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)

Data obtained in experimental murine tumors and in clinical specimens of human breast cancer have suggested that the nm23 gene may function as a metastasis suppressor gene. In this report we examined the nm23 mRNA level in tumor tissue obtained from distant metastases in 33 patients with malignant melanoma. The gene was differentially expressed in the tumors with a 20-fold range in hybridization intensities. The levels of nm23 mRNA in benign nevi obtained from 12 of the 33 patients were relatively low, with a mean value of 17% of that in the melanomas. In attempts to relate the level of nm23 expression in the tumor metastases to progression of the disease, the time from biopsy of the primary tumor to the appearance of metastases was used as a clinical end point. It was found that patients developing metastases during the first 2 years after diagnosis had significantly lower levels of tumor nm23 expression (56% of the mean value) compared to patients with less aggressive disease (164%) (P < 0.0004). In concordance with previous data the association found here between low levels of nm23 mRNA and the malignant potential of melanomas suggests that the nm23 gene may be implicated in the mechanism of disease progression in some types of human cancer.
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PMID:Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression. 135 24

Tumour and metastatic phenotypes, the pattern of mouse mammary tumour virus (MMTV) integration and expression, and the expression of a metastasis associated gene, nm23, were examined in three mammary tumour cell subpopulations, 66, 168 and 4526. Tumour growth, host survival, metastatic aggressiveness, and the distribution of different cell types in metastasis resulting from mixed cell inocula were also analysed. The results of these studies indicated that the cell lines were distinguishable from each other both phenotypically and genotypically. However, a rearrangement of the mammary tumour specific protooncogene, int-1, caused by MMTV was found to be a unique characteristic of the cell line 4526. Therefore, int-1 was used as a stable marker to examine the genotype of the metastatic colonies that developed in mice bearing tumours of mixed cell inocula. Highly metastatic 4526 cells influenced the metastatic range of poorly metastatic 66 cells. Line 66 cells that normally colonize only to lungs were also found to colonize liver when inoculated together with the liver-metastasizing 4526 cells. This acquired metastatic phenotype of 66 cells was transient. On the contrary, mixed cell inocula of 4526 and non-metastatic 168 cells did not produce any colony of 168 cells. The metastatic aggressiveness of 4526 cells was inhibited by both 66 and 168 cells. Furthermore, the metastatic behaviour of mixed inocula differed depending on the relative abundance of the component populations in the mixtures. These findings suggest that interaction between cells of different metastatic phenotypes may result in changes of their metastatic behaviour.
Clin Exp Metastasis
PMID:Mixed inocula of mouse mammary tumour cell subpopulations result in changes of organ-specific metastasis. 175 81

In order to improve survival in a disease where the majority of deaths occur from metastases, the integration of systemic chemotherapy is crucial. Research efforts must continue to focus on refining case selection criteria, improving complete response proportions, and overcoming drug resistance. The blanket recommendation of a single therapeutic strategy such as radical surgery, chemotherapy, or radiation therapy to all patients is quickly becoming an outdated approach. Refinements in the understanding of the clinical, pathologic, and molecular features of urothelial tumors will ultimately improve case selection. Evaluation of NM23 RNA levels, or DNA ploidy and T138 surface antigen expression, which have been shown to correlate with metastatic potential, may hold important therapeutic implications. The use of hematopoietic growth factors has the potential to improve both the tolerance of chemotherapy and complete response proportions, a prerequisite for cure. A recent report from Japan of granulocyte colony-stimulating factor with MVAC and other chemotherapy regimens for urothelial tumors corroborated an initial report in reducing the duration of neutropenia. However, the dose response curves for most of the known active agents are not well defined and, ultimately, new agents and strategies will be required. Gallium nitrate, when administered by continuous intravenous infusion, has significant single agent activity in cisplatin-refractory patients with 9/31 responses (29%), including 6 CRs (19%) and further studies are warranted. Drug resistance remains a major obstacle, and as the mechanisms are unravelled, more rational therapies can be designed. For example, resistance to Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and vinblastine, two components in the MVAC regimen, are mediated in part by the MDR1 gene. Attempts are ongoing to identify prospectively those tumors with high levels of expression that may be more amenable to treatment with drugs that are not affected by this mechanism. The neoadjuvant approach allows an in vivo assessment of response to chemotherapy as well as the potential for bladder preservation. In most cases additional therapy directed at the primary is required as clinical understaging is a significant problem and pCR proportions are less than 30%. For some patients, initial surgery followed by treatment based on pathologic criteria may represent a better strategy. In these cases the recommendation for adjuvant treatment potentially limits therapy to a population of patients for whom therapy is essential. Based on available data, this would include patients with positive lymph nodes at the time of surgery. Ideally, patients with invasive bladder cancer should be entered into clinical trials designed to assess the impact of these strategies on survival.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The evolving role of chemotherapy for muscle infiltrating bladder cancer. 177 75

Expression of a recently identified murine gene, nm23, has been previously proposed to be inversely correlated to tumor metastatic potential in rodent model systems. The present study was designed to investigate whether nm23 RNA was detectable in human tumor tissue, and if it was differentially expressed. nm23 RNA levels in 27 human primary infiltrating ductal breast carcinomas were determined by using Northern blots or in situ hybridization. These data were compared to traditional histopathological indicators of metastatic potential, including the number of involved (tumor bearing) lymph nodes, grade of differentiation, and hormone receptor status. A striking consistency was observed in all tumors from patients with involved lymph nodes. Using Northern blot or in situ hybridizations, all of these tumors expressed low levels of nm23 RNA. Quantitative in situ hybridization on tumors from patients with 0 involved lymph nodes identified two groups: (a) approximately 75% contained high nm23 RNA levels, and (b) 25% contained significantly (alpha = 0.05) lower nm23 RNA levels. Low nm23 RNA levels in the 0 involved lymph node tumors were accompanied by two additional histopathological indicators of high metastatic potential, low nuclear and cytoplasmic estrogen receptor content, and poorly differentiated histological grade. In contrast, none of the high nm23 RNA level tumors were both receptor negative and poorly differentiated. We conclude that nm23 RNA levels are differentially expressed in human breast tumors, and that low nm23 RNA levels are associated with histopathological indication of high metastatic potential. Short term (median follow-up of 16 months) clinical course data were consistent with nm23 RNA levels, in that 2 of 11 low nm23 RNA content patients (including one from the 0 involved lymph node group) developed metastases, while none of the high nm23 RNA patients have experienced recurrent disease.
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PMID:Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. 247 43

Tumour metastasis is the principal cause of death for cancer patients. We have identified the nm23 gene, for which RNA levels are reduced in tumour cells of high metastatic potential. In this report we identify the cytoplasmic and nuclear Nm23 protein, and show that it also is differentially expressed in metastatic tumour cells. We also find that the human Nm23 protein has sequence homology over the entire translated region with a recently described developmentally regulated protein in Drosophila, encoded by the abnormal wing discs (awd) gene. Mutations in awd cause abnormal tissue morphology and necrosis and widespread aberrant differentiation in Drosophila, analogous to changes in malignant progression. The metastatic state may therefore be determined by the loss of genes such as nm23/awd which normally regulate development.
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PMID:Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development. 250 41

Cell fusion experiments have predicted the existence of cancer metastasis suppressor genes. The E1a gene of Adenovirus 2 has been demonstrated to suppress c-Ha-ras induction of experimental metastatic potential in rat embryo fibroblasts. Another approach to the identification of candidate metastasis suppressor genes has utilized differential or subtraction hybridizations to clone genes which are downregulated as cells become highly metastatic. To date, three such genes have been identified: nm23, WDNM1, and fibronectin. With regard to nm23, downregulation of nm23 RNA levels in high metastatic potential cells has been demonstrated in a wide variety of rodent metastasis systems, including K-1735 murine melanoma cell lines, nitrosomethylurea-induced rat mammary tumors, MMTV-induced mouse mammary tumors, and ras +/- E1a transfected rat embryo fibroblasts. Whether the expression of the nm23 gene, and other down-regulated genes in tumor metastasis, correlates with changes in metastatic potential, or actually has suppressive activity, will require transfection experiments.
Invasion Metastasis 1989
PMID:Search for metastasis suppressor genes. 253 85

Reduced expression of nm23/NDP kinase and increased expression of cathepsin D seem to be correlated with the high metastatic potential in a variety of malignancies. The expression of nm23/NDP kinase and that of cathepsin D have been evaluated by means of an immunohistochemical technique in paraffin-embedded tissues from 44 primary medullary carcinomas of the thyroid gland (MCT) and from the corresponding lymph node metastases in 32 of these cases. In addition, lymph node metastases from 4 cases were studied. We found that 36 of 44 (82%) primary and 26 of 36 (72%) lymph node metastatic MCT were nm23/NDP kinase positive, whereas 14 of the 44 (32%) primary and 17 of the 36 (47%) lymph node metastatic MCT were cathepsin D positive. We found no indication that the nm23/NDP kinase level has any prognostic significance in MCT. The cathepsin D level is close to being prognostically significant in this study, and we cannot exclude the possibility that it could be of prognostic value. However, it seems to be quite weak, and therefore of little use in a clinical situation.
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PMID:Immunohistochemical detection of nm23/NDP kinase and cathepsin D in medullary carcinomas of the thyroid gland. 749 99

Freshly resected human non-small cell lung cancer (NSCLC) has been successfully transplanted and propagated subcutaneously in nude mice (Cancer Letters 61 (1991) 53-60). We used this model to study the changes of the human metastasis suppressor genes, nm23-H1 and nm23-H2, through the process of propagation and metastasis of human NSCLC. Using a non-radioisotopic Southern analysis, the nm23-H1 and nm23-H2 genes were detected without evidence of deletion in the early generations of the tumor grafts. These genes, however, were absent from the tumor grafts sampled past 4 generations of propagation and from all the propagated metastases originated from the subcutaneous grafts. Further restriction analysis revealed that only mouse DNA, but no human Alu DNA, was present in the tumor specimens which lacked the human nm23 genes. Thus, there is a loss of human DNA but a gain of mouse DNA in the propagated tumors originated from the transplanted human NSCLC. The mechanisms of loss of human DNA in these propagated tumors in nude mice have yet to be delineated.
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PMID:Loss of nm23 and Alu DNA in human lung cancer propagated in nude mice. 749 58

The NM23 gene family (nm23-H1 and nm23-H2) has been reported as a measure of metastatic potential. The goal of this study was to discriminate nm23-H1 and nm23-H2 gene expression in benign and malignant human prostate tissue and to determine the relationship of their expression to tumor stages. Specimens included 5 benign prostatic hyperplasias (BPH), 11 primary prostate adenocarcinomas (CaP) (5 stage B, 5 stage C and 1 stage D1), 2 pelvic lymph nodes with metastases and 3 prostate cancer cell lines derived from metastatic lesions. Polymerase chain reaction analysis of mRNA (RNA/PCR) was used to amplify transcripts of both NM23 genes and a normalizing gene (c-N-ras) to determine the relative levels of expression. A significant difference was shown between the BPH specimens and the cell lines from metastatic prostate cancer for nm23-H2 expression (p = 0.037) and the nm23-H1/nm23-H2 gene expression ratio (p = 0.037). The nm23-H1/nm23-H2 ratio increased significantly (p = 0.026, tau-b = 0.377) from BPH, through the CaP stages, to the cell lines. The expression of nm23-H2 decreased significantly (p = 0.002, tau-b = -0.517) from BPH, through the CaP stages, to the cell lines. Thus, while nm23-H2 appears to be significant for characterizing stages of CaP, an understanding of the metastatic phenotype will require further analysis of both NM23 genes.
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PMID:Quantitation of NM23 expression in human prostate tissues. 751 52

Genetic changes related to cancer metastasis are overviewed. hst-1/int-2 co-amplification is closely related to the metastatic potential of esophageal carcinomas. Multiple autocrine and paracrine loops including EGF, TGF-alpha/EGF receptor system and HGF/c-met system are related to the biological malignancy of gastric carcinoma in general. On the other hand, K-sam and c-erbB2 amplification are frequently found in the metastatic foci of poorly and well-differentiated type gastric carcinoma. Various splice variants of cell adhesion molecule CD44 are the potent marker of human carcinomas themselves as well as metastases. Reduction in the expression of nm23 is a relatively common event in the metastasis of various human cancers, including stomach and colorectal carcinomas.
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PMID:[Metastasis-related genes]. 752 1


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