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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory fibrosarcoma (commonly referred to as inflammatory myofibroblastic tumor) has become increasingly recognized as part of a spectrum of inflammatory myofibroblastic proliferations. It is a potentially locally aggressive myofibroblastic tumor that occurs predominantly in the mesentery of children and young adults. No reliable morphological parameters have been identified that predict prognosis. We evaluated the ultrastructural and immunophenotypic features of 16 cases of inflammatory fibrosarcoma and studied Ki67 (MIB1), PCNA, bcl-2, and p53 in an effort to identify prognostic markers. p53 was not detected immunohistochemically in any case. None of the markers were found to correlate with local recurrences, metastases, or tumor deaths. Low proliferative activity (Ki67 < 10%) was seen in all cases. A characteristic immunophenotype was reconfirmed in which lesional myofibroblasts stained for vimentin, alpha-smooth muscle actin, cytokeratins, and rarely desmin. Ultrastructural studies of seven cases confirmed the presence of a fibroblastic-myofibroblastic spectrum. Because inflammatory myofibroblastic tumor-inflammatory fibrosarcoma is associated with systemic symptoms, polymerase chain reaction studies for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were performed in 12 cases. Evaluable results in nine cases did not show evidence of either virus. The results of this study indicate that inflammatory fibrosarcoma has a low proliferative activity, which is in keeping with the impression that this is a low-grade sarcoma; that myofibroblasts can participate in true neoplasia; and that EBV and CMV do not play a role in the pathogenesis of inflammatory fibrosarcoma. The variable phenotype of the myofibroblast and its role in reactive and neoplastic processes are discussed. A perspective on the position of inflammatory fibrosarcoma in the spectrum of inflammatory myofibroblastic tumors is also given in light of the current study and the literature.
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PMID:Inflammatory fibrosarcoma: update, reappraisal, and perspective on its place in the spectrum of inflammatory myofibroblastic tumors. 960 4

We investigated immunohistochemically the clinical relevance of the over-expression of the apoptosis-regulating proteins p53 and bcl-2 in a homogeneous series of 149 laryngeal squamous-cell carcinomas. p53 was over-expressed in 75 cases and bcl-2 in 39 cases. p53 and bcl-2 co-expression was found in 21 cases. p53 and bcl-2 immunoreactivity was significantly associated with poor histological differentiation and lymph-node metastases. Moreover, a significant statistical correlation was found between bcl-2 expression, supraglottic tumor site and advanced disease stage. p53/bcl-2 co-expression was significantly associated with poor differentiation, tumor extension, the presence of lymph-node metastases and advanced clinical stage. Univariate analysis showed that a lower probability of survival was significantly associated with supraglottic site, tumor extension, advanced clinical stage and p53/bcl-2 co-expression, but not with p53 or bcl-2 considered separately. In multivariate analysis, only tumor extension and supraglottic site retained their prognostic value. Our data suggest that clinical staging remains the most reliable predictive indicator of survival in patients with laryngeal carcinoma.
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PMID:Clinical relevance of p53 and bcl-2 protein over-expression in laryngeal squamous-cell carcinoma. 964 48

Biopsy specimens from 12 patients with metastatic melanoma were longitudinally analysed to evaluate changes in proliferation activity and CD4+/CD8+ ratios during the course of the disease. The primary tumours of the patients who subsequently had metastatic disease were also each matched with tumours from two controls whose disease remained localized, and were compared with regard to tumour proliferation. Immunohistochemistry was performed using the avidin-biotin complex (ABC) immunoperoxidase technique, using bcl-2, p53, mdm-2 and Ki-67 as the primary monoclonal antibodies, and the percentage of positively stained melanocytic cells was calculated. Frozen sections were also available from metastatic lesions excised from eight of our patients before treatment initiation and at the time of disease progression. These specimens were prepared for microscopy, and quantitative characterization of CD4+ (OKT 4a) and CD8+ (OKT 8) cells was performed. Compared with the localized melanomas bcl-2 expression was higher in those primary melanomas that later metastasized (P = 0.068, Wilcoxon; P = 0.038, median test). Mdm-2 and Ki-67 expression did not differ in the primary tumours of patients and controls, but a statistically significant trend was observed towards increasing expression with the progression of the disease (two-sided exact P-values: 0.04 and 0.05, respectively). Patients with a low Ki-67 index in their first metastasis had a better prognosis when compared with patients with high indexes (P = 0.008, log-rank). Furthermore, most patients with decreasing CD4+/CD8+ ratios had increasing p53 immunoreactivity. Our findings suggest that Ki-67 and bcl-2 may be useful for predicting the prognosis of melanoma patients. Mdm-2 is a new but promising marker in melanoma and deserves further evaluation.
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PMID:Prognostic value of biomarkers in malignant melanoma. 966 52

In a retrospective case-control study on 46 metastasized and 34 non-metastasized primary tongue carcinomas, the nuclear morphology and chromatin pattern were assessed in 3 microns thick, formalin-fixed, paraffin-embedded, and Feulgen-stained tissue sections of surgical resection specimens, by means of high-resolution computer-assisted image analysis. The aim of this study was to disclose differences in karyometric features, such as nuclear size-, shape-, and chromatin-pattern features, between these groups, with a view to developing a discriminant function that can predict the occurrence of metastasis for the individual patient. In addition, the lymph node metastases of 31 patients and the normal tongue epithelium of 21 patients were also assessed, to study the possible differences between these two groups and primary tumours. In the metastasized tumours, the chromatin was significantly more condensed (P = 0.01) and exhibited significantly less variation in chromatin condensation (P < 0.001) than in the group of non-metastasized carcinomas. Comparison of lymph node metastases with their primary tumours disclosed only minor differences in chromatin pattern. These findings suggest that only minor genetic differences exist between primary tongue carcinomas and their metastases. Tumour cells of tongue carcinomas showed highly significant differences from cells of normal tongue mucosa for most karyometric features. Logistic regression analysis resulted in a classifier, based on the circularity of the nucleus (CIRC) and the standard deviation of the chromatin condensation (SD COND), to predict the occurrence of lymph node metastases. After cross-validation, the percentages of correct classifications in the group of metastasized and non-metastasized tumours were 72 and 62 per cent, respectively. These results are comparable to the classification results obtained from a classifier based on the clinical T-stage, but our karyometric classification results show a much more equal distribution between the sensitivity and specificity. Karyometric features appeared to be more appropriate to predict metastases than biomarkers such as p53, bcl-2, and Ki-67.
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PMID:An image analysis study on nuclear morphology in metastasized and non-metastasized squamous cell carcinomas of the tongue. 971 44

The extracellular microenvironment of tumors differs from most normal tissues. Many tumors have relatively acidic extracellular pH (pHe), although the intracellular pH (pHi) of tumor cells remains normal due to efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms which regulate pHi, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the anti-apoptotic gene bcl-2 and its pro-apoptotic binding partner bax, the Stress Activated Protein Kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. While expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its pro-apoptotic function. Inhibition of SAPK, through expression of a dominant negative mutant of its activator, SEK1 protected cells from acid-induced cell death. Caspase activation, as measured by poly (ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of ICE proteases by the peptide z-VAD.fmk did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
Cancer Metastasis Rev 1998 Jun
PMID:Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. 977 Jan 20

Precise quantitation of apoptotic cells in solid tumors is necessary to determine the role of apoptosis in cancer growth, prognosis, and treatment. In this study, the intensity of apoptotic death was determined in 91 breast carcinomas with a novel cellular marker of apoptosis based on the staining of histological sections with a monoclonal antibody (MAb) to single-stranded DNA. Staining of apoptotic cells with the MAb reflected the decreased thermal stability of DNA induced by the digestion of nuclear proteins, as demonstrated by the elimination of staining in sections reconstituted with histones before heating. The high sensitivity and specificity of apoptosis analysis with the MAb is based on the central role of protease activation in the mechanism and control of apoptosis. Apoptotic indexes (AIs) in breast carcinomas ranged between 0 and 46%. Most of the carcinomas had relatively low AIs, whereas 29 cases were classified as carcinomas with intensive apoptosis (AI >/= 10%). The high level of apoptotic cell death was associated with negative immunostaining for bcl-2 protein, the loss of estrogen and progesterone receptors, high proportion of cells in S-phase, and increased risk of lymph node metastases. There was no correlation between AI and tumor size or p53 immunostaining. Lymph node metastases were detected in 59% of patients with high levels of apoptosis in primary carcinomas and in only 21% of patients with AIs below 10% in primary carcinomas. Thus, the high sensitivity of the MAb assay made it possible to identify a subset of breast carcinomas with intensive apoptosis and markers of poor prognosis. These results demonstrate that the measurement of apoptosis in breast carcinomas provides valuable prognostic information.
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PMID:Apoptosis in breast carcinomas detected with monoclonal antibody to single-stranded DNA: relation to bcl-2 expression, hormone receptors, and lymph node metastases. 981 6

The frequency of bcl-2 protein expression was evaluated using immunocytochemical staining during the progression of human and rat prostate cancer from an androgen-sensitive nonmetastatic to an androgen-independent metastatic phenotype. Previous studies (A. S. Shabaik et al., J. Urol. Pathol., 3: 17-27, 1995) demonstrated that 0 of 20 high-grade prostatic intraepithelial neoplasias and only 3 (7%) of 41 pathologically localized stage B human prostatic cancers had detectable bcl-2 staining. In the present study, 5 (17%) of 30 lymph node metastases from pathologically disseminated D1 disease and 14 (52%) of 27 bone metastases from pathologically disseminated D2 disease expressed detectable bcl-2 protein. These data demonstrate that there is a statistically significant (P < 0.05) association between expression of bcl-2 and the progression of human prostatic cancer cells to a metastatic phenotype. Such bcl-2 expression is not absolutely required, however, for either androgen independence or metastatic ability by human prostatic cancer cells. Likewise, within a series of eight distinct Dunning R3327 rat prostatic cancer sublines, which differ widely in their progressional state, there is also a significant association (P < 0. 05) between bcl-2 expression and progression (four of six androgen-independent rat sublines expressed bcl-2 protein). Again in this rodent system, bcl-2 expression is not an absolute requirement for either androgen independence or metastatic ability. For example, the androgen-independent highly metastatic Dunning AT-3 subline, while expressing bax protein, does not express bcl-2 protein. If such AT-3 cells are genetically engineered to express bcl-2, these expressing cells are now cross-resistant to a variety of mechanistically diverse noxious insults (e.g., viral infection or exposure to antimetabolites, alkylating agents, or agents which elevate the intracellular free Ca2+). The ability of bcl-2 to inhibit the programmed death of AT-3 cells induced by these agents involves a late step in the death process, since the early induction of expression of a series of genes associated with apoptosis is not impaired by bcl-2 expression. These data demonstrate that the development of androgen independence and/or metastatic ability can be associated with the expression of bcl-2 protein but that bcl-2-independent mechanisms also exist for such progression.
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PMID:Expression of bcl-2 and the progression of human and rodent prostatic cancers. 981 82

Extensive study of Bcl-2 protein expression in prostate cancer (CaP) tissues by means of immunocytochemistry (IC) has provided evidence that it positively correlates with high grade and stage of CaP and is associated with resistance to anti-androgen hormone therapy. In the present study, we investigated the expression of bcl-2 mRNA by non-isotopic in situ hybridization (ISH) in a series of 36 CaP with or without previous anti-androgen hormone treatment and performed a comparison with IC-detected Bcl-2 protein expression. Expression of Bcl-2 mRNA detected by ISH consistently differed from that detected by IC, especially in lymph node metastases (whereas no relevant variations of Bcl-2 mRNA levels were found in treated vs. untreated CaP patients). In particular, high content of Bcl-2 mRNA was found in 25/36 cases of CaP (in 13/18 hormone-treated and 12/18 untreated patients). Conversely, Bcl-2+ immunostaining was observed in only 7/36 CaP (in 4/18 hormone-treated and 3/18 untreated patients). Furthermore, ISH revealed Bcl-2 mRNA in 4/7 lymph node metastases, all 7 of which were Bcl-2(-) by IC. We conclude that, in the absence of a demonstrated post-transcriptional control of the bcl-2 gene, detection of mRNA by ISH in prostate archival tissues appears to be a reliable alternative method to assess differential expressions of the bcl-2 gene.
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PMID:Discrepancies between detection of Bcl-2 by in situ hybridization and immunocytochemistry in human prostate cancer tissues. 984 70

Apoptosis (programmed cell death) inhibition may be an important mechanism by which gastrointestinal mucosal cells containing damaged DNA evade normal clearance mechanisms and grow to become invasive tumours. Since bcl-2 is an apoptosis inhibitor, bcl-2 mRNA expression was measured in 21 metastases of colorectal cancer using reverse transcription-polymerase chain reaction analysis. The mean bcl-2 mRNA expression (0.45 U, P < 0.0001) was lower than that of normal mucosal controls (= 1 U). p53 expression was inversely correlated with bcl-2 expression (P = 0.021) in 19 evaluable samples, and in tumours where p53 expression was over twice that of normal colonic mucosal values, bcl-2 mRNA was significantly decreased (mean 0.30, P = 0.0052). c-myc was also inversely correlated with bcl-2 expression (P = 0.025). Decreased bcl-2 expression in metastatic colorectal cancer may be partly due to allelic loss, given the proximity of bcl-2 to the frequently deleted DCC gene on chromosome 18q. However, the inverse correlation to p53/c-myc suggests an active downregulation of bcl-2, possibly following delegation of its apoptosis inhibiting role to other genes.
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PMID:bcl-2 expression is reciprocal to p53 and c-myc expression in metastatic human colorectal cancer. 984 90

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
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PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25


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