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)

Carcinoma cell lines are frequently refractory to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. Whether and how TGF beta signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether TGF beta signaling might be disrupted by inactivation of the key signaling molecule, the TGF beta type I (T beta R-I) receptor, and whether or not T beta R-I inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the T beta R-I gene in fine-needle aspirates of 23 head-&-neck cancer metastases. We encountered 4 different mutations of T beta R-I, 3 of which have not been previously identified. In 1 case, we found a somatic intragenic 4-bp deletion predicting for a truncation of the receptor protein. This is the first example of a true loss-of-function mutation of T beta R-I in a human epithelial neoplasm. In 2 other cases, we identified missense mutations located between the juxtamembrane- and serine-threonine kinase domains. One of these resulted in an alanine-to-threonine substitution (A230T), which disrupts receptor signaling activity by causing rapid protein degradation within the endoplasmatic reticulum. This represents a novel mechanism of inactivation of a TGF beta signaling intermediate. Finally, we identified a serine-to-tyrosine substitution at codon 387 (S387Y) in a metastasis but not in the corresponding primary tumor. We had previously shown this S387Y mutant to be predominantly associated with breast cancer metastases and to have a diminished ability to mediate TGF beta-dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGF beta signaling pathway occurs in a significant subset of human cancers.
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PMID:Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. 1147 74

Breast cancer is associated frequently with skeletal metastases, which cause significant morbidity. The main mechanism is an increase in osteoclast-mediated bone resorption. We postulated that osteoblasts could be other essential target cells and previously showed that conditioned medium (CM) of breast cancer cells (BCCs) inhibits the proliferation of osteoblast-like cells. In this study, we investigated the effects of BCC-secreted products on osteoprogenitor cells using a clonal fetal human bone marrow stromal preosteoblastic cell line (FHSO-6) that expresses alkaline phosphatase (ALP) activity, type I collagen (COLI), and increased osteocalcin (OC) and osteopontin under treatment with dexamethasone (Dex), 1,25-dihydroxyvitamin D [1,25(OH)2D], or recombinant human bone morphogenetic protein 2 (rhBMP-2). Treatment with MCF-7 CM inhibited FHSO-6 cell survival in a dose-dependent and irreversible manner. Morphological investigation indicated that MCF-7 CM increased both apoptotic and necrotic cell number. MCF-7 CM increased caspases activity and a broad inhibitor of caspase activity (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone [z-VAD-fmk]) partly reversed the CM-induced inhibition of FHSO-6 cell survival. Western blot analyses revealed an increased bax/bcl-2 ratio in MCF-7 CM-treated FHSO-6 cells. MCF-7 cells exhibit FasLigand as membrane-bound protein and as a soluble cytokine in the CM. Deprivation of MCF-7 CM from active FasLigand by saturation with a soluble Fas molecule suppressed the induction of FHSO-6 apoptosis, whereas fibroblast CM, which did not contain FasLigand, only weakly modified FHSO-6 cell survival because of increased cell necrosis. These data indicate that FasLigand secreted by BCCs induces apoptosis and necrosis of human preosteoblastic stromal cells through caspase cascade modulated by the bax and bcl-2 protein level. The induction of apoptosis in human bone marrow stromal cells by BCCs may contribute to the inappropriately low osteoblast reaction and bone formation during tumor-induced osteolysis in bone metastases.
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PMID:Breast cancer cells release factors that induced apoptosis in human bone marrow stromal cells. 1154 30

Female transgenic FVB mice transfected with the mammary erbB-2/neu oncogene were injected 0.1 ml 0.9% solution of sodium chloride (control), 1 meg Vilon peptide (Lys-Glu) or Epitalon peptide (Ala-Glu-Asp-Glu), s.c., 5 days in succession once a month, beginning from the age of 2 months. The characteristics of mammary tumor induction in the control and experimental groups did not differ until the age of 9 months. Later on, Epitalon-treated mice revealed distinct inhibition of carcinogenesis. One tumor per animal was detected in 7% (control), 4% (Vilon) and 16% (Epitalon) (p < 0.05). Two or more tumors per animal were in 75%, 95% and 56%, respectively (p < 0.05). Largest diameter of mammary adenocarcinoma in the Epitalon group was smaller than in controls by 33% (p < 0.05). Although the number of mice with metastases to the lung in all three groups was practically identical, their incidence in the Vilon group was 2.6 times higher than in Epitalon-treated animals (p < 0.05). Largest diameter of metastasis in the Epitalon group was the smallest, too. Our data point to inhibition of mammary carcinogenesis by Epitalon in transgenic erbB-2/neu mice.
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PMID:[Effect of Epitalon and Vilon treatment on mammary carcinogenesis in transgenic erbB-2/NEU mice]. 1210 68

Focal adhesion kinase (FAK) was first identified as a viral Src (v-Src) substrate, but the role of FAK in Src transformation events remains undefined. We show that stable expression of the FAK C-terminal domain (termed FRNK) in v-Src-transformed NIH 3T3 fibroblasts inhibited cell invasion through Matrigel and blocked experimental metastases in nude mice without effects on cell motility. FRNK inhibitory activity was dependent upon its focal contact localization. FRNK expression disrupted the formation of a v-Src-FAK signaling complex, inhibited p130Cas tyrosine phosphorylation, and attenuated v-Src-stimulated ERK and JNK kinase activation. However, FRNK did not affect v-Src-stimulated Akt activation, cell growth in soft agar, or subcutaneous tumor formation in nude mice. FRNK-expressing cells exhibited decreased matrix metalloproteinase-2 (MMP-2) mRNA levels and MMP-2 secretion. Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive (Ala-404) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK. Our findings show the importance of FAK in Src-stimulated cell invasion and support a role for Src-FAK signaling associated with elevated tumor cell metastases.
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PMID:FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. 1245 36

Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.
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PMID:Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice. 1245 48

Proton spectroscopy can noninvasively provide useful information on brain tumor type and grade. Short- (30 ms) and long- (136 ms) echo time (TE) (1)H spectra were acquired from normal white matter (NWM), meningiomas, grade II astrocytomas, anaplastic astrocytomas, glioblastomas, and metastases. Very low myo-Inositol ([mI]) and creatine ([Cr]) were characteristic of meningiomas, and high [mI] characteristic of grade II astrocytomas. Tumor choline ([Cho]) was greater than NWM and increased with grade for grade II and anaplastic astrocytomas, but was highly variable for glioblastomas. Higher [Cho] and [Cr] correlated with low lipid and lactate (P < 0.05), indicating a dilution of metabolite concentrations due to necrosis in high-grade tumors. Metabolite peak area ratios showed no correlation with lipids and mI/Cho (at TE = 30 ms), and Cr/Cho (at TE = 136 ms) best correlated with tumor grade. The quantified lipid, macromolecule, and lactate levels increased with grade of tumor, consistent with progression from hypoxia to necrosis. Quantification of lipids and macromolecules at short TE provided a good marker for tumor grade, and a scatter plot of the sum of alanine, lactate, and delta 1.3 lipid signals vs. mI/Cho provided a simple way to separate most tumors by type and grade.
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PMID:Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. 1254 Dec 41

Our objective was to evaluate the usefulness of proton magnetic resonance spectroscopy ((1)H MRS) in categorizing brain tumours. In vivo single-voxel (1)H MRS at an echo time of 136 ms was performed in 108 patients with brain neoplasms that included 29 meningiomas (MEN), 15 low-grade astrocytomas (LGA), 12 anaplastic astrocytomas (AA), 25 glioblastomas (GBM) and 27 metastases (MET). Time-domain fitted areas of nine resonances were evaluated in all spectra. Twenty-five additional tumours were prospectively included as independent test set. Differences in at least two resonances were found in all pairwise comparisons of tumour groups except in GBM vs MET. Large lipid resonance at 1.30 ppm was found to be characteristic of GBM and MET, and alanine was characteristic of MEN. Significant differences were found between LGA and AA in choline-containing compounds and total creatine resonances. When implemented in a stepwise algorithm, these findings correctly classified 84% (21 of 25) tumours in the independent test set. Some additional utility was found in glycine/myo-inositol at 3.55 ppm for bilateral differentiation between GBM and MET (9 of 11, 82% correct classification in the test set). (1)H MRS provides useful information to categorize the most common brain tumours that can be implemented in clinical practice with satisfactory results.
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PMID:Proton magnetic resonance spectroscopy ((1)H MRS) of human brain tumours: assessment of differences between tumour types and its applicability in brain tumour categorization. 1259 62

Our aim was to evaluate the usefulness of proton MR spectroscopy ((1)H MRS) in the diagnosis of radiologically atypical brain meningiomas. We studied 37 patients with intracranial meningiomas with MRI and (1)H MRS (TE 136 ms). Their spectra were quantitatively assessed and compared with those of 93 other intracranial brain neoplasms: 15 low-grade and 14 anaplastic astrocytomas, 30 glioblastomas and 34 metastases. The most characteristic features of meningiomas were the presence of alanine, high relative concentrations of choline and glutamine/glutamate and low concentrations of creatine-containing compounds, N-acetyl-containing compounds and lipids. These resonances were assembled in algorithms for two-way differentiation between meningioma and the other tumours. The performance of the algorithms was tested in the 130 patients using the leave-one-out method, with 94% success in differentiating between meningioma and other tumour. Of the 37 meningiomas, five (14%) were thought atypical on MRI, and in only one of these, found to be malignant on histology, was a diagnosis other than meningioma suggested by the algorithm. The other four were correctly classified. We suggest that (1)H MRS provides information on intracranial meningiomas which may be useful in diagnosis of radiologically atypical cases.
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PMID:Utility of proton MR spectroscopy in the diagnosis of radiologically atypical intracranial meningiomas. 1268 13

Yet meningiomas have characteristic neuroimaging features, some other lesions are still confusing with meningiomas. The aim of this study was trying to find the typical (1)H-MRS metabolic factors of histologic subtyped meningiomas, schwannomas, metastases, and other brain tumors for differential diagnosis among them. (1)H-MRS using STEAM (TE/30 ms, TR/2 sec) and PRESS (TE/288 ms, TR/2 sec) sequences were performed on 44 untreated brain tumors. Obtained metabolic patterns from the typical spectra of meningioma, schwannoma, metastasis were compared with each other or other brain tumors to evaluate the usefulness for diagnosis between them. Alanine(Ala) was observed in 15 cases of the 19 meningiomas with a little variation to three histologic subtypes, while minimal lipids were observed in every 19 meningiomas. Elevated glutamate/glutamine(Glx) was detected in 12 cases of the meniningiomas. Increased myo-inositol(mI) was detected in 11 cases of the 13 schwannomas. Dominant lipids signals as well as long-T2 lipids were detected in every metastasis in conjunction with elevated choline (Cho). Enhanced Glx was observed in 4 cases of the 8 metastases without correlation of primary tumor site or types. Hemangiopericytoma showed different spectral patterns from typical meningiomas: only dominant Cho, minimal lipids and absence of Ala or Glx signals. These metabolic patterns in typical tumors may provide a basis for differential diagnosis (average value of chi(2) = 23.33, p < 0.01) between meningiomas and schwannomas as well as metastases. However proton spectral distinction among the different histologic subtypes of meningiomas was not definite.
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PMID:(1)H-MRS metabolic patterns for distinguishing between meningiomas and other brain tumors. 1291 98

Magnetic resonance spectroscopy facilitates non-invasive determination of metabolic changes in vivo. The main metabolites are the neuronal marker N-acetylaspartate (NAA), cholines reflecting membrane turnover, creatine, lactate, and mobile lipids. Primary brain tumours exhibit reduced NAA and increased choline resonances compared to normal brain, and these abnormalities increase with higher malignancy. Increasing choline resonances on follow-up studies correlate with tumour progression, whereas the reduction of initially increased choline resonances indicates a transition from viable tumour to necrotic tissue. Metastases as non-neuroectodermal tumours lack NAA, but demonstrate elevated choline, lactate and lipid resonances. Lymphomas are characterised by massively increased lipid resonances with markedly elevated choline. Prominent alanine resonances are often observed in meningioma. Cystic/necrotic lesions demonstrate elevated lactate regardless of their aetiology. The characteristic finding of prominent resonances from acetate, succinate, and alanine, of leucine, isoleucine and valine in untreated bacterial abscesses allows the differentiation of bacterial abscesses from cystic/necrotic brain tumours.
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PMID:[Magnetic resonance spectroscopy of brain tumours]. 1534 36


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