Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bcl-2 protein is found to be over-expressed in many types of human tumours and is a potent inhibitor of apoptosis. The exact mechanism by which bcl-2 prevents apoptosis and exercises its oncogenic effect is still unclear. Other studies on cell lines have reported that bcl-2 over-expression is related to suppression of p21 (WAF1/CIP). We have investigated the relationship between bcl-2 protein over-expression and expression of the p21 protein in a series of human breast carcinomas. Selected tumour samples from 100 breast-cancer patients (38 with abnormal p53 status, scored as protein accumulation and/or mutation, and 62 without detectable p53 alterations), were immunostained for bcl-2 protein, the p21 protein and the oestrogen-receptor (ER) protein. A highly significant association was found between reduced p21-protein expression and over-expression of bcl-2 in tumours with no detectable p53 alterations (p < 0.001). A significant association was seen between ER immunoreactivity and expression of the bcl-2 protein, as well as between bcl-2 protein expression and tumours of the higher differentiation grade (grade-2 tumours). No association was seen between bcl-2 over-expression and the presence of metastases. Our findings indicate that down-regulation of p21 may be a result of up-regulation of bcl-2 independent of p53.
 ...
PMID:Interaction between bcl-2 and p21 (WAF1/CIP1) in breast carcinomas with wild-type p53. 933 7

Tumour progression is characterised by an imbalance between cell proliferation and apoptosis. The aim of our study was to estimate the importance of proliferation and apoptosis associated parameters in primary squamous cell carcinomas (SCCs) of the oral cavity and oropharynx. For determination of apoptosis, the enzymatic labelling of DNA fragmentation with a terminal transferase reaction was used in 156 tissue samples of 107 patients, including corresponding lymph-node metastases in nine cases. P53, bcl-2, and Ki-67 were determined immunohistologically. P53 was detectable in 50.5% of the cases. Positive staining was associated significantly with decreased apoptosis (P<0.003). Bcl-2 was upregulated in 31.8% of the cases depending on the tumour grading (P<0.001) and correlated negatively with apoptosis (P<0.001). Proliferation (P<0.006) and apoptosis (P<0.03) were enhanced in larger tumours, though a direct correlation between these two parameters was not proven. Nevertheless, in contrast to the conventional tumour staging and grading, neither the expression of p53 or bcl-2 nor the apoptosis or Ki-67 measurements were able to predict survival or recurrence-free survival of the patients suffering from a SCC in the oral cavity or oropharynx. Our observations suggest that the function of wild-type p53 to induce apoptosis is lost in at least half of the SCCs under study and that the physiological function of bcl-2 as potent inhibitor of apoptosis is widely preserved in oral SCC.
 ...
PMID:Prognostic significance of apoptosis and associated factors in oral squamous cell carcinoma. 1075 98

Melanoma is the most aggressive form of skin cancer. Patients with advanced disease, such as lymph node involvement and distant metastases, have 5-year survival rates of 50% and 10-20%, respectively. This poor prognosis largely results from resistance to conventional chemotherapy, namely cytotoxic drugs. The basis for drug resistance in melanoma is most likely dysregulation of apoptosis, although other mechanisms including drug transport, detoxification, and enhanced DNA repair may also play a role. Defects at multiple levels and in both major apoptotic pathways have been described in melanoma. Our laboratory has identified an inhibitor of apoptosis, termed survivin, that is expressed in melanoma and required for maintenance of melanoma cell viability. Targeting of survivin and other apoptotic regulators increases the sensitivity of melanoma cells to cytotoxic drugs, and may provide a promising new therapeutic approach to cancer.
Cancer Metastasis Rev 2001
PMID:Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. 1183 44

The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor generates potent, specific, and long-lasting antitumor immunity through improved tumor antigen presentation by dendritic cells and macrophages. A phase I clinical trial of this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T and B cell infiltrates that effectuated substantial tumor necrosis and fibrosis. To delineate the target antigens of this vaccine-stimulated tumor destruction, we screened a melanoma cDNA expression library with postimmunization sera from a long-term responding patient (K030). High-titer IgG antibodies recognized melanoma inhibitor of apoptosis protein (ML-IAP), a caspase antagonist containing a single baculoviral IAP repeat and a COOH-terminal RING domain. Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching. Moreover, lymphocyte infiltrates in necrotic metastases included CD4+ and CD8+ T cells specific for ML-IAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis. Whereas melanoma cells in densely infiltrated lesions showed strong ML-IAP expression by immunohistochemistry, lethal disease progression was associated with the loss of ML-IAP staining and the absence of lymphocyte infiltrates. These findings demonstrate that ML-IAP can serve as a target for immune-mediated tumor destruction, but that antigen-loss variants can accomplish immune escape.
 ...
PMID:Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. 1262 61

Survivin is a novel inhibitor of apoptosis. It is detected in fetal and neoplastic adult tissue, but not in normal tissues. Several recent studies have shown that survivin not only inhibits apoptosis, but also accelerates cancer cell proliferative activity. Expression of the protein may be of prognostic significance and therapeutic relevance in many cancers. We investigated survivin expression in hepatocellular carcinoma, correlating results with proliferation (MIB-1), prognostic factors, and outcome. Paraffin-embedded sections of 72 hepatocellular carcinoma were immunostained for survivin and MIB-1 using tissue microarray technology. Expression was evaluated in nuclei and cytoplasm as intensity (0-3+), and percentage of positive cells scored on a four-tiered system with less than 10%=negative; 10-25%=1; 26-50%=2; 51-75%=3; and 76-100%=4. Frequency of nuclear survivin expression was 43%. There was a significant correlation between nuclear survivin expression and nuclear grade (P=0.0271), microvascular invasion (P=0.0064), mitotic rate (P=0.0017), and MIB-1 (P=0.0001), as well as local recurrence (P=0.0487), and disease-free survival (P=0.0098). Histologic grade (P=0.0544) and stage (P=0.0548) tended to correlate with survivin expression, which did not correlate with cirrhosis, tumor necrosis, multiple tumors, metastatic disease, or overall survival. Survivin expression correlates with poor prognostic parameters (high nuclear and histologic grade, microvascular invasion, increased proliferation (mitotic count, MIB-1)), local recurrence, and shorter disease-free survival, but does not correlate with overall survival. An important role is suggested for survivin in progression, recurrence, and treatment of hepatocellular carcinoma.
 ...
PMID:Survivin expression in hepatocellular carcinoma: correlation with proliferation, prognostic parameters, and outcome. 1519 12

Melanoma is the most fatal skin cancer, often highly resistant to chemotherapy. Here we show that treatment with an 11-base DNA oligonucleotide homologous to the telomere 3' overhang sequence (T-oligo) induces apoptosis of several established human melanoma cell lines, including the aggressive MM-AN line, whereas normal human melanocytes exposed to the same or higher T-oligo concentrations show only transient cell cycle arrest, implying that malignant cells are more sensitive to T-oligo effects. When MM-AN cells were briefly exposed to T-oligo in culture and injected into the flank or tail vein of SCID mice, eventual tumor volume and number of metastases were reduced 85-95% compared with control mice. Similarly, T-oligos administered intralesionally or systemically selectively inhibited the growth of previously established MM-AN tumor nodules in the flank and peritoneal cavity by 85 to 90% without detectable toxicity. We previously showed that T-oligos act through ATM, p95/Nbs1, E2F1, p16INK4A, p53, and the p53 homologue p73 to modulate downstream effectors and now additionally demonstrate striking down-regulation of the inhibitor of apoptosis protein livin/ML-IAP. We suggest that T-oligo mimics a physiologic DNA damage signal that is frequently masked in malignant cells and thereby activates innate cancer prevention responses. T-oligos may provide a novel therapeutic approach to melanoma.
 ...
PMID:Telomere-based DNA damage responses: a new approach to melanoma. 1533 80

Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin(96-104) epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.
 ...
PMID:Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. 1560 88

A novel strategy achieved the eradication of lung tumor metastases by joint suppression of angiogenesis in the tumor neovasculature and induction of tumor cell apoptosis. This was accomplished by CTLs induced by a DNA vaccine encoding secretory chemokine CCL21 and the inhibitor of apoptosis protein survivin, overexpressed by both proliferating endothelial cells in the tumor vasculature and tumor cells. Oral delivery of this DNA vaccine by doubly attenuated Salmonella typhimurium (dam(-) and AroA(-)) to such secondary lymphoid organs as Peyer's patches in the small intestine, elicited marked activation of antigen-presenting dendritic cells, and an effective CD8(+)T cell immune response against the survivin self-antigen. This resulted in eradication or suppression of pulmonary metastases of non-small cell lung carcinoma in both prophylactic and therapeutic settings in C57BL/6J mice. Moreover, the suppression of angiogenesis induced by the vaccine did not impair wound healing or fertility of treated mice. It is anticipated that such novel DNA vaccines will aid in the rational design of future strategies for the prevention and treatment of cancer.
 ...
PMID:A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. 1569 99

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive gastrointestinal cancers and is thought to arise from noninvasive precursors-pancreatic intraepithelial neoplasia (PanIN). Aberrantly prolonged cell survival due to apoptosis suppression is likely to contribute to carcinogenesis and carcinoma progression where the inhibitor of apoptosis proteins (IAPs) may play an important role. IAPs specifically inhibit caspases 3, 7, and 9 and prevent apoptosis. Survivin is a unique member of the IAPs family that is expressed in most human cancers including PDA but is not expressed in most normal adult tissues. To measure survivin transcript levels in normal pancreatic ducts, PanINs, and PDA, we used laser capture microdissection and real-time polymerase chain reaction. Survivin protein expression in normal pancreatic ducts, PanINs, PDA, and its metastases to lymph nodes were evaluated by immunohistochemistry. In microdissected tissues, we found a steady and close to exponential increase in survivin transcript levels from low-grade lesions (PanINs-1) to high-grade lesions (PanINs-2 and 3) and further to PDA. This observation was strictly mirrored by survivin protein expression. In addition, survivin was localized to the nucleus in high-grade lesions (starting at PanIN-2 stage), PDA, and nodal metastases, suggesting that nuclear translocation of survivin may be an early event in transformation to malignancy.
 ...
PMID:Survivin expression in pancreatic intraepithelial neoplasia (PanIN): steady increase along the developmental stages of pancreatic ductal adenocarcinoma. 1672 55

Inhibition of apoptosis is a critical step in tumorigenesis in many cancers, including Merkel cell carcinoma; however, the exact regulatory mechanisms are not fully understood. Survivin is an inhibitor of apoptosis that is undetectable in most terminally differentiated normal human tissues, strongly expressed in embryonic and fetal organs and is strongly expressed in many different human cancers. In this study, we investigated the expression of survivin in cutaneous Merkel cell carcinoma using immunohistochemistry and correlated the findings with long-term clinical follow-up. We collected and immunostained 19 cases of Merkel cell carcinoma with antibodies to survivin. The median patient age was 79 years, with an average follow-up of 17 months, and a male/female ratio of 7:11. All but one sample represented primary lesions and two cases were obtained from one patient. Clinical follow-up was obtained in 15 cases (79%). All 19 cases of Merkel cell carcinoma demonstrated strong immunoreactivity for survivin. Survivin protein was localized and classified into predominately nuclear (N=8) or cytoplasmic (N=4) compartments. A mixed pattern of survivin expression was also seen in three cases. Cases with a nuclear staining pattern were distinguished by an aggressive clinical course, with seven of eight patients developing metastases or dead of disease on follow-up. Furthermore, all of the cases with predominately cytoplasmic survivin localization (N=4) were free of disease on follow-up. Merkel cell carcinomas represent aggressive malignancies regulated by apoptotic pathways. We demonstrate that survivin, a protein with a dual role in inhibition of apoptosis and regulation of cellular proliferation is expressed in Merkel cell carcinoma. Moreover, nuclear subcellular localization of survivin in Merkel cell carcinomas may portend a poor prognosis and identification of these cases may assist clinical management.
 ...
PMID:Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma. 1842 79


1 2 3 Next >>