, noted above, is central to our understanding of human cancer.
Cancer Metastasis Rev 1994 Mar
PMID:The cell cycle and the retinoblastoma protein family. 814 45

The DNA index, expression of cell-cycle-related proteins--proliferating cell nuclear antigen (PCNA, cyclin) and Ki-67--and the content of silver-binding nucleolar organizer regions (AgNORs) were evaluated in 30 unselected consecutive primary squamous cell carcinomas of the larynx. Results were compared and subsequently related to histological grading, lymph node status, pT category, and pathological stage. DNA content was non-diploid in 9 cases (30%). Mean AgNOR counts per tumor ranged from 2.52 to 8.76. PCNA and Ki-67 expressions were similar in 10 cases (33%). In the remaining cases, PCNA-positive cells usually outnumbered Ki-67-positive cells. No significant correlation was found among DNA index, PCNA and Ki-67 expressions, and AgNOR counts. Although there was a positive trend when Ki-67 was compared with histological grading, findings were not statistically significant. In contrast, a significant correlation was found between DNA index and lymph node status (P = 0.035), with a higher incidence of neck node metastases in non-diploid tumors. These data suggest that tumor ploidy can be correlated with lymph node spread in laryngeal squamous cell carcinoma and might be used as an additional prognostic factor when planning treatment.
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PMID:DNA index, cellular proliferative activity and nucleolar organizer regions in cancers of the larynx. 867 55

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control. p21 can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in normal breast and in 91 breast carcinomas [three in situ ductal carcinomas (DCIS) with microinfiltration and 88 infiltrating carcinomas, 17 of which with an associated DCIS; 57 node negative and 34 node positive] with long-term follow-up (median = 58 months). Seven additional breast carcinomas with known p53 gene mutations were investigated. In normal breast p21 expression was seen in the nuclei of rare luminal cells of acinar structures, and in occasional myoepithelial cells. Poorly differentiated DCIS showed high p21 expression, whereas well-differentiated DCIS tumours showed few p21-reactive cells. p21 was seen in 82 (90%) infiltrating tumours; staining was heterogeneous; the percentage of reactive nuclei ranged from 1% to 35%. High p21 expression (more than 10% of reactive cells) was seen in 24 (26%) cases, and was associated with high tumour grade (P = 0.032); no associations were seen with tumour size, metastases, oestrogen receptor status, MIB1 expression and p53 expression. p21 expression in cases with p53 gene mutations was low in six cases and high in one. High p21 expression was associated with short relapse-free survival (P = 0.003).
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PMID:p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival. 868 23

Immunohistochemical analysis of the expression of the cyclin kinase inhibitor p21WAF1/CIP1 in a panel of primary and metastatic human melanocytic tumors was performed. It was found that, independent of the p53 status, approximately 30% of the primary melanomas and 40% of the metastases completely lacked expression of this cell cycle inhibitor. Some tumors were also analyzed by Northern blotting, and in most of the cases a consistant correlation between mRNA and protein expression was observed. In four benign nevi studied, WAF1/CIP1 mRNA was expressed whereas the protein was not detected, suggesting a post-transcriptional regulation of the inhibitor in these cases. In superficial spreading melanomas, a significant correlation between protein expression and tumor thickness was found, with thin lesions showing low protein levels. Interestingly, by comparing primary and metastatic specimens obtained from the same patient, a reduction in p21WAF1/CIP1 antibody staining was observed in the latter, probably reflecting a more aggressive phenotype of the metastases. In conclusion, our results demonstrate the complexity in the relationship between p21WAF1/CIP1 expression and tumor phenotype and furthermore suggest that aberrant expression of the cyclin-dependent kinase inhibitor may be of importance in the development and progression of sporadic malignant melanoma.
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PMID:Cyclin kinase inhibitor p21WAF1/CIP1 in malignant melanoma: reduced expression in metastatic lesions. 895 18


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