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

Despite the steadily increasing number of patients suffering from squamous cell carcinomas of the oropharyngeal region, little is known about the molecular steps involved in the induction of these neoplasms. The aim of this study was to determine the incidence and type of p53 mutations in oropharyngeal squamous cell carcinomas. Five of 38 patients had lymph node metastases, three patients had multiple primary carcinomas and two patients presented with multiple primary tumours and lymph node metastases. Exons 5 through 8 of the p53 gene were screened by single-strand conformation polymorphism analysis followed by direct DNA sequencing. A total of 16 tumours (42%) contained point mutations scattered throughout exons 5 to 8. Most mutations (56%) were transitions, predominantly G-->A. G-->T mutations prevailed among the transversions that have also been found in smoking-related lung cancer. One carcinoma of the soft palate showed a mutation which was retained in a lymph node metastasis. The status of p53 differed in primary carcinomas of patients with multiple tumours indicating an independent generation of these neoplasms. The frequent occurrence of p53 mutations in oropharyngeal carcinomas supports the view that this gene plays a role in initiation or progression of the malignant phenotype.
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PMID:p53 mutations in oropharyngeal carcinomas: a comparison of solitary and multiple primary tumours and lymph node metastases. 753 94

To study the interactions between dominantly acting oncogenes and tumor suppressor genes we used p53 'knockout' mouse urogenital sinus tissue for retroviral transduction of ras and myc in the mouse prostate reconstitution (MPR) model system. Epithelial hyperplasia was observed in all wild-type p53 MPRs with one small focal cancer and no evidence of metastasis. Prostatic cancer was found in 100% of the heterozygous and homozygous p53 mutant MPRs with metastatic deposits in 95% of the mice. The pattern of metastasis was remarkably similar to that in human prostate cancer with gross metastatic deposits in the lung, lymph nodes, bone and liver of many animals. Progression of carcinomas in the ras+myc-initiated heterozygous p53 mutant MPRs was invariably associated with either complete loss, partial deletion or loss of expression of the wild-type p53 allele. Southern blotting analysis of proviral-cellular DNA junction fragments in primary carcinomas and cell lines derived from metastatic deposits revealed that metastases do not necessarily seed out from the most abundant clone in the primary carcinoma.
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PMID:Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. 753 99

Activation of cellular oncogenes and inactivation of anti-oncogenes have been postulated as important mechanisms during hepatocarcinogenesis. This study was conducted to detect abnormal levels of several proto-oncogenes (c-jun, c-fos, c-H-ras) and of the p53 and the alpha-fetoprotein gene in the liver during cirrhosis, a pathological process which predisposes to the development of hepatocarcinoma. Liver tissue from 11 patients with cirrhosis of different etiologies, and seven histologically normal liver fragments taken at the periphery of benign liver tumors of metastases were studied. Transcripts of the various oncogenes and of the alpha-fetoprotein gene were detected by in situ hybridization, and the p53 protein was revealed by immunocytochemistry. No overexpression of any of the mRNA tested or of the p53 protein was found in histologically normal liver in contact with benign or metastatic tumors. In contrast, 10 of the 11 specimens with cirrhosis (90.9%) displayed abnormally high levels of c-H-ras transcripts. Five samples with cirrhosis revealed a moderate increase in the level of c-fos mRNA. Only one case and two cases, respectively, exhibited increased levels of c-jun and alpha-fetoprotein mRNA. No cases were positive for the p53 antigen. Liver-cell proliferation, as assessed by immunocytochemistry with the Ki 67 monoclonal antibody, was low in both the group with cirrhosis and the control groups (0.49% and 0.55% positive cells, respectively). These data demonstrate that activation of c-H-ras mRNA is an almost constant finding in hepatocytes of livers with cirrhosis. This gene overexpression is not linked to hepatocellular proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of ras oncogene in livers with cirrhosis. 753 24

We have investigated the expression of platelet-derived endothelial-cell growth factor/thymidine phosphorylase (PD-ECGF/dThdPase) in human breast-cancer tissues by the immunocytochemical method using anti-PD-ECGF/dThdPase monoclonal antibody. Out of 100 invasive-ductal-carcinoma tissue samples, 39 (39%) were evaluated as PD-ECGF/dThdPase-positive. The expression of PD-ECGF/dThdPase was identified mainly in the cytoplasma of tumor cells. The expression of PD-ECGF/dThdPase was significantly associated with the microvessel density assessed by immunostaining to factor-VIII-related-antigen (p < 0.05). However, there was no correlation between expression of PD-ECGF/dThdPase and menopausal status, tumor size, axillary lymph-node metastases, hormone-receptor status, epidermal-growth-factor receptor, or erb-B-2-protein and p53-protein expression. We suggest that expression of PD-ECGF/dThdPase plays an important role in the promotion of angiogenesis in human breast cancer.
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PMID:Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. 754 28

Histopathologic features alone fail to reliably stratify patients with clinical Stage A nonseminomatous germ cell tumors of the testis into groups with high and low risk for occult metastatic disease. Previous flow cytometric studies at Indiana University demonstrated a significant correlation between high proliferative activity and metastatic disease. The current study evaluated the prognostic significance of immunohistochemical markers related to tumor proliferation and aggressiveness in a consecutive series of clinical Stage A nonseminomatous germ cell tumors patients who underwent retroperitoneal lymph node dissection. Archival material of the orchiectomy specimens of 62 patients (45 pathologic Stage A, 17 with metastatic disease) was reviewed and immunohistochemically stained for Ki-67 antigen (MIB-1), proliferation-associated nuclear antigen (PC10), p53 protein (Pab1801), and Factor-VIII-related antigen (neovascularization). Staining with MIB-1 was significantly higher in the metastatic group (mean 80.2%, standard deviation [SD] 15.5) than in pathologic Stage A cases (66.3%, SD 27.9; P = 0.0032) and was predictive of metastatic status with a sensitivity of 82% and specificity of 69%. In this study, no patient with a MIB-1 value less than 52% had metastases. Proliferation-associated nuclear antigen and p53 staining correlated with MIB-1 values (R = 0.63 and 0.55, respectively) but did not correlate with metastatic status. Tumor angiogenesis was also not predictive of metastatic status. Assessment of proliferation rates using MIB-1 antibody in clinical Stage A nonseminomatous germ-cell-tumor patients may prove helpful in predicting metastatic status.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prognostic significance of immunohistochemical proliferation markers (Ki-67/MIB-1 and proliferation-associated nuclear antigen), p53 protein accumulation, and neovascularization in clinical stage A nonseminomatous testicular germ cell tumors. 754 14

Loss of function of one or both of the two tumour suppressor genes p53 and RB-1 has been recognised as an important step in the development of a variety of human neoplasias for some time. By virtue of the ability to manipulate the genome of murine embryonic stem cells in culture, it has become possible to generate strains of mice which bear inactivations of the murine counterparts of these genes. This article attempts to bring together some of the many results obtained from these murine strains which are shedding light both on the normal role played by both of these genes and the consequences of their dysfunction. Surprisingly neither gene product is revealed to have an indispensable role at the level of the single cell. Hence, even though the Rb-1 gene product clearly has an important role in cell cycle regulation animals constitutively deficient in this gene develop relatively normally for the first 10 days of embryogenesis. It is only at and beyond this stage of development that a requirement for Rb-1 becomes clear, in the regulation of certain cell populations through control of both proliferation and apoptosis. That loss of function of Rb-1 is associated with tumorigenesis is confirmed by the development of tumours of the pituitary gland within heterozygotes. The retinas of these animals, the target organ for tumorigenesis in human RB-1 heterozygotes, remain unaffected. The majority of mice homozygous for an inactivating p53 mutation survive to birth, but then rapidly succumb to tumorigenesis. Heterozygotes also develop tumours, but with a delayed time course and altered spectrum. Analysis of several tissue types from the mutant animals has shown p53 to be crucial for the normal induction of apoptosis following DNA damage, and it is thought that failure of this process is a key predisposing step towards tumorigenesis within the mutant animals. Finally, studies on these and other transgenic strains have revealed interactions between pathways governed by these two genes. For example, the fate of Rb-1 deficient cells has been shown, in some tissues at least, to be dependent upon the functional status of p53.
Cancer Metastasis Rev 1995 Jun
PMID:Murine models of neoplasia: functional analysis of the tumour suppressor genes Rb-1 and p53. 755 30

One of the most commonly detected abnormalities in human cancer is mutation of the p53 tumour suppressor gene. Intrinsic to the function of p53 is its ability to induce apoptotic cell death and to cause cell cycle arrest. Moreover, p53 plays an important role in controlling the cellular response to DNA damaging agents such as ionizing radiation and cancer chemotherapeutic drugs. Loss of p53 function causes increased resistance to radiation and chemotherapeutic agents, and there is increasing evidence that p53 mutational status is an important determinant of clinical outcome in cancer. This review will focus on recent data describing the biochemistry of p53 function, its role in mediating apoptosis and cell cycle arrest and in the control of tumour growth and death.
Cancer Metastasis Rev 1995 Jun
PMID:Apoptosis, cancer and the p53 tumour suppressor gene. 755 31

The synthetic dithiolethione Oltipraz has marked cancer chemopreventive and phase II enzyme inducing activity in various animal carcinogenesis models, but has not been examined in any animal models of ductal pancreatic cancer relevant to the human disease. The chemopreventive potential of Oltipraz on pancreatic tumor incidence and multiplicity was examined in the N-nitrosobis(2-oxopropyl)-amine (BOP)-induced ductal pancreatic adenocarcinoma model in Syrian hamsters. Animals were maintained on control semipurified diets or semipurified diets containing 300 and 600 mg/kg Oltipraz beginning 2 weeks prior to BOP initiation and throughout the 26 week study. Oltipraz at 300 mg/kg had no effect on the incidence or multiplicity of preneoplastic, neoplastic or metastatic lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancreatic adenocarcinomas was reduced significantly (P < or = 0.05) compared to BOP-treated controls. Dietary Oltipraz at both doses had a significant influence on reducing mortality and morbidity in tumor-bearing animals with metastatic disease. At 26 weeks, total hepatic glutathione-S transferase (GST) activity and GST mu activity were elevated significantly in Oltipraz-treated animals, while total pancreatic GST activity was reduced, albeit not significantly. Serum lipase activity, a marker for pancreatic damage, exhibited a progressive decline in BOP-treated animals administered Oltipraz compared to BOP-treated controls at 12 weeks of the study; by week 26, lipase activity was comparable in all groups and reduced compared to activity at week 12. Positive nuclear immunostaining for the p53 tumor suppressor protein, a hallmark of human pancreatic cancer and a transient response to DNA damage, was observed in only a small percentage of BOP-induced pancreatic lesions and was not influenced Oltipraz administration. Further chemoprevention and pharmacologic studies of Oltipraz in relevant animal models of ductal pancreatic cancer could provide a foundation for future studies in human populations at potential risk for pancreatic cancer.
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PMID:Chemopreventive activity of Oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters. 755 69

The tumor suppressor protein, p53, protects somatic cells against the accumulation of genomic alterations. Cells harboring mutant or inactivated wild-type p53 protein are at risk for the development of genomic instability. Nuclear accumulation of p53 protein is associated with the stepwise dedifferentiation of papillary carcinoma. We asked whether nuclear p53 accumulation is associated with two known indicators of poor prognosis in papillary carcinoma. We studied 55 consecutive papillary cancers (28 from Russia, and 27 from upstate New York). Nuclear p53 immunoreactivity was assessed using a monoclonal antibody, DO-1, on Formalin-fixed paraffin-embedded specimens. The DNA index was determined by computerized image analysis of Feulgen-stained sections. Nearly all cases were well differentiated and none were associated with distant metastases or extrathyroidal invasion. All primary lesions were less than 4 cm in diameter, and almost all patients were female. Nuclear p53 immunoreactivity was associated with a high-risk group characterized by two known indicators of poor prognosis: age > 50, aneuploid DNA content, or both. In the high-risk group (N = 24) 33% of cases displayed nuclear p53 positivity, compared with only 6% in a low-risk group (N = 31) which lacked both features (P = 0.015, two-tailed Fisher exact test). Nuclear accumulation of immunoreactive p53 protein is associated with two established indicators of poor prognosis in papillary carcinoma of the thyroid. This result is consistent with the idea that aberrations in p53 function are associated with the stepwise loss of differentiation in this cancer.
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PMID:Nuclear p53 immunoreactivity in papillary thyroid cancers is associated with two established indicators of poor prognosis. 755 91

We established a panel of 17 xenografts from primary human breast carcinomas. We examined which characteristics of the original tumours and the xenografts facilitate growth in animals. Tumours expressing medium or strong immunoreactivity for p53 protein had significantly (P < 0.05) higher incidence (92%) of in vivo tumour take than those showing weak or negative immunoreactivity (9.1%). No such association was observed between either c-erbB-2 or epidermal growth factor receptor (EGFR) expression in the original tumours and their in vivo tumour take. Following subcutaneous (s.c.) transplantation of original breast tumours or established xenografts, 7/17 tumours showed metastatic disease spread to distant sites (mainly lungs). This study suggests that selective growth of highly aggressive tumours occurs during in vivo propagation of malignant tumours, and these tumours will be of particular interest in evaluating various chemotherapeutic agents for breast cancer management.
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PMID:Overexpression of mutant p53 and c-erbB-2 proteins and breast tumour take in mice. 757 62


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