Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the cell death-inducing protein, Bak, was investigated in 41 cases of Hodgkin's disease and was correlated with Epstein-Barr virus (EBV) status. Overall, Bak immunostaining was observed in 35/41 cases (85%). Among the 22 EBV-positive cases, 20 cases (91%) expressed Bak while 15/19 EBV-negative cases (79%) contained Bak-positive Reed-Sternberg cells. The expression of Bak, as assessed by the staining intensity and the numbers of positive tumor cells, varied greatly from case to case but was high in 6 cases (15%). Our findings show that, similar to Bax, a second apoptosis-inducing gene Bak is frequently expressed in Hodgkin's disease. Whilst Bak is suspected to protect cells immortalized by EBV from apoptosis, its expression in Hodgkin's disease appears to be unrelated to the EBV status of Reed-Sternberg cells. Moreover, the potential pro-apoptotic functions related to Bak and Bax in Hodgkin's disease might be surpassed by a stronger expression of anti-apoptotic molecules thus explaining tumor progression.
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PMID:Detection of the cell death-inducing protein BAK in Reed-Sternberg cells of Hodgkin's disease. 1049 82

As part of our screening program for cancer inhibitory agents effective specifically in the promotion stage of cancer development, we have evaluated the possible inhibitory effects of 36 non-steroidal anti-inflammatory drugs (NSAIDs) on the Epstein-Barr virus early antigen (EBV-EA) activation which was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. All the drugs were observed to inhibit the EBV-EA activation at low doses with low toxicity. The two most active anti-tumor promoting agents were the arylacetic acid derivatives, etodolac and sulindac. We also report for the first time the activities of 14 new NSAIDs belonging to different classes as potential cancer chemopreventive agents. A structure-activity relationship study showed that among the salicylic acid derivative tested, the oxidation of the thiol group to dithiol derivatives results in the reduction of the activity. Introduction of amino group on the salicylic acid molecules also results in the reduction of activity in the EBV-EA assay. The results are of great interest in the development of NSAIDs as cancer chemopreventive agents, which halt cancer progression in multistage carcinogenesis, where successive activities are required to evolve into fully-fledged and metastatic cancer.
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PMID:Inhibition of epstein-barr virus early antigen activation promoted by 12-O-tetradecanoylphorbol-13-acetate by the non-steroidal anti-inflammatory drugs. 1109 Sep 73

To determine if p53 abnormalities could be involved in the pathogenesis of T- or natural killer (NK)-cell lymphomas, we investigated 51 cases of these lymphomas for the expression of p53 and its relationship with p53 gene mutations, the expression of the p21 protein as well as the proliferative and apoptotic indices. Overexpression of p53 was found in 19 cases (37%), whereas mutations of the p53 gene were observed in only 5 of 28 tested cases. The analysis of immunohistochemical data showed some entity-related phenotypic profiles. Anaplastic large cell lymphomas showed a frequent overexpression of p53 (7/8 cases) and p21 (6/8 cases) proteins and rare p53 mutations (1/7 cases), suggesting accumulation of a functional wild type p53 protein able to induce p21 expression. Nodal peripheral T-cell lymphomas unspecified showed relatively frequent overexpression of p53 protein (5/7 cases), infrequent p21 expression (2/7 cases), and rare p53 gene mutations (1/6 cases). In angioimmunoblastic lymphomas, the common phenotype was p53-/p21- (15/17 cases), with only a few scattered p53-positive cells, which, on the basis of double staining results, were mostly Epstein-Barr virus-infected B cells. A p53 gene mutation was only found in 1 case (1/8 cases) of angioimmunoblastic lymphoma, which showed cytologic tumor progression. Mycosis fungoides showed p53 overexpression in 2 of 4 cases, including 1 case with p53 gene mutation and features of cytologic tumor progression. Nasal NK/T lymphomas showed p53 overexpression in 2 of 5 cases, 1 of which had a p53 gene mutation. Finally, all lymphoblastic T-cell lymphomas (5 cases) and gammadelta hepatosplenic T-cell lymphomas (3 cases) were negative for expression of p53 and p21 proteins. We conclude that p53 protein overexpression is a common finding in some entities of T- and T/NK-cell lymphomas, whereas a p53 gene mutation is a rare, sporadic, and rather late event associated with tumor progression in some instances. The p53/p21 expression pattern appears to be variable in T- and T/NK-cell lymphoma entities, reinforcing the concept of distinct, entity-related mechanisms of pathogenesis in these tumors.
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PMID:Expression of p53 protein in T- and natural killer-cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations. 1123 Jul 7

Functional inactivation of the tumor suppressor protein p53 by accelerated ubiquitin/proteasome-dependent proteolysis is a common event in tumor progression. Proteasomal degradation is inhibited by the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen-1, which acts as a transferable element on a variety of proteasomal substrates. We demonstrate that p53 chimeras containing GAr domains of different lengths and positions within the protein are protected from proteolysis induced by the ubiquitin ligases murine double minute 2 and E6-associated protein but are still ubiquitinated and retain the capacity to interact with the S5a ubiquitin-binding subunit of the proteasome. The GAr chimeras transactivate p53 target genes, induce cell cycle arrest and apoptosis, and exhibit improved growth inhibitory activity in tumor cells with impaired endogenous p53 activity.
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PMID:Functional p53 chimeras containing the Epstein-Barr virus Gly-Ala repeat are protected from Mdm2- and HPV-E6-induced proteolysis. 1180 82

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein-Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV-infected human gastric cancer cell line sublines and their mock-infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (PD089035) and PI-3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor-induced pathways. Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness.
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PMID:EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. 1211 96

Squamous cancers of the oral cavity and esophagus are common worldwide, but no good genetically based animal model exists. A number of environmental factors as well as genetic alterations have been identified in these cancers, yet the specific combination of genetic events required for cancer progression remains unknown. The Epstein-Barr virus ED-L2 promoter (L2) can be used to target genes in a specific fashion to the oral-esophageal squamous epithelium. To that end, we generated L2-cyclin D1 (L2D1(+)) mice and crossbred these with p53-deficient mice. Whereas L2D1(+) mice exhibit a histologic phenotype of oral-esophageal dysplasia, the combination of cyclin D1 expression and p53 deficiency results in invasive oral-esophageal cancer. The development of the precancerous lesions was significantly reversed by the application of sulindac in the drinking water of the L2D1(+)/p53(+/-) mice. Furthermore, cell lines derived from oral epithelia of L2D1(+)/p53(+/-) and L2D1(+)/p53(-/-) mice, but not control mice, formed tumors in athymic nude mice. These data demonstrate that L2D1(+)/p53(+/-) mice provide a well-defined, novel, and faithful model of oral-esophageal cancer, which allows for the testing of novel chemopreventive, diagnostic, and therapeutic approaches.
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PMID:A mouse model of human oral-esophageal cancer. 1223 7

Reiterated terminal sequences of Epstein-Barr virus (EBV) DNA are numerically heterogeneous among infectious virions, providing a viral measure of clonality in infected cells. After in vitro infection, carcinoma cells bearing EBV episomes with fewer terminal repeats (TRs) proliferated faster. In single-cell clones, TR number varied inversely to the quantity of latent membrane protein 2A (LMP2A) transcripts whose unspliced precursors cross joined TRs. Thus, EBV clonality may reflect selection for a TR number that optimizes LMP2A-enhanced tumor progression, with infection occurring after epithelial cell transformation.
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PMID:Length of Epstein-Barr virus termini as a determinant of epithelial cell clonal emergence. 1285 25

Epstein-Barr virus (EBV) is a ubiquitous viral agent, well known to be associated with lymphoid, epithelial, and smooth-muscle malignancies in immunocompromised individuals. This report describes a 10-year-old patient with an EBV-related liver tumor occurring after kidney transplantation. The neoplasm presented a phenotypic spectrum, ranging from a smooth-muscle tumor to an inflammatory pseudotumor (IPT). The neoplastic cells failed to disclose CD21, CD35, or ALK expression, the latter confirmed by reverse-transcription polymerase chain reaction. Cytogenetic analysis revealed a single clonal cell population showing 46,XY,del (2)(p23),der(3)t (2;3)(p23;q29),der(21) t(Y;21)(q12;p13) karyotype. By metaphase FISH analysis, the neoplastic cells demonstrated the presence of two molecularly different but related aberrant clones, one with the loss of one ALK allele and the second with translocation of the 3'end of ALK kinase domain on the der(3) chromosome. Using FISH with an EBV-specific and 3'end ALK DNA probes, a co-localization of the viral DNA and the ALK sequences was found on the der(3) chromosome. Metaphases with loss of rearranged ALK did not show integrated virus; instead, viral particles together with an associated 3'end ALK domain formed an ex-chromosomal, episomal-like type configuration. The interphase study, using dual-color 5'/3' end ALK FISH assay, revealed 30% of nuclei with only one fused signal, confirming the total loss of one ALK allele in the subset of tumor cells. A combined immunofluorescence and FISH study indicated this separate clonal variant to correspond to desmin-positive smooth-muscle cells. In contrast, desmin-negative myofibroblasts showed the presence of both normal and rearranged ALK alleles. Our results indicate that ALK locus may be a target of EBV integration, a hitherto unreported finding. Although the sustained clonal expansion in EBV-related smooth-muscle tumors/IPTs may depend on functions provided by the EBV oncogenic proteins, the tumor phenotype may be further modified by the secondary genomic rearrangements imposed by the virus during and/or after the integration event. In this respect, the observed phenotypic heterogeneity most likely reflects divergence during neoplastic progression, with the subsequent expansion of morphologically and molecularly distinct but cytogenetically related clones.
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PMID:Complex genomic rearrangement of ALK loci associated with integrated human Epstein-Barr virus in a post-transplant myogenic liver tumor. 1293 32

There have been few studies regarding cancer progression from differentiated thyroid carcinoma to the undifferentiated one. To examine the possible involvement of Epstein-Barr virus (EBV) in this progression, 10 papillary carcinomas and 11 undifferentiated carcinomas were subjected to mRNA in situ hybridization, indirect immunofluorescence staining, polymerase chain reaction (PCR), and reverse-transcriptase PCR. mRNA in situ hybridization using a BamHIW probe revealed signals in all of the examined samples, although the signal strength was weaker in the papillary carcinomas than in the undifferentiated carcinomas. EBV nuclear antigen-2 (EBNA2) in situ hybridization produced almost the same results; however, the signals were detected less frequently in the papillary carcinomas. Indirect immunofluorescence using anti-EBNA2, anti-latent membrane protein-1 (LMP1), and anti-BZLF1 antibodies also showed positive results with high frequency and with more prominent fluorescence in undifferentiated carcinomas than in papillary carcinomas. An examination of thyroid carcinoma cell lines also confirmed these findings. EBV infected all of the thyroid carcinomas irrespective of the degree of pathological differentiation. The expression of EBV, especially of EBNA2 and LMP1 (both of which are oncogene products of EBV), was stronger in the undifferentiated carcinomas than in the papillary carcinomas. These results suggest that increased expression of EBV may be involved in the progression of thyroid papillary carcinoma to undifferentiated carcinoma.
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PMID:Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression. 1465 19

Immunodeficient patients have an increased incidence of neoplasms, whether the immunodeficiency is due to genetic disorder, the acquired immunodeficiency syndrome (AIDS), or immunosuppressive therapy. Leiomyosarcoma (LMS) is a rare neoplasm, even if its incidence has increased because of AIDS. Less than fifteen cases were described after organ transplantation. An intracranial localization is exceptional (five cases in the literature) and was never described after organ transplantation, to our knowledge. Our present report focuses on a 45-year-old immunocompromised patient, who received immunosuppressive therapy for renal transplantation. He suffered from atypical peri-orbital headaches six months after transplantation and a mass involving the cavernous sinus was identified. Surgical biopsy was performed. Histologic examination revealed a LMS. Epstein-Barr virus was identified by quantitative polymerase chain reaction in the LMS. Immunosuppression was reduced, the patient received adriamycin and protontherapy was realized. He died two years after the transplantation because of tumor progression and kidney failure.
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PMID:[Primary leiomyosarcoma of the cavernous sinus associated with Epstein-Barr virus in a kidney graft]. 1471 28


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