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)

An estrogen (E) independent sub-clone (EIIL) was separated from a human endometrial carcinoma cell line, Ishikawa, by culturing the wild type under an E free condition for 350 days. The cells were then implanted into nude mice subcutaneously and tumors allowed to develop for 35 days. The primary lesions were then excised to stimulate recurrence. One animal developed recurrence with multiple distant metastases. The primary tumor and metastatic tumors from the animal were studied for ErbB-2 expression by immunohystochemical techniques or by a reverse transcription followed by polymerase chain reaction (RT-PCR). Expressions of epidermal growth factor (EGF) receptors, aromatase, nidogen, E receptors, hepatocyte growth factors (HGF) and beta-actin were also examined. The results showed that metastatic lesions expressed high levels of ErbB-2, nidogen and aromatase but unchanged levels of EGF receptors and HGF. The metastatic lesions expressed one third of the E receptors which were detected in the EIIL in vitro. These observations suggest that a decrease in ER along with increased expression of nidogen and aromatase is associated with the process of metastasis and the model appears to be of value in studying the process of the acquisition of a metastatic phenotype.
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PMID:[Establishment of metastatic sub-clone from estrogen independent Ishikawa cells and its characterization in vitro and in vivo]. 769 85

Tumor necrosis factor (TNF) produced by tumor cells after gene transfer can effectively suppress the growth of locally growing tumors. We wanted to test the effects of "local" TNF on the growth of a highly metastatic cell line. Therefore, a recombinant retrovirus allowing expression of the TNF gene by the beta-actin promotor has been constructed and used to infect the two tumor cell lines EB and ESB, which grow as solid tumor or metastasize, respectively. Expression of TNF by EB cells resulted in their rapid and dose-dependent rejection. In sharp contrast, mice injected with ESB cells producing similar amounts of TNF showed no signs of tumor suppression, but rather had reduced survival rates that correlated with enhanced hepatic metastases. The accelerated formation of liver metastases by ESB TNF cells could be reversed by an anti-TNF mAb. These results demonstrate the opposite effects TNF may have on tumor growth: suppression of a locally growing tumor and promotion of metastasis formation.
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PMID:Expression of tumor necrosis factor by different tumor cell lines results either in tumor suppression or augmented metastasis. 831 91

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein, which removes alkyl groups from the O6 atom of guanine residues. Tumour cells which lack MGMT are sensitive to cytostatic drugs such as dacarbazine (DTIC), whose active species bind to this site. To explore whether analyses of MGMT expression can be used as a predictive test for clinical sensitivity to DTIC in melanomas, we developed a method to assay MGMT mRNA levels in cells obtained by fine needle aspiration biopsies of metastases. cDNA was synthesised from mRNA prepared from biopsy material. Polymerase chain reaction was performed using primers complementary to MGMT cDNA and to beta-actin, which served as an internal control. Analyses of 44 biopsies from 35 patients showed a considerable variation in MGMT mRNA, with 15 samples (34%) lacking detectable mRNA. In 6 out of 8 patients in whom more than one tumour was analysed, separate metastases had different levels of MGMT mRNA. There was no correlation between MGTM activity studied by a biochemical assay and MGMT mRNA levels when these were compared in 10 surgical biopsies.
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PMID:Analysis of O6-methylguanine-DNA methyltransferase mRNA in fine needle biopsies from human melanoma metastases by reverse transcription and polymerase chain reaction. 903 16

Considerable evidence links urokinase plasminogen activator (uPA) bound to its surface receptor (uPAR) with enhanced invasiveness of cancer cells. By blocking uPAR expression in human epidermoid carcinoma cells (HEp3), we have now identified an additional and novel in vivo function for this receptor by showing that receptor-deficient cells enter a state of dormancy reminiscent of that observed in human cancer metastasis. Its main characteristic is survival without signs of progressive growth. Five clones transfected with a vector expressing uPAR antisense RNA under the beta-actin promoter were isolated and shown to have uPAR (at the mRNA and protein levels) reduced by 50 to 80%; four clones, transfected with vector alone and having uPAR levels similar to those of parental cells, served as controls. In confirmation of our previous results, reduced uPAR always coincided with a significantly reduced invasiveness. Each of the control clones produced rapidly growing, highly metastatic tumors within 2 wk of inoculation on chorioallantoic membranes (CAMs) of chick embryos. In contrast, each of the clones with low surface uPAR, whose proliferation rate in culture was indistinguishable from controls, remained dormant for up to 5 mo when inoculated on CAMs. Thus, the reduction in uPAR altered the phenotype of HEp3 tumor cells from tumorigenic to dormant. Although protracted, tumor dormancy was not permanent since in spite of maintaining low uPAR levels, each of the in vivo-passaged antisense clones eventually reemerged from dormancy to initiate progressive growth and to form metastases at a level of 20 to 90% of that of fully malignant control. This observation suggested that other factors, whose expression is dependent on cumulative and prolonged in vivo effects, can compensate for the lack of a full complement of surface uPAR required for the expression of malignant properties. These "reemerged," uPAR-deficient clones were easily distinguishable from the vector-transfected controls by the fact that after only 1 wk in culture, the invasion of CAM by all five clones and tumorigenicity of four of the five clones were reduced back to the values observed before in vivo maintenance. In contrast, dissociated and in vitro-grown cells of control tumors were fully invasive and produced large, metastatic tumors when reinoculated on CAMs. Quantitation of the percent of apoptotic and S-phase cells in vivo, in the control and uPAR-deficient, dormant clones, showed that the mechanism responsible for the dormancy was a diminished proliferation.
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PMID:Reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy. 915 80

Transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of epithelial cell proliferation. Signal transduction by TGF-beta1 involves direct binding to the TGF-beta Type-II receptor and then the formation of a heterodimeric complex of TGF-beta Type-I and Type-II receptor. To explore the role of TGF-beta1 in thyroid carcinoma, we examined the expression of TGF-beta1 and TGF-beta Type-II receptor mRNA by northern blotting analysis in both 14 papillary thyroid carcinomas and surrounding normal thyroid tissues. Relative mRNA level was determined by scanning densitometry of the autoradiogram and corrected for loading differences using a human beta-actin cDNA probe. The relative mRNA levels of TGF-beta1 in 12 out of 14 papillary thyroid carcinomas were higher than those in surrounding normal thyroid tissues. In contrast, the relative mRNA levels of TGF-beta Type-II receptor were reduced to 60.1+/-18.3% of those of normal thyroid tissues in 10 papillary thyroid carcinomas. There were no clear relationships between the relative mRNA levels for TGF-beta1 and TGF-beta Type-II receptor and the histological characteristics of papillary thyroid carcinomas. The relative mRNA levels for TGF-beta1 and TGF-beta Type-II receptor did not show significant differences in thyroid carcinomas with or without lymph node metastases. There was a negative correlation between the TGF-beta Type-II receptor mRNA level and tumor size, while no significant correlation was observed between the TGF-beta1 mRNA level and tumor size. In conclusion, most papillary thyroid carcinomas overexpress TGF-beta1 mRNA but exhibit a reduction in TGF-beta Type-II receptor mRNA. The reduction of TGF-beta Type-II receptor mRNA may play a role in the pathogenesis of papillary thyroid carcinoma.
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PMID:Expression of transforming growth factor-beta1 and transforming growth factor-beta Type-II receptor mRNA in papillary thyroid carcinoma. 985 70

Several cytokines including members of the transforming growth factor-beta (TGF-beta) and tumor necrosis factor (TNF) families have been implicated in the homing mechanism of breast cancer metastasis. We hypothesize that primary breast tumor tissues differentially express modulators of bone cell function and that this expression pattern contributes to their aggressive and metastatic potential and to their capacity to establish and grow in bone. We, therefore, examined the gene expression pattern of the TGF-beta family members (inhibin/activin betaA subunit (activin betaA), inhibin alpha subunit, and bone morphogenetic protein-2 (BMP-2)), the TNF family members (receptor activator of NF-KB ligand (RANKL) and osteoprotegerin (OPG)), and osteopontin (OPN) in normal, non-invasive, invasive, and metastatic human breast cancer specimens. The mRNA transcript levels of these genes were quantified by reverse transcription (RT) and fluorescent-based kinetic PCR in 18 normal breast tissues, five ductal carcinoma in situ (DCIS). 24 primary breast tumor tissue, and five distant metastases. The mRNA transcript level of each gene was normalized to the amount of beta-actin present in the samples. We observed differential gene expression of the selected TGF-beta family members as well as OPN in breast cancer progression. The average gene expression of the putative tumor suppressor, inhibin alpha, did not significantly change in any of the tumor tissues examined compared to normal breast tissue. The mRNA level of BMP-2, a protein with anti-proliferative effects in breast cancer cell lines and involved in bone formation, significantly decreased in non-invasive, invasive, and liver metastatic breast tumor tissue compared to normal breast tissue. The gene expression of activin betaA, a protein involved in cell proliferation and osteoclast induction, increased in invasive and bone metastatic tumor tissue compared to normal breast tissue. The mRNA level of OPN, a bone matrix protein associated with enhanced malignancy, increased in non-invasive, invasive, and liver and bone metastatic breast tumor tissue compared to normal breast tissue. In contrast, the average gene expressions of the TNF family members, RANKL and OPG, proteins involved in the regulation of osteoclastogenesis, were only slightly if at all changed in the different stage breast tumor tissues. These results suggest that differential gene expression of bone-related proteins, especially OPN, activin betaA, and BMP-2, by primary breast tumor tissues may play a significant role in the invasiveness and metastatic potential of breast cancer.
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PMID:Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. 1220 15

Deoxycytidine kinase (dCK) is required for the phosphorylation of several deoxyribonucleoside analogues that are widely employed as chemotherapeutic agents. Examples include cytosine arabinoside (Ara-C) and 2-chlorodeoxyadenosine (CdA) in the treatment of acute myeloid leukaemia (AML) and gemcitabine to treat solid tumours. In this study, expression of dCK mRNA was measured by a competitive template reverse transcriptase polymerase chain reaction (CT RT-PCR) in seven cell lines of different histological origin, 16 childhood and adult AML samples, 10 human liver samples and 11 human liver metastases of colorectal cancer origin. The enzyme activity and protein expression levels of dCK in the cell lines were closely related to the mRNA expression levels (r=0.75, P=0.026 and r=0.86, P=0.007). In AML samples, dCK mRNA expression ranged from 1.16 to 35.25 (x10(-3)xdCK/beta-actin). In the cell line panel, the range was 2.97-56.9 (x10(-3)xdCK/beta-actin) of dCK mRNA expression. The enzyme activity in liver metastases was correlated to dCK mRNA expression (r=0.497, P=0.05). In the liver samples, these were not correlated. dCK mRNA expression showed only a 36-fold range in liver while a 150-fold range was observed in the liver metastases. In addition, dCK activity and mean mRNA levels were 2.5-fold higher in the metastases than in the liver samples. Since dCK is associated with the sensitivity to deoxynucleoside analogues and because of the good correlation between the different dCK measurements in malignant cells and tumours, the CT-RT PCR assay will be useful in the selection of patients that can be treated with deoxycytidine analogues.
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PMID:Expression of deoxycytidine kinase in leukaemic cells compared with solid tumour cell lines, liver metastases and normal liver. 1262 50

Vascular endothelial growth factor-A (VEGF-A) is an important mediator of angiogenesis in normal and neoplastic tissues. Total VEGF-A levels have been associated with melanoma progression, but the relative contributions of each isoform is unknown. To determine whether differences in the production of any or all of the major VEGF-A isoforms are related to stage of progression, we compared message levels for the three major isoforms of VEGF in melanoma specimens from different stages of progression.Primary melanomas (N = 18), primary recurrences (N = 5), regional dermal metastases (N = 11), nodal metastases (N = 12), normal lymph nodes (N = 18), and distant metastases (N = 9) were prospectively collected. Samples from the horizontal and vertical growth phases of primary tumors were also collected from five additional patients. Message levels for the three major VEGF-A isoforms were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and normalized to beta-actin mRNA levels. There was a marked increase in the expression of all three VEGF-A isoforms from the vertical growth phase tissue as compared with the horizontal growth phase tissue. Primary tumors, local recurrences, regional dermal metastases, nodal metastases, and distant metastases all produced more VEGF(121) and VEGF(165) than negative nodes. Nodal metastases produced the highest level of these two isoforms, higher even than distant metastases. There was no significant difference in VEGF(189) message among the groups. Melanomas in the vertical growth phase produce more VEGF-A (all isoforms) than in the horizontal growth phase. Nodal metastases produce the highest levels of VEGF(121) and VEGF(165), but not VEGF(189) as compared with other stages of progression. These data suggest that the soluble forms of VEGF-A might be an important factor in melanoma metastasis to regional lymph nodes.
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PMID:Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. 1294 96

The object of this study was to examine whether MUC-1 can be detected in the axillary lymphatic drainage of patients who have undergone conservative surgery for breast cancer and to assess the correlations between the presence of MUC-1 and prognostic factors in breast cancer. Sixty-eight women with invasive ductal carcinoma of the breast underwent wide local excision and axillary lymph node dissection. Axillary drains were inserted in all these cases, and the presence of MUC-1 and beta-actin was evaluated by RT-PCR in the lymphatic fluid collected after the operation. Prognostic factors included tumour size and grade, vascular and lymphatic invasion, clearance margins of the resected specimens and status of the axillary lymph nodes. RT-PCR assays for MUC-1 in the axillary fluid were positive in 17 patients (25%). The presence of MUC-1 was associated with increased tumour size and showed a positive correlation with axillary lymph node metastases and incomplete resection of the tumour. RT-PCR can disclose cancer cells in the axillary fluid after conservative surgery for breast cancer. The presence of MUC-1 in the axillary drainage may be associated with poor prognostic features, and its detection may have implications for therapy as it suggests that re-excision should be considered.
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PMID:Detection of cancer cells in the axillary drainage using RT-PCR after operations for breast cancer. 1475 16

The KiSS-1 gene encodes a 145 amino acid residue peptide that is further processed to a final peptide, metastin, a ligand to a G-coupled orphan receptor (OT7T175/AXOR12). KiSS-1 has been identified as a putative human metastasis suppressor gene in melanomas and in breast cancer cell lines. This study aimed to determine the expression and distribution of KiSS-1 and its receptor in human breast cancer tissues and to identify a possible link between expression levels and patient prognosis. Frozen sections from breast cancer primary tumours (matched tumour 124 and background 33) were immuno-stained with KiSS-1 antibody. RNA was reverse transcribed and analyzed by Q-PCR (standardized using beta-actin, and normalized with cytokeratin-19 levels). Levels of expression of KiSS-1 were higher in tumour compared to background tissues (3,124+/-1,262 vs 2,397+/-1,181) and significantly increased in node positive tumours compared to node negative (3,637+/-1,719 vs 2,653+/-1,994, P = 0.02). KiSS-1 expression was also increased with increasing grade and TNM status. There were no such trends with the KiSS-1 receptor. Expression of KiSS-1 was higher in patients who had died from breast cancer than those who had remained healthy (4,631+/-3,024 vs 2,280+/-1,403) whereas expression of the receptor was reduced (480+/-162 vs 195+/-134). Immunohistochemical staining showed increased expression of KiSS-1 in tumour sections. Insertion of the KiSS-1 gene into the human breast cancer cell line MDA-MB-231, resulted in cells that were significantly more motile and invasive in behaviour, with reduced adhesion to matrix, using respective assays. In conclusion, KiSS-1 expression is increased in human breast cancer, particularly in patients with aggressive tumours and with mortality. Over-expression of KiSS-1 in breast cancer cells result in more aggressive phenotype. Together, it suggests that KiSS-1 plays a role beyond the initial metastasis repressor in this cancer type.
Clin Exp Metastasis 2005
PMID:KiSS-1 expression in human breast cancer. 1632 Jan 13


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