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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.
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PMID:Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. 1239 83

Apoptosis and necrosis represent two distinct types of cell death. Apoptosis possesses unique morphologic and biochemical features which distinguish this mechanism of programmed cell death from necrosis. Extrinsic apoptotic cell death is receptor-linked and initiates apoptosis by activating caspase 8. Intrinsic apoptotic cell death is mediated by the release of cytochrome c from mitochondrial and initiates apoptosis by activating caspase 3. Cancer chemotherapy utilizes apoptosis to eliminate tumor cells. Agents which bind to the minor groove of DNA, like camptothecin and Hoechst 33342, inhibit topoisomerase I, RNA polymerase II, DNA polymerase and initiate intrinsic apoptotic cell death. Hoechst 33342-induced apoptosis is associated with disruption of TATA box binding protein/TATA box complexes, replication protein A/single-stranded DNA complexes, topoisomerase I/DNA cleavable complexes and with an increased intracellular concentration of E2F-1 transcription factor and nitric oxide concentration. Nitric oxide and transcription factor activation or respression also regulate the two apoptotic pathways. Some human diseases are associated with excess or deficient rates of apoptosis, and therapeutic strategies to regulate the rate of apoptosis include inhibition or activation of caspases, mRNA antisense to reduce anti-apoptotic factors like Bcl-2 and survivin and recombinant TRAIL to activate pro-apoptotic receptors, DR4 and DR5.
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PMID:Apoptosis: biochemical aspects and clinical implications. 1241 95

Survivin, one of the most tumor-specific gene products, has been implicated in both anti-apoptosis and cytokinesis. However, the mechanism by which survivin regulates these two different processes is still elusive. Here, we show that survivin binds to the catalytic domain of Aurora-B. We demonstrate that in the presence of survivin, Aurora-B phosphorylates histone H3 much more efficiently than in the absence of survivin in a cell-free system. Furthermore, we confirm that cells lacking survivin due to survivin antisense oligonucleotide-treatment have lower Aurora-B kinase activity, whereas cells overexpressing survivin have higher Aurora-B kinase activity. We also provide evidence that depletion of survivin by survivin antisense oligonucleotide treatment causes significant reduction of endogenous phosphorylated histone H3 and mislocalization of Aurora-B. These results indicate that survivin stimulates Aurora-B kinase activity and helps correctly target Aurora-B to its substrates during the cell cycle, thus providing a mechanism as to how survivin exerts its function in human cells.
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PMID:Survivin enhances Aurora-B kinase activity and localizes Aurora-B in human cells. 1241 97

The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.
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PMID:Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. 1246 12

Cervical cancer can be classified into two histological types: squamous cell carcinoma (SCA) and adenocarcinoma (ACA). Reportedly ACA has poorer prognoses, metastasizes more easily to lymph nodes, and is more resistant to radiotherapy than SCA. To clarify the cause of characteristic differences between these histological types, we examined the expressions of apoptosis inhibiting and tumor-invasion related factors in both histological types. We reviewed the 34 cases of cervical cancer (17 ACA, 17 SCA) that had surgery as their initial treatment at Osaka City University Medical School Hospital between 1996 and 2001. The differences of survivin, and matrix metalloproteinase (MMP-2, and MMP-7) expressions between both histological types were immunohistochemically assayed, and the correlation between the expression of each protein and clinicopathological characteristics was analyzed. Survivin was expressed significantly stronger in ACA cases (p=0.035). The number of patients who expressed MMP-2 and MMP-7 simultaneously was significantly higher in SCA cases (p=0.039). MMP-2 and MMP-7 had tendencies to be expressed stronger in SCA (p=0.057 and p=0.084, respectively). These results suggest that the differences of the expression of survivin (an apoptosis inhibiting factor), MMP-2, and MMP-7 (tumor-invasion related factors) between ACA and SCA were causes of the characteristic differences between the two histological types.
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PMID:Expression of survivin and matrix metalloproteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix. 1246 43

Malignant pleural mesothelioma is a rare and aggressive tumor characterized by rapid progression, late metastases, and poor prognosis. In this study, we investigated the expression of survivin, a member of the inhibitors of apoptosis protein gene family, in mesothelioma and an antisense oligonucleotide-based gene therapy for mesothelioma using survivin as a target. Initially, we documented the expression of survivin in human mesothelioma cell lines and fresh tissues using reverse transcription-PCR and Western blot analysis. Our results showed that survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To investigate the use of survivin as a therapeutic target on mesothelioma, we carried out transfections with antisurvivin oligonucleotides to induce apoptosis in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and subsequent analysis using the flow cytometry demonstrated that antisurvivin oligonucleotides induced significantly greater apoptosis rates in the survivin-positive mesothelioma cell line H28 (42.5%) as compared with the control oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time course evaluation by Western blot analysis showed that survivin was inhibited by antisurvivin oligonucleotides within 12 h after transfection. Our results show, for the first time, that survivin, an inhibitors of apoptosis protein family gene member, is highly overexpressed in malignant pleural mesothelioma. Down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach to the treatment of mesothelioma.
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PMID:Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides. 1247 65

The classification of thymic epithelial tumors is controversial because prediction of the biological behavior of these tumors from their morphologic appearance is difficult. The aim of this study was to evaluate the proliferative activity and rate of apoptosis of thymic epithelial tumors classified according to World Health Organization histological classification. We also attempted to determine the importance of a number of proapoptotic factors in these processes. We investigated 46 surgically resected thymic epithelial tumors (8 Type A, 8 Type AB, 7 Type B1, 7 Type B2, 6 Type B3, and 10 Type C). Immunohistochemical staining was performed to determine the tumor expression of p53 protein, Bax, Bcl-2, and survivin. In addition, the Ki-67 labeling index (LI) and apoptotic index (AI) of these tumors were evaluated. Type C thymoma had a higher LI (16.55 +/- 12.12%) than did the other histological subtypes. Stage IV thymoma (12.36 +/- 9.99%) had a higher LI than did Stage I tumor. The AI was significantly elevated in Type B1 thymoma (1.47 +/- 0.55%). Overexpression of p53 protein was observed in Type B3 and C thymomas. p53 protein-positive tumors had a higher LI than did p53 protein-negative tumors (P <.0001). Bcl-2 expression was observed in Type A, AB, and C thymomas. Bcl-2-positive thymoma had a lower AI than did Bcl-2-negative thymoma (P =.0157). These results suggest that overexpression of p53 protein is associated with a higher tumor proliferative activity and that Bcl-2 acts as an inhibitor of apoptosis in thymoma. Bcl-2 and p53 protein expression may be useful markers in differentiating thymoma subtypes.
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PMID:Proliferative activity and apoptosis in thymic epithelial neoplasms. 1248 Oct 14

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)-->Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.
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PMID:Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. 1251 2

Survivin, a member of the inhibitor of apoptosis protein family, has attracted growing attention due to its expression in various tumors and its potential application in tumor therapy. However, its subcellular localization and function have remained controversial: Recent studies revealed that survivin is localized at the mitotic spindle, binds caspases, and could thus protect cells from apoptosis. The cell cycle-dependent expression of survivin and its antiapoptotic function led to the hypothesis that survivin connects the cell cycle with apoptosis, thus providing a death switch for the termination of defective mitosis. In other studies, survivin was detected at kinetochores, cleavage furrow, and midbody, localizations being characteristic for chromosomal passenger proteins. These proteins are involved in cytokinesis as inferred from the observation that RNA interference and expression of mutant proteins led to cytokinesis defects without an increase in apoptosis. To remedy these discrepancies, we analyzed the localizations of a survivinDsRed fusion protein in HeLa cells by using confocal laser scanning microscopy and time-lapse video imaging. SurvivinDsRed was excluded from the interphase nucleus and was detected in centrosomes and at kinetochores. It dissociated from chromosomes at the anaphase/telophase transition and accumulated at the ends of polar microtubuli where it was immediately condensed to the midbody. Overexpression of both survivinDsRed and of a phosphorylation-defective mutant conferred resistance against apoptosis-inducing reagents, but only the overexpressed mutant protein caused an aberrant cytokinesis. These data characterize in detail the dynamics of survivin in vertebrate cells and confirm that survivin represents a chromosomal passenger protein.
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PMID:Localization, dynamics, and function of survivin revealed by expression of functional survivinDsRed fusion proteins in the living cell. 1252 28

The positivity rates of mRNA expression in breast cancer of the tumor-related genes for c-erbB2, PLU-1 and survivin are unclear. We quantitatively analyzed tissue samples from 39 breast cancers and non-cancerous parts of the same specimens for the above three mRNAs using a TaqMan reverse transcription-polymerase chain reaction (RT-PCR). Using the mean + 2SD of non-cancerous sample as a cut-off value, the positivity rates of the tumors for c-erbB2, PLU-1 and survivin were 20.5%, 7.7% and 69.2%, respectively. Combining consideration of survivin with c-erbB2 and or PLU-1 increased the positivity ratio (survivin plus either of others, 76.9%; survivin plus both, 79.5%). Analysis by histological type indicated that survivin showed the highest positivity in ductal carcinoma and that survivin and PLU-1 showed the same positivity rate (40.0%) in the five carcinomas classified histologically as either solid-tubular or mucinous. Further, all cases that were positive for PLU-1 were negative for survivin. Survivin mRNA expression appeared more useful as a marker for diagnosis of breast cancer than c-erbB2 or PLU-1. However, PLU-1 appeared to vary independently of survivin, enhancing the usefulness of assays considering both in combination.
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PMID:Relevance of c-erbB2, PLU-1 and survivin mRNA expression to diagnostic assessment of breast cancer. 1253 26


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