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

Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel antiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient's response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immunohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreatment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy.
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PMID:Apoptotic and proliferative indexes in esophageal cancer: predictors of response to neoadjuvant therapy [corrected]. 1255 88

Induction of cutaneous squamous cell carcinoma (SCC) in mice, by topical chemical [9,10-dimethylbenzanthracene (DMBA) and phorbol 12-myristate 13-acetate (PMA)] application, is a multistep process involving papilloma formation and progression to carcinoma. We have generated a transgenic (Tg) mouse [keratin-14 (K14)-survivin] with skin expression of survivin, an inhibitor of apoptosis expressed in most human skin cancers and premalignant lesions. K14-survivin mice were resistant to DMBA-induced keratinocyte apoptosis. To investigate the role of survivin and apoptosis in cutaneous carcinogenesis, mice were treated once topically with DMBA followed by twice weekly with PMA for 32 weeks. Surprisingly, tumor formation was less frequent (31% versus 43%) and significantly delayed (P = 0.01) in K14-survivin mice compared with non-Tg littermates. On the other hand, papilloma regression was not observed in Tg mice, whereas 20% of papillomas regressed in non-Tgs; one SCC was generated in Tg mice, whereas none were seen in non-Tgs. To increase tumor formation and SCC in particular, a second experiment was performed with mice on a p53+/- background. Again, DMBA/PMA-induced tumor formation was less (71% versus 89%) and significantly delayed (P = 0.02) in K14-survivin p53+/- animals compared with p53+/- non-Tgs. Papilloma regression was also not observed in Tg p53+/- mice, whereas 10% of papillomas regressed in p53+/- non-Tgs. The rate of papilloma progression to SCC was 21% in Tg p53+/- mice compared with 12% in p53+/- non-Tgs. Papillomas did not reveal significant differences in mitotic or apoptotic indices. Survivin expression was detected in all of the tumors. These results indicate that despite a paradoxical negative effect on tumor formation, survivin expression prevents papilloma regression and promotes conversion to SCC, consistent with its expression in most skin cancers and their precursors.
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PMID:Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. 1256 97

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in almost all types of malignancies, making this protein a useful tool for the development of broadly applicable vaccination therapies. We used a recently identified HLA-A2 binding peptide and dendritic cells (DCs) from healthy donors to induce survivin-specific cytotoxic T lymphocytes (CTLs) in vitro. These T cells efficiently lysed target cells pulsed with the cognate peptide. Furthermore, survivin-specific CTLs recognized HLA-A2-matched tumor cell lines and primary malignant cells from patients with leukemia in an antigen-specific and HLA-restricted manner as demonstrated with the use of cold target inhibition assays and blocking antibodies. To validate the immunogenicity of survivin we performed the experiments in an autologous setting and used monocyte-derived DCs as targets. Interestingly, we found that DCs up-regulate survivin expression on stimulation with tumor necrosis factor alpha (TNF-alpha). However, these mature DCs were not recognized by survivin-specific CTLs, whereas they lysed autologous mature DCs pulsed with the antigenic peptide or transfected with whole tumor RNA purified from a survivin-expressing cell line. To further analyze the possible use of survivin-specific CTLs in cancer therapies, we induced survivin-specific CTLs using peripheral blood mononuclear cells (PBMNCs) and DCs from a patient with chronic lymphocytic leukemia (CLL). The in vitro-generated T cells efficiently recognized autologous malignant CLL cells, whereas they spared autologous-purified nonmalignant B cells or DCs. Our results demonstrate that survivin epitopes are presented on a broad variety of malignancies and can be applied in vaccination therapies.
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PMID:Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. 1257 30

Cancer sera contain antibodies which react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs). This study determines whether a mini-array of multiple TAAs would enhance antibody detection and be a useful approach to cancer detection and diagnosis. The mini-array of TAAs comprised full-length recombinant proteins expressed from cDNAs encoding c-myc, p53, cyclin B1, p62, Koc, IMP1, and survivin. Enzyme immunoassay was used to detect antibodies in 527 sera from six different types of cancer. Antibody frequency to any individual TAA was variable but rarely exceeded 15-20%. With the successive addition of TAAs to a final total of seven antigens, there was a stepwise increase of positive antibody reactions up to a range of 44-68%. Breast, lung, and prostate cancer patients showed separate and distinct profiles of reactivity, suggesting that uniquely constituted antigen mini-arrays might be developed to distinguish between some types of cancer. Distinct antibody profiles were not observed in gastric, colorectal, and hepatocellular carcinomas with this set of seven TAAs. Detection of autoantibodies in cancer can be enhanced by using a mini-array of several TAAs as target antigens. Additional studies in early cancer patients and high-risk individuals and the design of unique antigen panels for different cancers would help to determine whether multiple antigen mini-arrays for the detection of autoantibodies might contribute a clinically useful noninvasive approach to cancer detection and diagnosis.
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PMID:Enhancement of antibody detection in cancer using panel of recombinant tumor-associated antigens. 1258 23

Survivin is a 16.5-kDa protein that belongs to the inhibitor of apoptosis (IAP) family. It is expressed at high levels in the G2/M phase and is rapidly down-regulated after cell-cycle arrest. It was suggested that survivin plays a pivotal role in linking cell death and cell proliferation. Although present during fetal development, survivin disappears in terminally differentiated adult tissues. Its expression is aberrantly enhanced in transformed cell lines, and in all the most common human cancers. Adult T-cell leukemia (ATL), which is abundant with Fas (Apo-1/CD95), has the characteristic feature of high tumor burden, suggesting that ATL cells probably prolong their lives as a result of escape from apoptosis. Survivin is prominently and consistently expressed in all cases of ATL and ATL cell lines. Its mRNA expression levels among the subtypes of ATL and ATL cell lines are characteristic and informative, low in chronic type, low to high in acute type and extremely high in ATL cell lines. In addition, when the survivin mRNA expression is higher, the survival of the patient is shorter. Its overexpression may account for a growth advantage in vivo and subsequently the malignant behavior of ATL. So quantification of survivin mRNA is important for clinical laboratory examinations. Among all of the current clinical tests for survivin mRNA quantification, the real time PCR is desirable. Despite some technological problems of standardization, quantification of survivin mRNA was shown to be a biological marker for clinical stages or minimal residual disease (MRD).
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PMID:Survivin an important determinant for prognosis in adult T-cell leukemia: a novel biomarker in practical hemato-oncology. 1261 9

Apo-2L/TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor superfamily and has recently been shown to induce apoptosis through engagement of the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). The transcription factor nuclear factor (NF)-kappa B regulates the expression of genes involved in cancer cell invasion, metastasis, and resistance to chemotherapy. In normal unstimulated cells, NF-kappa B is maintained in the cytoplasm with its inhibitor protein I kappa B, whereas in cancer cells, NF-kappa B is in the nucleus and constitutively activates target genes. To understand the function of NF-kappa B in TRAIL-induced apoptosis, we have analyzed the specific roles of NF-kappa B subunits. Overexpression of a transdominant-negative mutant of the inhibitory protein I kappa B alpha results in down-regulation of constitutively active NF-kappa B, induction of DR5, and tumor necrosis factor receptor (TNFR) 1-associated death domain expression and enhancement of TRAIL sensitivity. Overexpression of RelA or a transcriptional-deficient mutant of c-Rel inhibits TRAIL-induced apoptosis. Depletion of RelA in mouse embryonic fibroblasts increases cytokine-induced apoptosis, whereas depletion of c-Rel blocks this process. Overexpression of RelA subunit inhibits caspase-8 and DR4 and DR5 expression and enhances expression of cIAP1 and c-IAP2 after TRAIL treatment. By comparison, overexpression of c-Rel enhances DR4, DR5, and Bcl-X(s) and inhibits cIAP1, cIAP2, and survivin after TRAIL treatment. These results suggest that the RelA subunit acts as a survival factor by inhibiting expression of DR4/DR5 and caspase-8 and up-regulating cIAP1 and cIAP2. The dual function of NF-kappa B, as an inhibitor or activator of apoptosis, depends on the relative levels of RelA and c-Rel subunits. Thus, NF-kappa B activity may play an important role in tumor progression, and down-regulation of RelA or up-regulation of c-Rel represents a possible therapeutic target for the treatment of cancer.
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PMID:Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. 1261 23

A cohort study was designed to evaluate the efficiency of gene transfer and whether biological activity from the expressed therapeutic gene resulted after administration of a recombinant adenovirus containing the human wild-type p53 (p53(wt)) gene (rAd-p53 SCH 58500). The cohort study was conducted in five trial subjects with recurrent ovarian cancer. Each trial subject received multiple cycles of rAd-p53 SCH 58500, each cycle comprised of doses of 7.5 x 10(13) particles on each of five consecutive days. Subjects were treated with rAd-p53 SCH 58500 alone during Cycle 1 and in combination with gemcitabine during the subsequent cycles. Both tumor biopsies and peritoneal aspirates were collected and evaluated for gene transfer and evidence of the biological activities of the expressed p53(wt) gene. Using quantitative PCR and RT-PCR, and in situ PCR, gene transfer and expression were documented in tumor biopsies (four of five patients) collected from Cycle 1. Furthermore, upregulation of p21/WAF1, bax and mdm-2, and downregulation of survivin were observed in these same tumor biopsy samples, suggesting that intraperitoneal administration of rAd-p53 SCH 58500 leads to detectable p53 biological activity in target tumor tissue. In addition, gene transfer and its expression were observed in cells obtained from peritoneal aspirates. These fluids were mainly comprised of polymorphonuclear neutrophils, indicating that successful gene transfer can be achieved by multiple cycle intraperitoneal administration of recombinant adenovirus.
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PMID:Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. 1263 44

Gastric cancer is one of the most common malignant tumors of the gastrointestinal tract. However, the molecular pathways involved in the regulation of gastric carcinogenesis are not completely elucidated. In the last decade, basic cancer research has been focused on the deregulation of apoptosis as a central event in the process of carcinogenesis. Caspase-3 and survivin are regulators of apoptosis and have been implicated in the development of gastric cancer. The aim of the present study was to compare the expression of mRNA and protein for survivin and caspase-3 in the gastric cancer and in the cancer margin with that in normal human gastric mucosa. Fifteen patients with advanced gastric cancer (all H. pylori-positive) and 15 matched control subjects with normal gastric mucosa were included in this study. The biospy specimens for histology and for molecular analyses were taken from gastric tumor, tumor surrounding gastric mucosa and in normal patients from the mucosa of antrum and corpus. Survivin mRNA expression was very weak, but detectable, in the normal gastric mucosa. However, at the protein level, no expression for survivin was detected in the normal gastric mucosa. In the biopsy specimens from tumor and surrounding gastric mucosa, a significant increase in survivin mRNA and protein expression was observed. The expression of survivin was higher in the tumor than in the tumor margin. The mRNA and protein expression of caspase-3 was detected in the gastric mucosa of normal subjects. In gastric cancer only the expression of procaspase-3 was observed, while the expression of active caspase-3 was completely undetectable. In the gastric mucosa surrounding gastric cancer, no gene and protein expression for caspase-3 was detected. We conclude that the changes in the level of caspase-3 and survivin play an important role in the transformation from normal gastric mucosa to gastric career.
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PMID:Expression of survivin and caspase-3 in gastric cancer. 1264 1

Survivin is a member of the inhibitor of apoptosis (TAP) gene family that exhibits differential expression in nearly all human cancers but not in most normal tissues. Recent progress identified a multifunctional survivin pathway positioned at the interface between mitotic progression and apoptosis inhibition, and required to preserve viability of dividing tumor cells (Altieri, 2001; Andersen and Thor, 2002; Jaattela, 1999). The unique properties of survivin have recently found concrete applications for cancer detection, diagnosis, and outcome prediction. In addition, targeting the survivin pathway may offer new therapeutic prospects to lower a general survival threshold in cancer cells. This chapter will focus on the current developments in the field of survivin and its role in apoptosis regulation and mitotic progression. Current perspectives on exploiting the survivin pathway for cancer diagnosis and treatment will be highlighted.
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PMID:Survivin and apoptosis control. 1266 52

Survivin, an inhibitor of apoptosis (IAP) containing one baculovirus IAP repeat (BIR) domain, has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. Survivin splice variants, survivin-DeltaEx3 and survivin-2B, have apparently retained and lost anti-apoptotic potential, respectively. As survivin was first discovered due to its high homology with effector cell protease receptor (EPR-1), a protein involved in blood coagulation, it has been suggested (but not proven) that EPR-1 may act as a natural anti-sense to survivin in cells. Survivin homologs have been found in non-human species. Survivin expression has been described during embryonic development and in adult cancerous tissues, with greatly reduced expression in adult normal differentiated tissues, particularly if their proliferation index is low. Survivin has been defined as a universal tumor antigen and as the fourth most significant transcriptosome expressed in human tumors. Although survivin is usually located in the cell cytoplasmic region and associated with poor prognosis in cancer, nuclear localisation, indicative of favorable prognosis, has also been reported. Survivin expression has also been reported in a number of proliferating normal adult tissues. Extensive research has been conducted, aimed at increasing our understanding of survivin, by determining its sub-cellular structure and location, mechanism(s) of action and control of expression. While much important information on this molecule has been accumulated, there are still many areas of controversy or limited information. Further research may enable exploitation of survivin overexpression in cancer compared to normal tissues, making survivin a potentially attractive target for cancer therapeutics.
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PMID:Survivin: role in normal cells and in pathological conditions. 1267 16


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