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)

Overexpression of the anti-apoptotic proteins bcl-2 and bcl-xL is implicated in breast cancer development, tumor progression and drug resistance. Here we describe the use of the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 to sensitize breast carcinoma cells to anti-cancer drugs routinely used in breast cancer therapy. MCF7 cells were treated with oligonucleotide 4625, doxorubicin, paclitaxel or cyclophosphamide alone, or with combinations of oligonucleotide and the anti-cancer drugs. As measured in cell viability assays, treatment with the various combinations reduced the number of viable MCF7 cells more effectively than treatment with the single drugs alone. Treatment with a sequence control oligonucleotide did not affect cell viability. All combination treatments induced apoptosis as demonstrated by the appearance of massive nuclear condensation in a high proportion of the cells. To further characterize the interaction between 4625 and doxorubicin, paclitaxel or cyclophosphamide, the median-effect method was used. In MCF7 cells all combinations resulted in potent synergistic effects over a broad range of toxicity with combination indices ranging from 0.8 to 0.1. Similarly, strong synergistic interactions between oligonucleotide 4625 and the anti-cancer drugs were also observed in cultures of the breast carcinoma cell line MDA-MB-231. Our data suggest the use of 4625 as a potent adjuvant in breast cancer chemotherapy.
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PMID:Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. 1245 53

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.
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PMID:Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. 1275 37

Apoptosis is one of the critical biological factors that correlate with the biological behavior of malignant tumors including cancer progression and clinical outcome. The present study was performed to clarify the clinical implications of BAG-1, a bcl-2 binding protein in esophageal squamous cell carcinoma (ESCC). Seventy-one cases with ESCC were investigated. Immunohistochemical study of BAG-1 was performed on resected specimens. The expression pattern of BAG-1 in nuclei and/or cytoplasm was analyzed and correlated with TNM classification, vessel invasion, survival period after surgery. BAG-1 expression in the nuclei was related to the depth of tumor invasion (P = 0.0381) but not to any other clinicopathologic parameters. The cytoplasmic staining pattern of BAG-1 exhibited no correlation with clinicopathologic parameters. Univariate analysis (P < 0.05), but not multivariate analysis, revealed significantly poor prognosis for ESCC cases exhibiting positive nucleic staining for BAG-1. Our data suggests that BAG-1 expression in the nuclei of ESCC plays an important role in tumor development and may be useful for predicting the prognosis after surgery.
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PMID:Nuclear BAG-1 expression is a biomarker of poor prognosis in esophageal squamous cell carcinoma. 1282 8

Ku70/80 nonhomologous end-joining activity is essential for resolving random DNA double-strand breaks, and the Ku70/80 protein complex has been proposed as "caretaker" of genomic stability. We studied the Ku70/80 heterodimer activity in a patient affected by multiple basal cell carcinomas with a personal history of moderate exposure to ionizing radiation. The Ku70/80 DNA-binding activity was analyzed, by electrophoretic mobility shift assay, in five tumor biopsies from different sites and at distinct clinical stages, and in three matched normal skin samples from the same patient. As control normal tissues from healthy individuals were also tested. The five basal cell carcinomas were classified as "non aggressive" and "aggressive" on the basis of morphologic parameters and expression of the molecular markers bcl-2, Ki67/MIB1, and p53. A 62% increase in the Ku70/80 DNA-binding activity was found in normal skin from the patient, compared to unexposed individuals (p<0.0001). The nuclear activity of the heterodimer was further increased in nonaggressive basal cell carcinomas compared to both matched normal skin from the patient (31%, p=0.0001) and tissues from healthy controls (73%, p=0.0001). Strikingly, the two aggressive basal cell carcinomas tested showed very low Ku70/80 DNA-binding activity with a reduction of 87% compared to normal skin from the patient (p<0.0001) and 64% compared to controls (p=0.001). Although these results are limited to only one patient, together with other recent studies they support the hypothesis that downregulation of the nonhomologous end-joining pathway may be associated with tumor progression.
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PMID:Differential modulation of Ku70/80 DNA-binding activity in a patient with multiple basal cell carcinomas. 1292 25

Apoptosis plays a central role in the development and/or progression of cancer. There are several methods for detection of apoptotic cells in tissue sections including light and electron microscopy, in situ nick end-labeling (ISEL), TdT-mediated dUTP nick-end labeling (TUNEL) and immunohistochemical detection of proteins associated with apoptosis. Apoptosis was assessed by the monoclonal antibody M30 CytoDEATH (M30), which is specific for neo-epitope in cytokeratin 18 that becomes available at an early caspase cleavage during apoptosis. Expression of bcl-2 protein was evaluated, because bcl-2 protein plays an important role in the regulation of apoptosis. Twenty-six invasive ductal adenocarcinomas of the pancreas were studied immunohistochemically with antibodies M30 and bcl-2. The mean apoptotic index (AI, the percentage of apoptotic cells of the total tumor cells number) was 2.75%. High AI (> 10%) was observed in 4 cases of the 26 pancreatic carcinomas (15%). Protein bcl-2 was expressed in 3 cases (11.5%). The AI did not correlate with the expression of protein bcl-2. In conclusion, the detection of neo-epitope in cytokeratin 18 by monoclonal antibody M30 can be used for quantification of apoptotic cells with immunohistochemical techniques in tissue sections. It is a new approach to evaluate apoptosis in pancreatic carcinomas. The low positivity of bcl-2 expression in pancreatic adenocarcinomas suggests that bcl-2 protein does not play a central role in pancreatic tumorigenesis and cancer progression.
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PMID:[Apoptosis and expression of bcl-2 protein in invasive ductal adenocarcinoma of the pancreas]. 1466 27

Lethal phenotypes of human prostate cancer are characterized by progression to androgen-independence and metastasis. For want of a clinically relevant animal model, mechanisms behind this progression remain unclear. Our study used an in vivo model of androgen-sensitive LNCaP human prostate cancer cell xenografts in male SCID mice to study the cellular and molecular biology of tumor progression. Primary tumors were established orthotopically, and the mice were then surgically castrated to withdraw androgens. Five generations of androgen-independent tumors were developed using castrated host mice. Tumor samples were used to determine expressions of cellular and molecular markers. Androgen-independent tumors had increased proliferation and decreased apoptosis compared to androgen-sensitive tumors, outcomes associated with elevated expression of p53, p21/waf1, bcl-2, bax and the bcl-2/bax ratio. Blood vessel growth in androgen-independent tumor was associated with increased expression of vascular endothelial growth factor. Overexpression of androgen receptor mRNA and reduced expression of androgen receptor protein in androgen-independent tumors suggest that the androgen receptor signaling pathway may play an important role in the progression of human prostate cancer to androgen-independence. The in vivo orthotopic LNCaP tumor model described in our study mimics the clinical course of human prostate cancer progression. As such, it can be used as a model for defining the molecular mechanisms of prostate cancer progression to androgen-independence and for evaluating the effect of preventive or therapeutic regimens for androgen-independent human prostate cancer.
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PMID:Progression to androgen-independent LNCaP human prostate tumors: cellular and molecular alterations. 1517 Jun 60

Transitional cell carcinoma of bladder (TCC) is a relatively common cancer among men. Tumor progression is associated with expression or modulation of several gene products that control apoptosis and proliferation. Apoptosis is a negative growth regulatory mechanism in tumors. The aim of this study is to examine apoptosis and related regulatory molecular markers in a group of patients with TCC. Paraffinembedded tissues from 49 patients with TCC were examined for the expression of bcl-2, p53 and Ki-67 by immunohistochemistry. Apoptosis was detected by TUNEL method. Correlation between apoptotic index (AI), proliferation index (PI) and bcl-2 and p53 expression with each other and with pathological grade was determined. Apoptosis was observed in 28.1% of TCC cases. The mean AI of all cases was 13.7+/-24. No correlation was found between apoptosis and differentiation status of carcinoma. Bcl-2 expression was weakly detected in only one sample. P53 expression was detected in 26 of cases with mean staining index of 102+/-96. A significant correlation between p53 and Ki-67 staining indices was observed (r=0.521, p=0.001). Both p53 and Ki-67 expression showed a good association with the pathological grade (p=0.0001 and p=0.004, respectively). None of the markers showed significant correlation with AI and no correlation was found between the ratio of AI to PI and other parameters either. In conclusion, the frequency of apoptosis in TCC of bladder appears not to be associated with tumor grade, and with bcl-2, p53 and Ki-67 expression.
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PMID:Apoptosis in transitional cell carcinoma of bladder and its relation to proliferation and expression of p53 and bcl-2. 1544 51

Bcl-2, the protein product of the Bcl-2 gene, is a member of the Bcl-2 family of proteins that play a crucial role in a complex mechanism of apoptosis. It was recently proposed that bcl-2 could inhibit cancer progression. In this study, we evaluated the expression patterns of Bcl-2, estrogen receptors (ER), progesterone receptors (PR) in 71 primary invasive breast carcinomas and their association with other clinicopathological parameters. Samples from 71 patients with invasive breast cancer with follow-up ranging from 4-103 months (median 57 months) were included in the study. Forty-six patients (66%) obtained a complete response, while 5 (9%) were considered non-responders during the follow up period of 103 months. Eighteen (25%) patients died, 15 (21%) from primary disease and 3 (4%) from other disease. In unvaried analysis, tumor size (<2 cm), lymph node (<4 lymph nodes), hormonal status and Bcl-2 expression are correlated with longer overall (OS) and relapse-free survival (RFS). Patients with 4 or more positive axillary lymph nodes had significantly shorter OS (p=0.01) and RFS (p=0.009). Higher expression of Bcl-2 was associated with longer OS (p=0.02) and RFS (p=0.03), and this result were independent of axillary lymph nodes and tumor size in Cox multivariate analysis.
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PMID:The Bcl-2 protein: a prognostic indicator strongly related to ER and PR in breast cancer. 1562 88

Adenoid cystic carcinoma (ACC) is an indolent tumor that pursues a protracted clinical course with recurrences and late metastases. The aim of this study was to investigate immunohistochemically the expression of p53, bcl-2 protein, and Ki-67 in 21 cases of ACC of the palate, all with a minimum of 10 years and a maximum of 22 years of clinical follow-up. These results were also analyzed with regard to different clinical prognoses of the histologic subtypes of ACC. High expression of p53 and bcl-2 was noted in 19 out of 21 ACC cases (90%), in which most tumor cells (from 66% to 99%) proved to be immunopositive. A relation to the histologic types, clinical staging, and survival was not found. Therefore, the high immunoreactivity against these oncoproteins in the same tumor cells suggests that these two oncogenes may be involved since the early stage of carcinogenesis. Loss of function of the p53 protein combined with bcl-2 upregulation might give the tumor cells a double growth advantage, because uncontrolled proliferation is combined with a reduced cell death rate. The interaction with other oncogenes may then trigger a multistep process able to promote tumor progression. The low labeling index Ki-67 was detected in nine out of 21 cases (42%), with a low percentage of tumor cells (from 3% to 15%) being positive, whereas the remaining 12 cases were negative. We found no relation to the histologic types, clinical staging, and survival; however, the low proliferation rate could explain the natural course of tumor.
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PMID:P53, bcl-2 and Ki-67 expression in adenoid cystic carcinoma of the palate. A clinico-pathologic study of 21 cases with long-term follow-up. 1579 22

In this study, we demonstrated that bcl-2 overexpression in human melanoma cells consistently enhanced the activity of multiple metastasis-related proteinases, in vitro cell invasion, and in vivo tumor growth. In particular, by using the M14 parental cell line, the MN8 control clone, and two bcl-2 overexpressing derivatives, we found that bcl-2 overexpressing cells exposed to hypoxia, when compared to parental cells, expressed higher level of several metalloproteases (MMPs) such as MMP-2, MMP-7, MT1-MMP, and tissue inhibitors of metalloproteases-1 and -2. Moreover, bcl-2 overexpression in melanoma cells enhanced in vitro invasion on matrigel and, in vivo tumor growth. The more aggressive behavior of bcl-2 transfectants tumors is significantly associated to an increase in MMP-2 expression as well as in a more elevated microvessel density as compared to the parental line. Taken together, our data suggest that bcl-2 plays a pivotal role in the regulation of molecules associated with the migratory and invasive phenotype, contributing, in cooperation to hypoxia, to tumor progression.
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PMID:Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. 1592 Jul 59


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