Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we found that MUC2 mucins could activate monocytes/macrophages through a scavenger receptor leading to cyclooxygenase (COX) 2 induction and overproduction of prostaglandin E2 (PGE2). To investigate the role of mucins in the tumor-bearing state, we compared s.c. tumor formation by using mucin-producing (TA3-Ha) and mucin-non-producing (TA3-St) cloned variants of mouse mammary adenocarcinomas. Expression of COX2 mRNA and protein and production of PGE2 were elevated in peritoneal macrophages stimulated with epiglycanin, which is a mucin-like glycoprotein produced by TA3-Ha cells. S.c. tumor tissues comprising TA3-Ha cells grew much faster than tissues comprising TA3-St cells. COX2 protein and vascular endothelial growth factor in TA3-Ha tumor tissues were elevated compared with the TA3-St tumor tissues. Although similar numbers of macrophages were observed immunochemically in the two types of tumor tissues, COX2 was induced prominently in the infiltrating macrophages in TA3-Ha tumor tissues but only faintly in TA3-St tumor tissues. Furthermore, angiogenesis progressed remarkably in TA3-Ha tumor tissues but only slightly in TA3-St tumor tissues. Epiglycanin-induced overproduction of PGE2 down-regulated interleukin-12 production by macrophages. IFN-gamma-producing CD4 T cells in spleens obtained from TA3-Ha tumor-bearing mice were significantly reduced compared with TA3-St tumor-bearing mice, suggesting that mucins cause PGE2-mediated immune suppression. Actually, the tumor growth of a TA3-Ha cell xenograft was suppressed effectively by oral administration of a COX2 inhibitor but that of a TA3-St cell one was not. These results suggest that mucins play an important role in tumor progression through overproduction of PGE2.
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PMID:Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. 1677 91

Patients with metastatic cancer commonly have increased serum galectin-3 concentrations, but it is not known whether this has any functional implications for cancer progression. We report that MUC1, a large transmembrane mucin protein that is overexpressed and aberrantly glycosylated in epithelial cancer, is a natural ligand for galectin-3. Recombinant galectin-3 at concentrations (0.2-1.0 microg/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast (ZR-75-1) and colon (HT29-5F7) cancer cells to human umbilical vein endothelial cells (HUVEC) by 111% (111 +/- 21%, mean +/- S.D.) and 93% (93 +/- 17%), respectively. Recombinant galectin-3 also increased adhesion to HUVEC of MUC1 transfected HCA1.7+ human breast epithelial cells that express MUC1 bearing the oncofetal Thomsen-Friedenreich antigen (Galbeta1,3 GalNAc-alpha (TF)) but did not affect adhesion of MUC1-negative HCA1.7-cells. MUC1-transfected, Ras-transformed, canine kidney epithelial-like (MDE9.2+) cells, bearing MUC1 that predominantly carries sialyl-TF, only demonstrated an adhesive response to galectin-3 after sialidase pretreatment. Furthermore, galectin-3-mediated adhesion of HCA1.7+ to HUVEC was reduced by O-glycanase pretreatment of the cells to remove TF. Recombinant galectin-3 caused focal disappearance of cell surface MUC1 in HCA1.7+ cells, suggesting clustering of MUC1. Co-incubation with antibodies against E-Selectin or CD44H, but not integrin-beta1, ICAM-1 or VCAM-1, largely abolished the epithelial cell adhesion to HUVEC induced by galectin-3. Thus, galectin-3, by interacting with cancer-associated MUC1 via TF, promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. This suggests a critical role for circulating galectin-3 in cancer metastasis and highlights the functional importance of altered cell surface glycosylation in cancer progression.
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PMID:Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. 1709 May 43

The epithelial mucin MUC1 is a high molecular weight membrane glycoprotein frequently overexpressed and aberrantly glycosylated in adenocarcinoma. Mucins normally contain high amounts of O-linked carbohydrate structures that may influence immune reactions to this antigen. During malignant transformation, certain glyco-epitopes of MUC1, such as Tn-antigen, TF-antigen and their sialylated forms become exposed. The role of these glycan structures in tumor biology is unknown, but their presence is known to correlate with poor prognosis in several adenocarcinomas. We analyzed the potency of MUC1 containing Tn-antigens (MUC1-Tn) to target C-type lectins that function as carbohydrate recognition and uptake molecules on dendritic cells (DC). We identified the macrophage galactose type C-type lectin (MGL), expressed by both DC and macrophages, as the receptor for recognition and binding of MUC1-Tn. To validate the occurrence of MGL-MUC1 interactions in situ, we studied the binding of MGL to MUC1 in primary colon carcinoma tissue. Isolation of MUC1 out of colon carcinoma tissue showed strong binding activity to MGL. Interestingly, MGL binding to MUC1 was highly correlated to binding by the lectin Helix pomatia agglutinin (HPA), which is associated with poor prognosis in colorectal cancer. The detection of MGL positive cells in situ at the tumor site together with the modified glycosylation status of MUC1 to target MGL on DC suggests that MGL positive antigen presenting cells may play a role in tumor progression.
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PMID:The C-type lectin MGL expressed by dendritic cells detects glycan changes on MUC1 in colon carcinoma. 1719 76

Mucins are large, heavily O-glycosylated proteins expressed by epithelial tissues. The canonical function of membrane mucins is to provide protection to vulnerable epithelia by forming a steric barrier against assault, and by contributing to the formation of protective extracellular mucin gels. The aberrant overexpression of mucins is thought to contribute to tumor progression by allowing tumor cells to evade immune recognition, and by aiding in the breakdown of cell-cell and cell-matrix contacts to facilitate migration and metastasis. Recent evidence suggests that we should now modify our thinking about mucin function by considering their roles in signaling pathways leading to cellular growth control. Here we review the markedly divergent mechanisms by which membrane mucins, specifically MUC1 and MUC4, influence pathways contributing to cellular proliferation and survival. The cytoplasmic domain of MUC1 serves as a scaffold for the assembly of a variety of signaling proteins, while MUC4 influences the trafficking and localization of growth factor receptors, and hence their responses to external stimuli. We also discuss how tumor cells exploit these mechanisms to promote their own growth and metastasis.
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PMID:Contribution of membrane mucins to tumor progression through modulation of cellular growth signaling pathways. 1733 13

Prostate cancer (CaP) is one of the most common malignancies in men, and the incidence of CaP is increasing. Because of the limitations of current therapeutic approaches, many patients die of secondary disease (metastases). Mucins are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression. There is a growing interest in mucins as treatment targets in human malignancies, including CaP. So far, 21 mucin genes have been identified. Of these, MUC1 has been investigated most extensively. In neoplastic tissues, MUC1 is underglycosylated compared with that in normal tissues. The reduced glycosylation permits the immune system to access the peptide core of the tumor-associated underglycosylated MUC1 antigen (uMUC1) and reveal epitopes that are masked in the normal cell. This feature makes it possible to design an antibody that discriminates between normal and adenocarcinoma cells and target tumor-associated MUC1 with toxins or radionuclides, or use a vaccine targeting tumor-associated MUC1 antigen. The results from our recent study have shown that over-expression of MUC1 plays a very important role in CaP progression and MUC1 is an ideal target for targeted therapy to control micrometastases and hormone refractory disease. This review will cover our current understanding of the structure and functions of MUC1, summarize its expression on human CaP tissues and focus on the MUC1-based immunotherapy for control of metastatic CaP.
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PMID:MUC1 is a promising therapeutic target for prostate cancer therapy. 1750 23

The mucin-type transmembrane glycoprotein podoplanin (also known as T1alpha, gp38 or Aggrus) is well established as one of the lymphatic-specific markers. Podoplanin was also reported to be associated with tumor-induced platelet aggregation and tumor metastasis. Here, we generated a novel monoclonal antibody (clone; 7B10) that specifically recognized human podoplanin, as assessed by enzyme-linked immunosorbent assay, Western blot analyses, immunohistochemistry and flow cytometry. 7B10 stained not only lymphatic vessels but also type I alveolar cells in the lung, podocytes in the kidney and myoepithelial cells in the breast. In addition, podoplanin expression was analyzed by immunostaining on tissue microarrays that included 12 different cancer types using 7B10. Consequently, we found that podoplanin was expressed by cancer cells derived from esophagus, lung, liver, colon and breast, as well as lymphatic endothelial cells. These findings suggest a potential role of podoplanin in tumor progression in diverse types of human cancers.
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PMID:Immunohistochemical detection of the lymphatic marker podoplanin in diverse types of human cancer cells using a novel antibody. 1767 75

T-Antigen (Gal-beta1,3-GalNAc-alpha-O-Ser/Thr) is an important precursor of mucin-type O-glycans. T-Antigen is found to be closely associated with cancer progression and metastasis and has been used to develop carbohydrate-based anticancer vaccines. Enzymatic synthesis of T-antigen disaccharides have relied on the use of beta-1,3-galactosyltransferases recently cloned and characterized from several eukaryotic organisms. However, its application is limited by the difficulty of obtaining homogeneous enzymes and the strict substrate specificity of enzymes. Recently, a number of bacteria have been found to express carbohydrate structures that mimic host glycans. The corresponding glycosyltransferases have been exploited in the facile synthesis of a number of clinically important glycoconjugate mimics. In this study, we biochemically characterized a bacterial beta-1,3-galactosyltransferase (WbiP) from Escherichia coli O127, which expresses a T-antigen mimic in the lipopolysaccharide (LPS) structure. Substrate study showed that WbiP could readily glycosylate a series of N-acetylgalactosamine (GalNAc) analogues with alpha-substitutions at the reducing end, including glycosylated Ser and Thr (GalNAc-alpha-O-Ser/Thr), which illustrates the use of WbiP for the facile synthesis of T-antigens. Alignment of a group of putative bacterial beta-1,3-galactosyltransferases revealed the presence of two conserved DXD motifs, possibly suggesting a different functional role of each motif. Site-directed mutagenesis, enzyme kinetics as well as UDP-bead binding assays were carried out to investigate the role of each DXD motif in WbiP. The results suggest that 88DSD90 is critical in the binding of sugar donor UDP-Gal, whereas 174DYD176 may participate in the binding of the sugar acceptor. This study expands the scope of using bacterial glycosyltransferases as tools for in vitro synthesis of glycoconjugate mimics with clinical significance.
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PMID:Characterization of a bacterial beta-1,3-galactosyltransferase with application in the synthesis of tumor-associated T-antigen mimics. 1817 56

Mucinous endocervical adenocarcinoma is characterized by increased watery vaginal discharge, but the early diagnosis is sometimes difficult because biopsy specimen might only serve to sample a superficial part of the tumor. The patient presented with complaints of abdominal distention. No vaginal bleeding or watery discharge was observed. Hydrometra was suspected by imaging studies. Rapid reaccumulation of hydrometra was seen despite drainage. Papanicolaou smear of endocervix and endometrium followed by fractional curettage was performed, but failed to confirm the diagnosis. To investigate the unknown origin of hydrometra, an exploratory laparotomy with total hysterectomy and bilateral salpingo-oophorectomy was performed, followed by pelvic lymphadenectomy because biopsy specimens during operation suggested adenocarcinoma of the cervix. The final pathologic study of surgical specimens revealed mucinous adenocarcinoma, which was located on the proximal area of cervix. Adjacent to carcinoma tissue, lobular endocervical glandular hyperplasia (LEGH) was detected. Pyloric gland mucin (HIK1083), MUC6, and MUC5AC were diffusely immunopositive in the cytoplasm of LEGH cells and the immunoreactivity became weaker in adenocarcinoma cells with tumor progression and loss of differentiation. Based on histopathologic features of the present case, there seems to be a possible link between LEGH and conventional mucinous endocervical adenocarcinomas. The physician should keep in mind the possible existence of endocervical adenocarcinoma in a patient showing rapid reaccumulation of hydrometra, when uterine malignancies are clinically suspected and biopsy finding fails to confirm the diagnosis.
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PMID:Endocervical adenocarcinoma associated with lobular endocervical glandular hyperplasia showing rapid reaccumulation of hydrometra. 1821 72

Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin secretion, proliferation, invasiveness, metastasis and bad prognosis. But, the role of MUC1 in cancer progression is still controversial and somewhat confusing. While Mukherjee and colleagues developed MUC1-specific immune therapy in a CRC model, Lillehoj and co-investigators showed recently that MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. In carcinoma cells the polarization of MUC1 is lost and the protein is over expressed at high levels over the entire cell surface. A competitive interaction between MUC1 and E-cadherin, through beta-catenin binding, disrupts E-cadherin-mediated cell-cell interactions at sites of MUC1 expression. In addition, the complex of MUC1-beta-catenin enters the nucleus and activates T-cell factor/leukocyte enhancing factor 1 transcription factors and activates gene expression. This mechanism may be similar to that just described for DCC and UNC5H, which induced apoptosis when not engaged with their ligand netrin, but mediate signals for proliferation, differentiation or migration when ligand bound.
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PMID:MUC1 and colorectal cancer pathophysiology considerations. 1840 86

The human gene MUC4 encodes a transmembrane mucin, ligand of ErbB2, that is associated with pancreatic tumor progression. In the normal pancreas, MUC4 is not expressed, whereas activation of its expression is observed in the early steps of pancreatic carcinogenesis. The molecular mechanisms responsible for MUC4 gene activation are however still unknown. The MUC4 5'-flanking region being GC-rich and including two CpG islands, we hypothesized that epigenetic regulation may be involved and undertook to decipher the molecular phenomenons implied. By treating cancer cell lines with 5-aza-2'-deoxycytidine (5-aza) and trichostatin A (TSA), we were able to restore MUC4 expression in a cell-specific manner. We showed by bisulfite-treated genomic DNA sequencing and chromatin immunoprecipitation that methylation of five CpG sites and establishment of a repressive histone code at the 5'-untranslated region were associated with MUC4 silencing and impaired its activation by Sp1. Direct involvement of DNMT3A, DNMT3B, HDAC1, and HDAC3 was demonstrated by RNA interference and chromatin immunoprecipitation. Moreover, inhibition of histone deacetylation by TSA was associated with strong MUC4 repression in high-expressing cells. In conclusion, this work shows for the first time the importance of epigenetics in regulating MUC4 expression and may represent a new strategy to inhibit its expression in epithelial tumors.
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PMID:Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases. 1849 26


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