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)

c-erbB2/neu is a transforming oncogene that encodes a 185-kDa transmembrane glycoprotein. In many but not all studies, amplification and/or overexpression of the human c-erbB2/neu oncogene has been correlated with poor prognosis and the number of lymph node metastases in node-positive breast cancer patients. We have shown that expression of the activated rat c-erbB2/neu oncogene in mouse embryo fibroblast 3T3 cells is sufficient to induce experimental metastases in nude mice. Important steps in the metastatic event are tumor cell adhesion to endothelial cells and invasion of basement membranes. Therefore, we further examined the ability of c-erbB2/neu oncogene-transformed 3T3 cells to adhere to microvessel endothelial cells and secrete basement membrane-degradative enzymes. The c-erbB2/neu oncogene-transformed 3T3 cells were shown to be more adherent and have higher gelatinase activities. Since we had previously shown that the adenovirus 5 E1A gene product can suppress c-erbB2/neu-induced transformation of 3T3 cells, we examined the possibility that E1A can abrogate the metastatic properties of c-erbB2/neu-transformed 3T3 cells. We found that introduction of the E1A gene into c-erbB2/neu-transformed 3T3 cells reduced the formation of experimental metastatic tumors and inhibited metastasis-associated properties, such as adhesion to microvessel endothelial cells, migration through a layer of reconstituted basement membrane (Matrigel) and secretion of basement membrane-degradative enzymes. The results indicate that the mechanism by which the c-erbB2/neu gene induces higher metastatic potential is to promote adhesion and invasion steps of the metastatic cascade. The E1A gene, which functions by inhibiting these steps, is thus a suppressor gene for c-erbB2/neu-induced experimental metastasis.
 ...
PMID:Mechanisms of c-erbB2/neu oncogene-induced metastasis and repression of metastatic properties by adenovirus 5 E1A gene products. 135 95

The human homolog of the rat neu oncogene, HER2 (also termed c-erbB2) has been demonstrated in amplified form in human breast tumors with poor prognosis. Although amplification of the gene correlates with expression of a 185-kDa transmembrane glycoprotein, no extensive information is available regarding the extent of tissue and tumor specificity of this gene product. We have addressed this issue by immunohistochemically evaluating the expression of p185 HER2 in normal tissue and various tumors using monoclonal antibodies (MAbs) to distinct epitopes of its extracellular domain. No detectable levels of p185 HER2 were found in fetal tissues analyzed, with the exception of renal tubules in 2 out of 3 specimens tested and in intestinal epithelium. In adult tissues, detectable levels of this glycoprotein were found in a restricted number of cell types, the expression being heterogeneous among individuals and cell histotypes. Among the neoplasms assayed p185 HER2 was expressed in 46% of primary breast cancers, in 28% of ovarian tumors and in 30% of colon rectum malignancies. No male breast adenocarcinomas were p185-positive. A large number of other tumors tested revealed only a low incidence of expression of the p185. In metastatic breast tumors p185 HER2 was demonstrated homogeneously among multiple autologous lesions and almost invariably (80%) the expression of p185 in the primary lesion correlated with that of the deriving metastases. Our findings indicate that the expression of the p185 HER2 represents a tumor marker of clinical relevance in breast cancer. Whether this holds true for other malignancies remains to be explored.
 ...
PMID:Expression of the p185 encoded by HER2 oncogene in normal and transformed human tissues. 196 37

Invasion is the cause of cancer malignancy. Invasion leads to metastasis and metastases turn cancer into an incurable disease. The only model of "true" invasion and metastasis is the natural human or animal tumor. Nevertheless, experimental models have largely contributed to the development of new concepts such as the multistep invasion process of metastasis, the growth-separate-from-invasion concept and the transient expression of the invasive phenotype by a subpopulation of cancer cells. All these aspects of invasion are considered within micro-ecosystems that are initiated by the cancer cells but in which host cells may play an equally important role. It is our opinion that invasion is regulated by the balance between the activation and inactivation of two sets of genes, invasion-promoter and invasion-suppressor genes. These genes encode molecules that determine the expression of the invasive and the noninvasive (normal) phenotype. E-cadherin is an invasion-suppressor gene product that belongs to the calcium-dependent homophilic cell-cell adhesion molecules. This transmembrane glycoprotein is involved not only in the mechanics of adhesion but also serves as a signal-transducer via its linkage with the catenins and the actin cytoskeleton. In human and in experimental cancers disturbance of the cadherin-catenin complex have been found at multiple levels. Candidate invasion-promoter molecules may be found among lytic enzymes and their associated molecules, motility factors and heterotypic cell-cell adhesion molecules. Investigation of the cellular interactions within the micro-ecosystem of bone metastasis has lead to the treatment of bone metastases with bisphosphonates. This application demonstrates the potential clinical benefit of a better understanding of the cellular and molecular mechanisms of cancer invasion and metastasis.
 ...
PMID:[When and why does cancer metastasize? An overview of current viewpoints OF the molecular mechanism of invasiveness]. 804 67

The molecular mechanisms by which human cancer cells spread to bone are largely unexplored. The process likely involves cell adhesion molecules (CAMs) that are responsible for homophilic and heterophilic cell-cell interactions. One relevant CAM may be the calcium-dependent transmembrane glycoprotein E-cadherin. To investigate the involvement of E-cadherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injections of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadherin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop radiographically detectable multiple osteolytic bone metastases and cachexia in this model. However, MDA-231 breast cancer cells that were transfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and histomorphometrical analyses of bones of mice bearing mock-transfected MDA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadherin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA-231 breast cancer cells survived longer than mice bearing mock-transfected MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nude mice were unchanged between mock-transfected and E-cadherin-expressing MDA-231, suggesting that these differences in metastatic behavior are not due to an impairment of cell growth and tumor-igenicity. Our results show the suppressive effects of E-cadherin expression on bone metastasis by circulating breast cancer cells and suggest that the modulation of expression of this CAM may reduce the destructive effects of breast cancer cells on bone.
 ...
PMID:E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model. 875 80

The cells of various normal and malignantly transformed tissues are connected by "adhering junctions"-plasma membrane domains characterized by close membrane-membrane contact, a dense cytoplasmic plaque and, in most cases, the attachment of cytoskeletal filaments. On the basis of their specific ultrastructural organization and molecular composition, three major types of intercellular adhering junctions can be distinguished: 1. Adherens junctions appear in different shapes and sizes (zonula adhaerens, fascia adh., punctum adh.) and contain the transmembrane glycoprotein E-cadherin. The cytoplasmic portion of E-cadherin forms complexes with alpha-, beta-, and gamma-catenin and plakoglobin which, together with other proteins such as vinculin and radicin, constitute a plaque at which actin microfilaments insert. 2. Desmosomes (maculae adhaerentes) are mostly isodiametric (diameters up to approximately 0.5 micron) membrane domains traversed by representatives of two types of desmosomal cadherins, the desmogleins (Dsg) and desmocollins (Dsc), whose cytoplasmic tails contribute to a dense plaque containing plakoglobin and desmoplakin I (with or without an alternative splice form, desmoplakin II) which anchor IFs. The specific Dsc and Dsg subtypes can differ in different cell types and up to three different human genes have so far been identified for each desmosomal cadherin. 3. Complexus adhaerentes are junctions of variable size and shape that occur in lymphatic endothelia. They have a desmoplakin- and plakoglobin-rich plaque, whose specific transmembrane proteins have not yet been fully elucidated but can include endothelial cadherin-5. In their most elaborate subform- the "syndesmos" connecting the retothelial cells of lymph node sinus-these junctions can occupy extended portions of the cell surface. The molecular arrangements in desmosomes and complexus adhaerentes have been studied to understand the assembly and disappearance of these structures. The diagnostic potential of their constituent proteins for cell typing in tumor diagnosis is emphasized, as is the role of transient junction dissociation during invasion and metastasis of carcinomas and the general importance of tumor cell interactions with the retothelial cell system in the formation of lymph node metastases.
 ...
PMID:The desmosome and the syndesmos: cell junctions in normal development and in malignancy. 898 60

CD44 is a transmembrane glycoprotein, the variant isoforms of which are coded for by alternative splicing, with the most prolific isoform being CD44 standard. CD44 is found in a wide variety of tissues including the central nervous system, lung, epidermis, liver, and pancreas, whereas variant isoforms of CD44 (CD44v) appear to have a much more restricted distribution. Variants of CD44 are expressed in tissues during development, including embryonic epithelia. Known functions of CD44 are cellular adhesion (aggregation and migration), hyaluronate degradation, lymphocyte activation, lymph node homing, myelopoiesis and lymphopoiesis, angiogenesis, and release of cytokines. The functions of CD44 are principally dependant on cellular adhesion in one setting or another. The role of CD44 in neoplasia is less well defined, although metastatic potential can be conferred on non-metastasising cell lines by transfection with a variant of CD44 and high levels of CD44 are associated with several types of malignant tumours. The physiological functions of CD44 indicate that the molecule could be involved in the metastatic spread of tumours. Many studies have investigated the pattern of CD44 distribution in tumours and some observations suggest that certain cells do not use CD44 in tumorigenesis or in the production of metastases. However, the data are extremely conflicting, and further studies are needed to establish the prognostic value of CD44 and its variant isoforms. The precise function of CD44 in the metastatic process and the degree of involvement in human malignancies has yet to be established fully.
 ...
PMID:The normal structure and function of CD44 and its role in neoplasia. 989 44

Reduced expression of E-cadherin (E-cad), a transmembrane glycoprotein, is associated with loss of differentiation, acquisition of an invasive phenotype, and an unfavorable prognosis in carcinomas from several sites. We used immunohistochemistry to study the expression of E-cad in 50 adenoid cystic carcinomas (ACCs) in salivary glands to evaluate correlations with clinicopathologic parameters and patient survival. Absent or low E-cad expression was observed more frequently in solid than in cribriform or tubular carcinomas. E-cad expression also was significantly correlated with histologic grade and the growth pattern. In addition, ACCs showing low or absent E-cad expression were more frequently larger than 4 cm in diameter, and distant metastases developed more frequently. Reduced expression correlated with shorter disease-free intervals and actuarial survival rates. Univariate and multivariate analysis identified tumor stage and E-cad expression as the only 2 parameters predictive of the disease-free interval. E-cad expression and tumor stage, grade, and type of growth were significant prognostic factors for survival in univariate analysis, while tumor stage, type of growth, and E-cad expression were the only significant covariates in multivariate analysis. These findings indicate that the loss of E-cad has an important role in the natural history of ACC, as it is associated with loss of differentiation and development of metastases. We also provide evidence that E-cad expression is an independent indicator of clinical aggressiveness in patients with ACC, together with clinical stage and type of growth at the periphery of the tumor.
 ...
PMID:Reduced E-cadherin expression correlates with unfavorable prognosis in adenoid cystic carcinoma of salivary glands of the oral cavity. 989 53

CD44 is a transmembrane glycoprotein involved in cell-cell and cell-substrate interactions. As a cell surface molecule, CD44 may be shed or released into the circulation by proteolytic enzymatic mechanisms. Therefore, soluble CD44 can be found in cell culture supernatants as well as in plasma. In this study we evaluated the levels of soluble total CD44 (sCD44) in serum samples of patients with breast and colorectal carcinoma as well as non-Hodgkin's lymphoma in order to correlate prognosis with sCD44 expression. Besides, we evaluated other clinical tumour markers routinely used, Cancer Antigen (CA) 15.3 and CA 19.9. We investigated 132 serological samples from breast cancer patients, 48 sera from colorectal tumours, 48 samples from stage IV non-Hodgkin's lymphoma and sera from 80 individuals without evidence of cancer or autoimmune disease. Breast cancer patients were divided into three groups: a) patients with no clinical evidence of positive nodules and no metastatic disease; b) patients with positive nodules; and c) patients with metastasis. sCD44 mean serum levels in these groups were 198+/-54 ng/ml, 221+/-78 ng/ml and 242+/-119 ng/ml, respectively, while the marker CA 15.3 values were 15.6+/-6.6 U/ml, 14.0+/-5.8 U/ml and 211.5+/-358.9 U/ml, respectively. sCD44 levels for colorectal tumour were 243+/-72 ng/ml, while CA 19.9 serum levels were 230+/-270 U/ml. Stage IV non-Hodgkin's lymphoma sCD44 levels were 398+/-160 ng/ml. sCD44, CA 15.3 and CA 19.9 values for healthy individuals without evidence of any cancer pathology were 223+/-58 ng/ml, 16.4+/-6.2 U/ml and 33+/-14 U/ml, respectively. From these results we conclude that sCD44 might be used as a reliable marker for patients with non-Hodgkin's lymphoma. However, sCD44 levels failed to correlate with prognosis, tumour burden or metastasis in breast and colorectal cancer patients. Neither was any correlation found between high CA 15.3 or CA 19.9 levels and soluble CD44 serum level.
 ...
PMID:Evaluation of soluble CD44 in patients with breast and colorectal carcinomas and non-Hodgkin's lymphoma. 1042 14

MUC1 mucin is a high molecular weight transmembrane glycoprotein expressed on the apical cell surface of normal glandular epithelia. In many human adenocarcinomas, this protein is up-regulated and/or underglycosylated, and its expression changes from apical to the entire cell membrane. It is thought that entire cell membrane expression of MUC1 reduces cell-cell and cell-extracellular matrix interactions and therefore may facilitate invasive growth and development of metastases. In this study, we determined immunohistochemically the expression of normal and underglycosylated MUC1 in normal breast tissue (n = 8) and in a spectrum of breast lesions, including usual ductal hyperplasia (n = 23), atypical ductal hyperplasia (n = 7), and ductal carcinoma in situ (DCIS) (n = 22). We used 4 monoclonal antibodies; 115D8 is directed to a glycopeptide, the other 3 to the peptide core of the molecule, of which 139H2 is not affected by the degree of glycosylation of MUC1, whereas SM3 and VU-4-H5 stain only underglycosylated forms. All cases showed apical positivity for 115D8 and 139H2. Entire cell membrane expression of fully (normal) glycosylated MUC1 was mainly found in DCIS lesions. Apical staining of SM3 was found in 38% of normal cases and 60% of the ductal lesions with no difference between the different subgroups. Apical staining of VU-4-H5 was found more often in DCIS (27%) than in normal tissue or ductal hyperplasia (3%). Membrane expression of underglycosylated MUC1 was found only in poorly differentiated DCIS. In conclusion, aberrant expression of MUC1, i.e., on the entire cell membrane and/or underglycosylated forms, can be found in ductal hyperplasia with atypia and especially in DCIS of the breast. This finding implies that these lesions with aberrant expression are at higher risk for developing subsequent invasive breast carcinoma.
 ...
PMID:Aberrant expression of MUC1 mucin in ductal hyperplasia and ductal carcinoma In situ of the breast. 1050 21

Loss of the CD44 transmembrane glycoprotein in primary prostate cancer has been shown to be associated with unfavorable clinical behavior. Moreover, the majority of prostate cancer metastases lack expression of this molecule. The mechanism of CD44 silencing in prostate cancer was investigated using both patient material and in vivo-propagated human prostate cancer xenografts. In 9 of 11 lymph node metastases of prostate cancer, we demonstrated by methylation-sensitive restriction enzyme digestion that the promoter region of the CD44 gene is methylated, indicating that this represents a major mechanism of CD44 silencing. Similarly, in 6 out of 12 in vivo-growing human prostate carcinoma xenograft models, hypermethylation of the CD44 gene was found. The extent of CpG island methylation was investigated by nucleotide sequencing after bisulphite modification of the CD44 promoter region. In the xenografts displaying hypermethylation, the examined 14 CpG sites in the CD44 transcription regulatory domain, including a Sp1 binding site, were consistently methylated. This correlated with reduced CD44 expression or lack of CD44 expression at mRNA and protein levels. In the xenografts lacking hypermethylation of the CD44 gene, high levels of CD44 mRNA and protein were expressed in some models, whereas in others CD44 mRNA expression was only detectable by RT-PCR and the CD44 protein could hardly be detected or was not detected at all. The results indicate that, in most prostate cancers, loss of CD44 expression is associated with extensive hypermethylation of the CpG island of the CD44 promoter region, but other, posttranscriptional mechanisms may also lead to CD44 loss.
 ...
PMID:Silencing of CD44 expression in prostate cancer by hypermethylation of the CD44 promoter region. 1095 Jan 20


1 2 3 4 5 Next >>