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)

Malignant melanoma is increasing in incidence, and, though early lesions are readily treatable, systemic therapy for metastatic disease remains disappointing. Integrins are a family of cell-surface molecules that mediate adhesion between the cell and the extracellular matrix. One member of the integrin family, the alpha v beta 3 integrin, is associated with progression of melanomas, in that the most malignant cells express the highest levels of alpha v beta 3. Like many members of the integrin family, alpha v beta 3 recognizes the sequence Arg-Gly-Asp (RGD) in its ligands, and other molecules that contain this sequence will complete with the natural ligands (such as vitronectin) for binding. There is growing evidence that integrins function as receptors for signal transduction, and that integrin-mediated signalling can affect cell behaviour and even cell survival. Under certain circumstances, loss of integrin-mediated signalling will induce apoptosis, or programmed cell death, and we have demonstrated that melanoma cells treated with a cyclic peptide with high affinity for the alpha v beta 3 integrin will undergo apoptosis within three days. This mechanism might be exploited therapeutically.
 ...
PMID:Adhesion molecules in melanoma--more than just superglue? 877 38

Nitric oxide (NO) may be an important mediator of tumour angiogenesis and metastasis formation. Tumour cell derived NO may be important in the regulation of angiogenesis and vasodilatation of the blood vessels surrounding a tumour. The aims of the present study were, firstly, to determine whether malignant melanoma cells and normal melanocytes had nitric oxide synthase (NOS) activity (measured by the conversion of L-arginine to L-citrulline) and, secondly, to determine whether there was a difference in NOS activity between malignant and normal cell types. This paper assays NOS activity directly in lysates from normal human melanocyte and malignant melanoma cell lines. The enzyme activity was not inducible with bacterial lipopolysaccharide and could be heat denatured. The activity of NOS was demonstrated to be both NADPH- and calcium-dependent and it was inhibitable in a dose-dependent manner by the NOS inhibitor Nw-nitro-L-arginine methyl ester. We conclude that melanoma and melanocyte cells express a constitutive form of NOS. Finally, nitric oxide synthase activity in melanoma cell lines was found to be significantly greater than in normal melanocytes. These findings suggest that NO synthesis is elevated in malignant melanoma. An elevated NO concentration in melanoma is expected to promote metastases by maintaining a vasodilator tone in the blood vessels in and around the melanoma.
 ...
PMID:Nitric oxide synthase activity is up-regulated in melanoma cell lines: a potential mechanism for metastases formation. 879 Dec 69

Interactions between metastasizing tumor cells and host cells in target organs determine the outcome of metastasis. This review discusses the dual role of activated host endothelial cells in the metastatic process. On one hand, the upregulation of the expression of particular adhesion molecules leads to increased tumor cell binding, and the stimulation of angiogenesis provides the vascular support for the growth of already established metastases. On the other hand, endothelial cells can contribute to host anti-metastatic responses, e.g. by production of the cytotoxic molecule nitric oxide (NO) from arginine with the help of the inducible nitric oxide synthase (iNOS). Using a well-characterized ESbL-lacZ mouse T lymphoma model with a typical three phasic growth profile, we showed during the period of growth retardation a stimulation of NO production by ex vivo isolated liver sinusoidal endothelial cells. The induction of NO synthesis in liver endothelial cells did not require the presence of Kupffer cells and appeared to be stimulated by and dependent on mature T lymphocytes. A breakdown of this NO synthesis coincided with the second tumor expansion phase.
Cancer Metastasis Rev 1996 Jun
PMID:Liver endothelial cells: participation in host response to lymphoma metastasis. 884 99

Adhesion of circulating tumor cells to microvascular endothelium plays an important role in tumor metastasis to distant organs. The purpose of this study was to determine whether nitric oxide (NO) would attenuate tumor cell adhesion (TCA) to naive or lipopolysaccharide (LPS)-treated postcapillary venules. A melanoma cell line, RPMI 1846, was shown to be much more adhesive to postcapillary venules isolated from rat mesentery than to corresponding precapillary arterioles. Although venules exposed to LPS for 4 h demonstrated an increased adhesivity for the melanoma cells, TCA to LPS-treated arterioles was not altered. Isolated venules exposed to DETA/NO (1 mM), an NO donor, for 30 min prior to tumor cell perfusion prevented the increment in adhesion induced by LPS and attenuated TCA to naive postcapillary venules. While L-arginine (100 microM), an NO precursor, failed to decrease TCA to naive postcapillary venules, this treatment abolished LPS-stimulated TCA to postcapillary venules. The effect of L-arginine was reversed by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), an NO synthase (NOS) inhibitor. These observations indicate that both exogenous and endogenous NO modulate TCA to postcapillary venules. To assess the role of NO-induced activation of cGMP in the reduction in TCA produced by DETA/NO, two additional series of experiments were conducted. In the first series, LY-83583 (10 microM), a guanylyl cyclase inhibitor, was shown to completely reverse the effect of DETA/NO on TCA to both naive and LPS-activated postcapillary venules. On the other hand, administration of 8-bromoguanosine 3',5'-cyclic monophosphate (8-B-cGMP) (1 mM), a cell permeant cGMP analog, mimicked the effect of DETA/NO and reduced TCA to LPS-stimulated postcapillary venules. These data suggest that (a) tumor cells are more likely to adhere to postcapillary venules than to corresponding precapillary arterioles, (b) LPS enhances TCA to postcapillary venules, (c) both exogenously applied (DETA/NO) and endogenously generated (L-arginine) NO attenuate the enhanced adhesion induced by LPS, but only DETA/NO reduced TCA to naive postcapillary venules, and (d) the NO-induced reduction in TCA to LPS-activated postcapillary venules occurs by a cGMP-dependent mechanism.
Clin Exp Metastasis 1996 Sep
PMID:Nitric oxide reduces tumor cell adhesion to isolated rat postcapillary venules. 887 7

The value of cathepsin B activity determination for evaluation of the extent of disease was investigated in 98 patients with the cervix uteri carcinoma and 25 women with cervix uteri dysplasia. The measurements were performed before treatment. Cathepsin B activity was estimated in serum using Z-Phe-Arg-NMec, and in tumor tissue using Z-Arg-Arg-pNA . HCl as substrates. The mean activity of the enzyme increased both in serum and tumor tissue with progression of neoplastic disease and was dependent on the clinical stage of cervical carcinoma. It should be stressed, however, that among the patients with the clinically observed early stage of the disease, higher cathepsin B activity was observed in those in whom metastases to pelvic lymph nodes were detected than in those in whom the disease was limited to cervix uteri.
 ...
PMID:A possible application of cathepsin B activity determination for estimating the spread of the cervix uteri carcinoma. 892 36

There is a worldwide increase in the incidence of melanoma. Without treatment, melanomas can progress to metastatic disease and result in death. It is now accepted that for a tumor to grow, non-tumorous host tissue must form blood vessels in and around the tumor. Tumor cells and blood vessels must form a highly regulated system whereby endothelial cells can be switched from a resting state to one of rapid growth. Tumor cells have been shown to produce diffusible angiogenic regulatory molecules. Nitric oxide [NO] and polyamines [PA] have been implicated in the angiogenic process. This paper hypothesizes that NO and PA regulate melanoma angiogenesis differently. During early stages of malignant melanoma an increase in PA synthesis is expected to promote endothelial cell proliferation and therefore angiogenesis. NO is expected to be maintained at low levels. During the vascular stage of malignant melanoma, NO synthesis is hypothesized to be elevated which will decrease endothelial cell proliferation and maintain a vasodilator tone in and around the tumor. PA concentrations are expected to be lower. A regulatory link between NO and PA may be involved in the maintenance of tumor homeostasis. The regulation of L-arginine metabolism in tumor angiogenesis requires investigation as it may lead to novel selective therapeutic interventions in cancer therapy.
 ...
PMID:The importance of L-arginine metabolism in melanoma: an hypothesis for the role of nitric oxide and polyamines in tumor angiogenesis. 898 Oct 51

Activation by point mutation of ras family genes as well as point mutations of the p53 tumor suppressor gene are found in many tumors. Here we describe a rare case of malignant neuroendocrine pancreatic tumor with multiple metastases in different organs showing strong positivity for synaptophysin, glucagon-like peptide 1, pan-cytokeratin, moderate positivity for chromogranin, Phe-5 and calcitonin and weak positivity for vasointestinal peptide. We found a point mutation at codon 61 of the c-N-ras oncogene, and point mutations in the p53 tumor suppressor gene in the primary tumor as well as in its metastases in liver. The mutation in the c-N-ras gene was a cytosine to adenine transversion, resulting in the amino-acid lysine. Allele specific hybridization showed that the mutation involved one of two c-N-ras alleles as the oligonucleotide for the normal codon also hybridized to amplified tumor DNA. Concomitant mutation of the p53 tumor suppressor gene at codons 248 and 249 was found. The mutation in codon 248 was a cytosine to guanine transversion resulting in the amino-acid glycine. The mutation in codon 249 was a third base, G- > T, transversion leading to a change from arginine to serine. This is the first time that concomitant point mutations in c-N-ras and p53 have been found in a neuroendocrine pancreatic tumor. Based upon these and our previous results, we concluded that these genetic changes may play a role in the development of this particular pancreatic tumor.
 ...
PMID:Concomitant point mutation of tumor suppressor gene p53 and oncogene c-N-ras in malignant neuroendocrine pancreatic tumor. 904 54

The integrins are receptors that regulate interaction between epithelial cells and the extracellular matrix. Previous studies have shown that a reduction in the expression of the alpha2beta1, alpha3beta1, alpha6beta1, alpha(v)beta1 and alpha(v)beta5 integrins in primary breast cancer is associated with positive nodal status. In order to assess the functional significance of altered integrin expression, primary breast cancer cells were derived from individual patients with known tumour characteristics using immunomagnetic separation. Purified human fibronectin, vitronectin, laminin and type IV collagen were used to represent the principal extracellular matrix proteins in an in vitro adhesion assay. Primary breast cancer cells from lymph node-positive patients were significantly less adhesive to each of the matrix proteins studied (P<0.001, Mann-Whitney U-test). Matrix adhesion of primary breast cancer cells from node-negative patients was inhibited by appropriate integrin monoclonal antibodies (P<0.001, paired Wilcoxon test). Adhesion to fibronectin, vitronectin and laminin, but not type IV collagen, was influenced by the inhibitor arginine-glycine-aspartate, suggesting that breast cancer cell recognition of collagen IV is mediated through alternative epitopes. Weak matrix adhesion correlated with loss of integrin expression in tissue sections from corresponding patients assessed using immunohistochemistry. This study demonstrates a link between altered integrin expression and function in primary breast cancers predisposed to metastasize.
 ...
PMID:Altered cell-matrix contact: a prerequisite for breast cancer metastasis? 904 16

The aims of this study were (i) to assess the prevalence and spectrum of codon 12 Ki-ras mutations in patients diagnosed with exocrine pancreatic cancer (EPC) in 2 general hospitals between 1980 and 1990, (ii) to analyze the association of this genetic alteration with clinical and pathological characteristics, and (iii) to determine the association of Ki-ras mutations with tobacco and alcohol consumption. DNA was amplified from paraffin-embedded tissue samples and mutations in codon 12 of Ki-ras were detected using the artificial RFLP technique. Cox proportional-hazards regression and unconditional logistic regression were applied. Codon 12 Ki-ras mutations were detected in 30 of 51 cases for which molecular results were available. The amino-acid substitutions were Asp (8), Val (6), and Arg (3). A double mutation, including always a Val, was detected in 5 cases. None of the 4 nonductal pancreatic neoplasms were mutated. The mutation prevalence was 79% in metastases and 54% in primary tumors. The risk of a mutated tumor was 3 times higher in alcohol drinkers than in non-drinkers, and a linear trend was apparent. When age, gender, hospital, and tobacco and alcohol consumption were taken into account, a high risk for mutations was detected in patients who only smoked and in patients who only drank, but less so in patients who both smoked and drank. These results raise novel hypotheses regarding the role of tobacco and alcohol in EPC.
 ...
PMID:Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators. 909 46

This paper describes the synthesis and biological evaluation of six partial retro-inverso peptidomimetic analogs of YIGSR-NH2, a synthetic peptide from the beta 1 chain of laminin, which has antimetastatic activity. The intent was to improve the antimetastatic potency of YIGSR-NH2 by limiting the in vivo enzymatic degradation through the incorporation of fraudulent peptide bonds. We have prepared the following retro-inverso peptides, Tyr-Ile-Gly-Ser-gArg-CHO (1), Tyr-gIle-mGly-Ser-Arg-NH2 (2), Tyr-gIle-mGly-Ser-gArg-CHO (3), gTyr-D-rIle-mGly-Ser-Arg-NH2 (4), Tyr-Ile-Gly-gSer-D-rArg-CHO (5) and Tyr-gIle-rGly-D-rSer-D-rArg-CHO (6). In vitro assays for B16F10 melanoma cell adhesion showed no significant activity for these six peptides. Peptides 1-3, 5 and 6 were further tested, in vivo, for their ability to inhibit tumor metastases to the lung in mice injected in the tail vein with B16F10 melanoma cells. All five of the retro-inverso peptides tested showed statistically significant inhibition of metastasis, but the most active peptides were 5 and 6, which showed 57 and 69% inhibition of metastasis, respectively.
 ...
PMID:Synthesis and activity of partial retro-inverso analogs of the antimetastatic laminin-derived peptide, YIGSR-NH2. 915 Dec 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>