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)

Epithelial mucins have obtained increasing clinical relevance since they were found in the serum of cancer patients and were shown to be elevated in metastatic disease. We report here the characterization of the monoclonal antibody (MAb) 436 which recognises the protein core of the polymorphic epithelial mucin (PEM) of the human breast. MAb 436 was generated by immunizing Balb/c mice with membrane-enriched fractions prepared from metastatic lesions in the axillary lymph nodes. The antigenic determinant recognized by the MAb 436 is expressed on the surface of breast cancer cells and was measured by ELISA on all of 50 cytosol preparations of primary breast tumors. Immunohistochemistry showed 98% of primary and 100% of metastatic breast cancer lesions to be positive with the 436 antigenic determinant expressed both in the cytoplasm and at the plasma membrane level of the tumor cells. Moreover, the antigen was expressed in a homogeneous fashion (80-100% of the total number of tumor cells) in more than 60% of the tumors. Reactivity with normal tissues was rare and scattered and restricted to glandular structures particularly at the luminal border level except for the distal and collecting tubules of adult and fetal kidney, where a cytoplasmic 436 antigen distribution was observed. Other cancers proved positive but the reactivity was always variable and heterogeneous. The antigen recognized by MAb 436 appears in Western Blotting as a M(r) of more than 200,000 daltons protein resolved in two bands. Epitope mapping experiments using overlapping octapeptides in the repeat unit of the PEM identified in the RPAP (Arg-Pro-Ala-Pro) sequence the binding site of the 436 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Characterization of monoclonal antibody 436 recognizing the Arg-Pro-Ala-Pro sequence of the polymorphic epithelial mucin (PEM) protein core in breast carcinoma cells. 137 74

Episialin, a mucus glycoprotein, is a well-known tumor-associated antigen used in a variety of tests to detect the presence of adenocarcinoma. With the introduction of the microparticle-captured enzyme immunoassay (MEIA), a new technique was introduced. We compared this assay with our standard method to detect adenocarcinomas, the measurement of carcinoembryonic antigen (CEA). In breast cancer, the breast cancer mucin (BCM) assay was more often positive in metastatic disease but was not better than CEA in stages I-III. In lung carcinomas, BCM and CEA gave similar results while in colorectal carcinoma, CEA was superior. BCM gave similar results to CA 15.3 in a group of breast cancer patients.
 ...
PMID:Breast cancer mucin: an automated assay to detect mucus glycoproteins. 162 80

The BC2 monoclonal antibody, which binds to an epitope on the peptide backbone of polymorphic epithelial mucin, was tested immunohistochemically for reactivity with epithelial ovarian carcinoma. This epitope was expressed in 90 of 91 malignant ovarian tumors; in 88% of these, more than 50% of the tumor cells expressed the epitope. In 94% of the positive tumors, the epitope was expressed on the cell membrane; in 56%, cytoplasmic expression was evident; and in 39%, secreted extracellular antigen was detected. Differences were not clearly discernible between dissimilar histotypes with respect to the percentage of cells expressing antigen and antigen localization. Thirteen of 19 benign ovarian cystadenomas also expressed the epitope, but staining was weak and restricted to the luminal surface of the cell membrane. A blind retrospective immunohistochemical analysis of all second-look laparotomy biopsy specimens from 20 patients also was performed. All four patients in whom microscopic disease was detected by standard pathologic assessment had BC2-positive metastases. Of seven patients in whom recurrent disease subsequently developed despite negative pathologic findings, four had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Of the nine patients with negative results on operation and no recurrence, one had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Mesothelial cells, although typically negative, expressed the epitope in one biopsy specimen, necessitating caution in the interpretation of positive cells. The BC2 antibody is reactive with most epithelial ovarian carcinomas and appears to be a useful tool for the detection of micrometastases.
 ...
PMID:Expression of a polymorphic epithelial mucin antigen defined by the monoclonal antibody BC2 in ovarian carcinoma. Use of the BC2 antibody for the detection of micrometastases. 171 43

The luminal and basal epithelial cells in the human mammary gland can be distinguished in tissue sections on the basis of the pattern of keratins they express. Moreover, the invasive cells in primary carcinomas show a keratin profile that corresponds to that of the dominant luminal cell (7, 8, 18, 19). When homogeneous populations of luminal epithelial cells from milk or from breast cancer metastases are cultured the profile of keratin expression seen in vivo is maintained. We have therefore used monospecific antibodies reactive with individual keratins to examine the phenotype of cells cultured in three different media from reduction mammoplasty tissue that contains both luminal and basal cells. The phenotype of cells cultured from primary breast cancers in one of these media (MCDB170) has also been examined. In characterizing cell phenotypes, antibodies to a polymorphic epithelial mucin (PEM) expressed in vivo by luminal cells, and to smooth muscle (a) actin, expressed in vivo by basal cells, have also been used. Our results show that proliferation of different cell phenotypes is selected for in different media. In milk mix (MX) developed for growth of luminal cells from milk, only the luminal cell phenotype proliferates (for only 1 or 2 passages). In medium MCDB 170, which was developed for long-term growth of human mammary epithelial cells from reduction mammoplasty organoids, cells from the basal layer proliferate, while in MM medium the basal phenotype dominates, but a few cells with the luminal phenotype are found. Around passage 3, in medium MCDB 170, most cells senesce and a subpopulation of cells proliferates on further passage. These cells retain expression of the basal epithelial keratins but also express some features characteristic of luminal epithelial cells, suggesting that the basal layer may contain a stem cell that can develop along the luminal lineage. In culture, however, they do not express keratin 19, which in vivo is a feature of the fully differentiated luminal cell. The cells cultured from primary breast cancer in medium MCDB 170 have a similar keratin profile to that of the normal cells cultured in this medium. They do not express keratin 19, even though the invasive cells in primary cancers homogeneously express this keratin in vivo. The invasive phenotype, which in its keratin profile corresponds to the differentiated luminal cell and that of the metastatic cancer lines, cannot be cultured from primary breast cancers using MX, which supports proliferation of the corresponding normal cell.
 ...
PMID:Keratin expression in human mammary epithelial cells cultured from normal and malignant tissue: relation to in vivo phenotypes and influence of medium. 248 23

We have compared the pattern of surface antigen expression, as detected by monoclonal antibodies (mAbs), in plasma membranes vs shed membrane vesicles of two human breast carcinoma cell lines, MCF-7 and 8701-BC. Antigen expression was detected on cells by immunofluorescence (IF) analysis, whilst, due to their small dimensions, the same technique was not applicable to vesicles. For these structures dot-blot analysis and immunoelectron microscopy (IEM) were employed. When applicable, both cell membranes and membrane vesicles were immunoprecipitated and the precipitate (IP) was analyzed by SDS-PAGE. Cells of both lines expressed HLA class I antigens, epithelial cytokeratins, beta 1 integrins, CEA and the glycoprotein detected by mAb 19.9, but only MCF-7 cells expressed Lewis Y, episialin and globo-H antigens and only 8701-BC cells expressed folate receptor. Membrane vesicles of both cell lines appeared to be rich in beta 1, alpha 3 and alpha 5 integrin chains, expressed HLA class I antigens and carried most of the plasma membrane antigens found in the cell membranes. Overall we have analyzed 17 antigens on the two cell lines and on their vesicles. The results obtained for cells (IF and IP) and those for vesicles (dot-blot and IP) were generally concordantly positive or concordantly negative. We obtained a total of 26 clearly concordant combinations on 34 analyses. In three cases we found discordant results, whereas in the remaining combinations we observed slight reactivity and we found difficulties in determining concordance. Discordant results concerned the expression of the following antigens: folate receptors, which were clearly expressed in 8701-BC cells but not detected by dot-blot analysis or IEM on their shed membrane vesicles; neu (c-erb-B2) receptor found in MCF-7 cell membranes but not in their vesicles; and the globo-H antigen recognized by mAb MBr1, detected at low levels on 8701-BC plasma membranes but undetectable on their membrane vesicles. Like vesicles shed in vitro by cultured cells, the vesicles shed in vivo by human breast carcinoma cells could be tagged with several antibodies against tumor-associated antigens. The vesicles shed in vivo were found in association with a fiber network. Some of the fibers had the characteristic fibrin periodicity. These data suggest that tumor markers detected in the circulation of carcinoma patients, at least in part, are carried by shed membrane vesicles. Moreover the observation that membrane vesicles carry both tumor-associated antigens and HLA class I molecules indicate that these structures could in principle present antigens to the immune system.(ABSTRACT TRUNCATED AT 400 WORDS)
Clin Exp Metastasis 1995 Jul
PMID:Membrane vesicles shed into the extracellular medium by human breast carcinoma cells carry tumor-associated surface antigens. 760 90

Polymorphic epithelial mucin (PEM) is a heavily glycosylated protein present at the apical surface of glandular epithelial cells which is shed into the lumen of epithelial tissue. In carcinomas cell polarisation is lost, PEM is overexpressed and found on the entire cell surface. High amounts of PEM are shed into the circulation of cancer patients. CA 15.3 is the first commercial assay for the detection of PEM. After roughly one decade of use in clinical practice it is considered valuable for breast cancer therapy monitoring and, in the follow up, for early detection of metastatic disease. The extreme polymorphism of this molecule, with its varying number of multiple epitopes and tremendous variation in glycosylation which can mask catcher/tracer epitopes, impairs its precise measurement. A further impediment is complex formation with autoantibodies, as revealed by a recently developed assay.
 ...
PMID:Quantitation of polymorphic epithelial mucin: a challenge for biochemists and immunologists. 765 93

Episialin, also designated MUC1, CA 15-3 antigen and PEM, is an established serum marker for breast cancer. Its function and possible involvement in tumor progression has not yet been completely established. The molecule is an extended rod-like molecule protruding high above the cell surface. It is often highly overexpressed in breast cancer relative to normal breast epithelium cells. Overexpression of episialin on cells in vitro reduces cell-cell and cell-extracellular matrix adhesion, because the rod-like molecule masks the adhesion receptors. Episialin also exerts its anti-adhesion effect in vivo. In certain human tumors, where episialin was present at the basal side of the cell, abnormal contacts between the plasma membrane and the stroma were observed. As a consequence of its anti-adhesion properties, episialin overexpression reduces the sensitivity of the cells for cytotoxic lymphocytes. This might be one of the reasons why episialin transfected cells are more potent to form experimental metastases after i.v. injection into nude mice.
 ...
PMID:Is episialin/MUC1 involved in breast cancer progression? 772 39

Experimental systems using human mammary tissue, secretions and tumours may be based on in vitro culture or on growth of tissue or tumour fragments in the nude mouse. In the development of in vitro culture systems, a detailed characterization of the cultured cells within the framework of the epithelial cell lineages found in vivo is crucial. Monoclonal antibodies are useful tools for defining the profile of antigens expressed by the basal and luminal cells in the normal gland and in distinguishing subclasses between these two major groups. When these same reagents are used to characterize breast cancers, the majority are found to show the phenotype of luminal cells, with a small subset showing some evidence of basal markers. Luminal epithelial cells cultured from milk or reduction mammoplasty tissue have a short life span in vitro but can be immortalized using SV40TAg. Demonstrably malignant cells are difficult to culture from primary breast cancer, but ER+ and ER- cell lines showing the luminal phenotypes have been readily developed from metastases: some ER- breast cancer cell lines show a more undifferentiated phenotype, and these may have developed from tumours expressing basal markers. As with in vitro culture, it is difficult to obtain tumour growth in the nude mouse from primary breast cancer specimens, and established cell lines are also difficult to grow in this animal. We have focused our studies on cell lines with the luminal phenotype developed from milk. These non-tumorigenic cell lines differ from breast cancer cell lines (a) in being able to form organized three dimensional structures in the presence of an extracellular matrix and (b) in the correct glycosylation of the polymorphic epithelial mucin, which is expressed and aberrantly glycosylated in cancers. These cell lines are therefore being used to study the mechanisms underlying morphogenesis and the processing of PEM, and also as recipients for oncogenes and proto-oncogenes.
 ...
PMID:Human models of breast cancer. 834 39

Specific tumour imaging with radiolabelled monoclonal antibodies has been extensively investigated. Although some success has been reported, there are many limitations due to the slow kinetics, poor extravasation, catabolism by the reticuloendothelial system, and non-specific uptake of macromolecules such as antibodies. We have tried to overcome some of the problems associated with monoclonal antibodies while retaining their specificity by using an antibody-derived synthetic peptide. A synthetic pentadecapeptide (alpha M2) derived from the third heavy-chain complementarity-determining region (CDR-3H) of a tumour-associated monoclonal antibody was produced and shown to retain its specificity against the pan-carcinoma cell-surface antigen, polymorphic epithelial mucin, detected by the parent antibody. The peptide was radiolabelled with technetium-99m and injected intravenously to image malignant lesions in 26 women with primary, recurrent, or metastatic breast cancer. Visualisation of breast tumours and their metastases was obtained shortly after administration of alpha M2, and was optimum by 3 h. Overall, 57 (77%) of 74 sites were visualised. Successful imaging was achieved in 14 of 15 primary tumour sites and all of eight local recurrences. Five of six metastases in the opposite breast, eight of 15 metastatic axillary lymph nodes, and all of six metastatic supraclavicular lymph nodes were imaged. Metastatic sites in the lungs, mediastinum, chest wall, and liver were poorly visualised because of background cardiac blood pool. alpha M2 detected small lesions ( < 2 cm) as efficiently as larger ones. The peptide was rapidly (3 h) cleared from the circulation. No acute or chronic adverse reactions due to the alpha M2 were observed. Specific tumour targeting with the radiolabelled anticancer peptide alpha M2 offers new opportunities for breast cancer imaging and possibly therapy.
 ...
PMID:Breast cancer imaging with radiolabelled peptide from complementarity-determining region of antitumour antibody. 855 23

To investigate the clinical significance of an immune response to the MUC-1 encoded polymorphic epithelial mucin (PEM) breast cancer, circulating immune complexes containing PEM (PEM.CIC) were measured in sera from 96 healthy women, in pretreatment serum samples from 40 patients with benign breast tumours and from 140 patients with breast cancer and in serum samples from 61 breast cancer patients with recurrent or progressive disease. PEM.CIC were measured using a sandwich enzyme-linked immunoassay, and PEM serum levels were measured with CA 15.3 IRMA (Centocor Inc., Malvern, Pennsylvania, U.S.A.). Cut-off levels used for PEM.CIC and CA 15.3 were 120 Optical Density Units (O.D.) x 10(3) and 30 U/ml, respectively. In benign tumours, positivity for PEM.CIC was 37.5% (15/40). 36 of the 140 patients (25.7%) in the breast cancer pretreatment group had elevated PEM.CIC values. In patients with advanced metastatic disease, positivity for PEM.CIC was 18% (11/61). PEM.CIC was elevated in 32% (24/74) of node-negative patients, but only in 20% (12/59) of node-positive patients and absolute values were higher in node-negative patients (Mann-Whitney U test, two-tailed P = 0.0168). There was an inverse correlation between positivity for PEM.CIC and extent of disease: while 3 of the 6 patients with a carcinoma in situ were positive, only 1 of the 15 patients with more than five nodes involved had elevated levels of PEM.CIC. All 7 patients with distant metastases at first diagnosis were PEM.CIC negative. 28 out of 133 patients had a recurrence during the observation period (median 55 months, range 27-84 months). 23 of these 28 patients (82%) were PEM.CIC negative at the moment of first diagnosis. None of the patients with pretreatment elevation of both PEM.CIC and CA 15.3 (n = 13) relapsed. Our preliminary clinical results suggest that a humoral immune response to PEM protects against disease progression, and further support the idea of using synthetic peptides or glycopeptides containing the immunogenic core of the mucin as cancer vaccines.
 ...
PMID:Humoral immune response to polymorphic epithelial mucin (MUC-1) in patients with benign and malignant breast tumours. 886 94


1 2 3 4 5 Next >>