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The clinicopathological profiles of histiocytoid carcinoma of the breast have not been well examined because of their rarity and heterogenous groups of ductal and lobular origin. A large foamy or granular cytoplasm of histiocytoid carcinoma was characterized by abundant mucin, but the properties of mucin in histiocytoid carcinoma have also not been well investigated. We selected eight cases of histiocytoid features of invasive lobular carcinoma (HLC) and compared with 14 age- and tumor size-matched cases of classical invasive lobular carcinoma (CLC). Mucin profiles were significantly different between the two groups: a fair number of HLC cases were immunopositive for MUC2 and MUC5AC (75 and 50%, respectively); in contrast, almost all CLC cases showed both as negative. Both groups were immunopositive for MUC1 and negative for MUC4 and MUC6. The prognosis of HLC was significantly worse than CLC; HLC showed shorter disease-free time than CLC (p=0.0262). In particular, HLC with MUC2 and MUC5AC expressions showed significantly shorter disease-free time and survival time than lobular carcinoma without the expressions of MUC2 and MUC5AC (p=0.0055 and p=0.0060, respectively). Therefore, the expression of 'non-mammary mucins', such as MUC2 and MUC5AC in HLC, is characteristic and indicates the more malignant transformation of tumor cells and poorer prognosis.

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

There are limited data regarding the prognostic value of the pattern of mucin expression in IM. To examine the role of the type of IM and pattern of mucin expression in IM as histological risk markers of gastric cancer, 80 patients with a history of endoscopic mucosal resection (EMR) for early gastric cancer and 80 sex and age-matched controls were studied. Serum levels of pepsinogen (PG) were measured by RIA, and MUC2, MUC5AC and MUC6 were evaluated immunohistochemically. There is a significant association between types of IM and atrophic scores or PG levels. The most incomplete IM (type II and III) preserving gastric mucin is the gastric and intestinal mixed (GI) type, whereas the complete type is the intestinal (I) type especially in the corpus lesser curve. Gastric cancer was most significantly associated with incomplete IM in the corpus lesser curve (OR=6.4; 95% CI, 2.0-21, p=0.002). Asynchronous multiple lesions were associated with incomplete IM in the corpus greater curve (OR=4.8; 95% CI, 1.4-16, p=0.01). Classification of IM obtained using fixed-point biopsy samples may enhance the ability of surveillance programs to detect patients at increased risk of gastric cancer.

Background: Gastric marker mucins (MUC5AC and MUC6) and intestinal marker molecules (MUC2 and CD10) have been used to determine the cell lineage of epithelial cell of gastric carcinoma (GC)., Methods: To clarify the characteristics of Epstein-Barr virus (EBV)-associated GC, 18 cases were immunohistochemically evaluated along with 56 cases of EBV-negative GC., Results: MUC2 expression was lower in EBV-associated GC: immunostaining grades 0, 1, 2, 3, and 4 were observed in 10, 6, 1, 1, and 0 cases of EBV-associated GC, respectively, and in 18, 11, 15, 6, and 6 cases of EBV-negative GC, respectively (P = 0.013). CD10 positivity (grades 2-4) in EBV-associated GC was 6%, significantly lower than in EBV-negative GC (34%) (P = 0.030). When phenotypes of GC were categorized by the combined positivities of gastric markers (either MUC5AC or MUC6) and intestinal markers (either MUC2 or CD10), EBV-associated GC included primarily null (44%) and gastric (39%) types, but EBV-negative GC comprised null (7%), gastric (30%), intestinal (27%), and mixed (36%) types. The age of patients with gastric types was significantly younger for both EBV-associated GC and EBV-negative GC cases., Conclusions: Neoplastic epithelial cells of EBV-associated GC did not express MUC2 or CD10, and most of them were categorized as null or gastric types. EBV infection may occur in the epithelial cells of null or gastric phenotypes, which may be devoid of transdifferentiation potential toward intestinal phenotypes.

Background: Cardiac myxoma, the most common primary tumor of the heart, has a variable clinical presentation and immunohistochemical profile. An abundant mucopolysaccharidic matrix exists, including mucin, within cardiac myxoma. This investigation first reports the expressions of mucin genes in cardiac myxoma., Methods: A retrospective study was conducted between December 1976 and February 2003, comprising 101 consecutive patients with cardiac myxoma who were treated with surgical excision. Detailed clinical parameters also were reviewed. Mucin genes, namely MUC1, MUC2 and MUC5AC, were studied immunohistochemically in 47 randomly selected patients., Results: The study group contained 57 (57%) women and 44 (43%) men, with a mean age of 38+/-21 years. Their presentations included: asymptomatic (41%), dyspnea (35%), stroke (23%), chest pain (7%), fever (6%), syncope (5%) and tricuspid regurgitation (70%). The sample included 90 myxoma located in the left atrium, 3 (3%) recurrent myxoma and 8 (8%) myxoma not located in the left atrium. The myxoma did not differ with location or clinical event in terms of pathological scores, such as vascular proliferation, inflammation, cellularity, hyaline, calcification and thrombosis. Cardiac myxoma is characterized by excessive mucus secretion. Expression of membrane-associated MUC1 was considerably higher than that of the secreted mucins, MUC2 and MUC5AC (P<0.05). Furthermore, expression of MUC5AC is related to lesser embolism (P<0.05)., Conclusions: This work first examined the immunohistochemical expression of mucin (MUC1, MUC2 and MUC5AC) in cardiac myxoma. This investigation then showed that the expression of representative membrane-associated mucin, MUC1, and/or secretory mucins, MUC2 and MUC5AC, in cardiac myxoma was associated with important tumor clinicopathological characteristics. Moreover, MUC5AC appears related to lesser embolism. This approach can help distinguish the potential roles of secretory mucins versus membrane-associated mucins in the development of cardiac myxoma.

Until now, survival analysis of gastric mucinous cancers showed either no difference or an even worse prognosis than stage-adjusted non-mucinous tumours. In the pancreas and breast, mucinous cancers showing well-demarcated mucin deposits (muconodular pattern), expansile growth and predominance of MUC2 mucin are known to have a more favourable prognosis. In this study, an attempt was made to separate, among 41 gastric mucinous cancers, a subgroup of tumours with muconodular expansile pattern, possibly predictive of a more favourable outcome. A group of 15 tumours was identified, which were characterised by overwhelming (80-100%) mucinous component, predominance of mucus over tumour cells inside muconodules, moderately aggressive growth of their epithelial component (reduced proliferative rate, moderate anaplasia, lack of angioinvasion and limited lymphoinvasion) and dominant expression of intestinal goblet cell markers, with special reference to MUC2 mucin. Univariate and multivariate survival analysis showed a significantly improved outcome of these lower grade muconodular tumours compared with the remaining mucinous cancers as well as with non-mucinous cancers of cohesive, diffuse (signet-ring cell included) and undifferentiated high-grade types.

Previous studies have shown that mucin expression can be used to evaluate differentiation patterns of gastric carcinoma: MUC5AC expression is associated with diffuse type and early gastric carcinomas, and MUC2 expression is associated with mucinous gastric carcinomas. The role played by MUC5B in the evaluation of differentiation and biological behaviour of gastric carcinoma is largely unknown. Our aim was to characterise the pattern of expression of mucins MUC1, MUC2, MUC5AC, MUC5B and MUC6 in a series of 50 gastric carcinomas to evaluate whether MUC5B expression was associated with the clinico-pathological characteristics of the cases and/or with the co-expression of other mucins. A panel of six monoclonal antibodies (HMFG1, SM3, PMH1, CLH2, EU-MUC5Ba and CLH5) was used to determine the expression of mucins (MUC1, MUC1 underglycosylated form, MUC2, MUC5B, MUC5AC and MUC6, respectively) using immunohistochemistry. Cases were considered positive if more than 5% of the cells expressed immunoreactivity for the several mucins evaluated. Our results showed that: (a) expression of MUC5B was observed in 11 cases (22.0%) and was associated with the "unclassified" histological type of gastric carcinoma according to Laurén ( P = 0.03) and with the absence of venous invasion ( P = 0.02); (b) in this series, MUC5B expression had no impact on survival of patients with gastric carcinoma; (c) the expression of MUC5B was associated with the co-expression of MUC5AC ( P = 0.02) and (d) none of the cases with the so-called complete intestinal phenotype of mucin expression expressed MUC5B.

Background: In the categorization of colorectal mucinous carcinomas, much attention has been paid to the amount of extracellular mucin, but little to that of intracellular mucin. Perhaps this factor would be useful in further categorization., Methods: We estimated the amount of intracellular mucin morphologically, and classified colorectal tumors (tubular adenomas, mucinous carcinomas, and nonmucinous carcinomas) into two categories each, those with and without intracellular mucus hyperplasia. From preliminary results, we chose a range of 50% or more for the ratio of intracellular mucus to the total area of tumor cells for our definition of such hyperplasia. Then, mucin expression in the different categories was examined immunochemically with antibodies to the mucin core proteins MUC1, MUC2, MUC5AC, and MUC6., Results: MUC1 expression was found in none of the 40 adenomas, 8 (17%) of the 48 mucinous carcinomas (with little difference in those with and without mucus hyperplasia), and 4 (16%) of the 25 nonmucinous carcinomas. MUC2 was found in all mucinous carcinomas. MUC5AC was found in 18 (86%) of the 21 mucinous carcinomas with mucus hyperplasia and 18 (90%) of the 20 adenomas with mucus hyperplasia, but in only 9 (33%) of the 27 mucinous carcinomas without mucus hyperplasia, 5 (20%) of the 25 nonmucinous carcinomas, and 2 (10%) of the 20 adenomas without mucus hyperplasia., Conclusions: Mucinous carcinomas with and without mucus hyperplasia may arise from adenomas with and without mucus hyperplasia, respectively. The amount of intracellular mucin may be a morphologic reflection of the origin of colorectal mucinous carcinomas.

Most adenomas and carcinomas of the small intestine and extrahepatic bile ducts arise in the region of the papilla of Vater. In familial adenomatous polyposis (FAP) it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis at an early tumor stage. In about 80%, curative intended resection is possible. Operability is the most relevant prognostic factor. Most ampullary carcinomas resp. carcinomas of the papilla of Vater develop from adenomatous or flat dysplastic precursor lesions. They can be sited in the ampulloduodenal part of the papilla of Vater, which is lined by intestinal mucosa. They also can develop in deeper parts of the ampulla, which are lined by pancreaticobiliary duct mucosa. Intestinal-type adenocarcinoma and pancreaticobiliary-type adenocarcinoma represent the main histological types of ampullary carcinoma. Furthermore, there exist unusual types and undifferentiated carcinomas. Many carcinomas of intestinal type express the immunohistochemical marker profile of intestinal mucosa (keratin 7-, keratin 20+, MUC2+). Carcinomas of pancreaticobiliary type usually show the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20-, MUC2-). Even poorly differentiated carcinomas, as well as unusual histological types, may conserve the marker profile of the mucosa they developed from. These findings underline the concept of histogenetically different carcinomas of the papilla of Vater which develop either from intestinal- or from pancreaticobiliary-type mucosa of the papilla of Vater. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear at different frequencies. In future studies, molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. Consequently, the histologic classification should reflect the histogenesis of ampullary tumors from the two different types of papillary mucosa.

There are a large number of stable pancreatic ductal carcinoma cell lines that are used by researchers worldwide. Detailed data about their differentiation status and growth features are, however, often lacking. We therefore attempted to classify commonly used pancreatic carcinoma cell lines according to defined cell biological criteria. Twelve pancreatic ductal adenocarcinoma cell lines were cultured as monolayers and spheroids and graded according to their ultrastructural features. The grading system was based on the integrity of membrane structures and on the presence of mucin granules, cell organelles, nuclear and cellular polymorphism, cell polarity, and lumen formation. On the basis of the resulting scores the cell lines were classified as well, moderately, or poorly differentiated. In addition, immunocytochemistry was performed for the markers cytokeratin 7, 8, 18, 19, carcinoembryonic antigen, MUC1 MUC2, MUC5, and MUC6. The population doubling time of monolayer cultures, determined by a tetrazolium salt based proliferation assay was correlated with the ultrastructural grade. The grading of the ultrastructural features of the monolayers, and particularly of the spheroids, revealed that Capan-1 and Capan-2 cells were well differentiated; Colo357, HPAF-2, Aspc-1, A818-4, BxPc3, and Panc89 cells were moderately differentiated and PancTu-I, Panc1, Pt45P1, and MiaPaCa-2 cells poorly differentiated. Membrane-bound MUC1 staining was a characteristic of well differentiated cell lines. The population doubling time of the monolayer cultures was related to the differentiation grade. No relationship was found between the p53, K-ras, DPC4/Smad4, or p16(INK4a) mutation status and the grade of differentiation. We conclude that the proposed ultrastructural grading system combined with the proliferative activity provides a basis for further comparative studies of pancreatic ductal adenocarcinoma cell lines.

Enteral probiotics such as Lactobacillus casei GG (LGG) have been used in the treatment of a variety of intestinal disorders in infants and children, including diarrhea, malabsorption, and Clostridium difficile colitis. Previous studies have identified the gene locus for mucin (MUC-2) and its expression in Caco-2 cells. Others have demonstrated that mucin, located on the surface of the intestinal epithelium, inhibits bacterial translocation (BT). We previously demonstrated that both mucin and the probiotic bacterium LGG have an inhibitory effect on BT in both an in-vitro Caco-2 cell model and a neonatal rabbit model. We hypothesized that the decline in BT by LGG is mediated by up-regulation of epithelial MUC-2. Human enterocyte Caco-2 cells were grown to confluence and incubated at 37 degrees C with either medium (control group) or 10(4) or 10(8) LGG for 180 min. Non-adherent LGG was washed away. Caco-2 cells were then lysed, purified, and quantified for MUC-2 protein and mRNA. The addition of LGG to the enterocyte monolayer surface resulted in significantly ( P < 0.05) increased MUC-2 expression compared to the untreated monolayers. Protein densities for MUC-2 significantly ( P < 0.05) increased with LGG. Density (expressed as ratio to control group) was 8.6 +/- 1.3 in the low-dose group (10(4) LGG) and 15.6 +/- 2.3 in the high-dose group (10(8) LGG). LGG may thus bind to specific receptor sites on the enterocyte and stimulate the up-regulation of MUC-2, resulting in increased inhibition of BT.

Background and Aims: To gain insight in intestinal epithelial proliferation, cell death, and gene expression during experimental colitis rats were treated with dextran sulfate sodium (DSS) for 7 days., Materials and Methods: Proximal and distal colonic segments were excised on days 2, 5, 7, and 28. Epithelial proliferation, cell death, enterocyte gene expression (carbonic anhydrase I (CA I) and goblet cell gene expression (mucin, MUC2; trefoil factor 3, TFF3) were studied immunohistochemically and biochemically., Results: Proliferative activity was decreased in the proximal and distal colon at the onset of disease (day 2). However, during active disease (days 5-7) epithelial proliferation was increased in the entire proximal colon and in the proximity of ulcerations in the distal colon. During DSS treatment the number of apoptotic cells in the epithelium of both colonic segments was increased. In the entire colon surface enterocytes became flattened and CA I negative during active disease (day 5-7). Additionally, CA I levels in the distal colon significantly decreased during this phase. In contrast, during the regenerative phase (day 28) CA I levels were restored in the distal colon and up-regulated in the proximal colon. During all disease phases increased numbers of goblet cells were observed in the surface epithelium of the entire colon. In the distal colon TFF3 expression extended to the bottom of the crypts during active disease. Finally, MUC2 and TFF3 expression was increased in the proximal colon during disease., Conclusion: DSS affected the epithelium by inhibiting proliferation and inducing apoptosis. DSS-induced inhibition of CA I expression indicates down-regulation of specific enterocyte functions. Accumulation of goblet cells in the surface epithelium and up-regulation of MUC2 and TFF3 expression in the proximal colon underline the importance of goblet cells in epithelial protection and repair, respectively.

Gastric carcinoma classifications differ in their value for distinguishing tumors according to their morphological pattern, functional properties, and biological significance. In this study we evaluated which of three established classification systems is best correlated with the expression patterns of certain mucins. A total of 160 gastric carcinomas from Turkey and Germany were screened immunohistochemically for the expression of MUC1, MUC2, MUC5AC, and MUC6, and the results were related to the different tumor categories in Lauren's, Carneiro's, and Goseki's classifications. It was found that in all three classifications carcinomas belonging to the gland-forming category most commonly expressed MUC1: 78% of Goseki's grade I carcinomas, 81.1% of Lauren's intestinal type carcinomas, and 82.8% of Carneiro's glandular type. MUC2 was expressed in all Goseki grade II carcinomas, which comprise the mucinous type, while it was not significantly associated with any of the other classifications. MUC5AC was found in all Goseki grade IV carcinomas, i.e., signet ring cell carcinomas. It was also significantly associated with Carneiro's mixed type and isolated cell type carcinomas, while there was no correlation with any of Lauren's types. MUC6 failed to show a relationship with any of the categories of the various classifications. We conclude that Goseki's classification is best correlated with MUC expression patterns because it distinguishes clearly between MUC1-positive gland-forming carcinomas, MUC2-positive mucinous ones, and MUC5AC-positive signet ring cell carcinomas. It is likely that each of these gastric carcinoma types has its own carcinogenesis.

Normal gastric mucosa expresses MUC1 and MUC5AC in foveolar epithelium and MUC6 in mucous neck cells of the body and deep glands of the antrum. Several studies have reported aberrant expression of an under-glycosylated form of MUC1, decreased expression of "gastric" mucins and aberrant expression of "non-gastric" mucins in gastric carcinoma. In this study, we analysed the expression profile of mucins MUC1, MUC2, MUC5AC and MUC6 in 94 gastric carcinomas using immunohistochemistry. Our results showed that: (1) mucin expression is associated with tumour type (MUC5AC with diffuse and infiltrative carcinomas and MUC2 with mucinous carcinomas) but not with the clinico-biological behaviour of the tumours; and (2) mucin expression is associated with tumour location (MUC5AC with antrum carcinomas and MUC2 with cardia carcinomas), indirectly reflecting differences in tumour differentiation according to tumour location.

Background/purpose: Mucins are high molecular weight glycoproteins that have oligosaccharides attached to the apomucin protein backbone by O-glycosidic linkages. Here, we report the expression of MUC1 mucin (membrane-bound mucin), MUC2 mucin (intestinal-type secretory mucin), and MUC5AC mucin (gastric-type secretory mucin) in invasive ductal carcinomas (IDCs; n = 46) and intraductal papillary-mucinous neoplasms (IPMNs; n = 33) of the pancreas, and the relationship of this expression with malignant potential., Methods: To clarify the precise expression pattern of mucins in IPMNs, we classified IPMNs into three histologic subtypes; IPMN-dark cell type ( n = 19), IPMN-clear cell type ( n = 10), and IPMN-compact cell type ( n = 4)., Results: IDC, with a poor outcome, showed a pattern of MUC1(+), MUC2(-), and MUC5AC(+ or -). In contrast, IPMN-dark cell type tumors, with a fairly favorable outcome, showed a pattern of MUC1(-), MUC2(+), and MUC5AC (+), and IPMN-clear cell type tumors, with a favorable outcome, showed a pattern of MUC1(-), MUC2(-), and MUC5AC(+). On the other hand, IPMN-compact cell type tumors showed a pattern of MUC1(+), MUC2 (-), and MUC5AC(+). In IPMN-dark cell type tumors with carcinomatous change showing invasive growth, the invasive areas acquired a characteristic of MUC1 expression that was usually seen in IDC, although their main noninvasive lesions showed no MUC1 expression. The IPMN-compact cell type tumors usually showed high cellular atypia and frequent MUC1 expression, even in the noninvasive areas., Conclusions: Our study of the mucin expression pattern in IDC and IPMN shows that this pattern may be related to the biological behavior of pancreatic tumors and their malignant potential.

The expression of mucin genes in the normal glandular epithelium of the endocervix has been well characterized. However, mucin gene expression in neoplastic or particular non-neoplastic glandular cervical lesions has not been addressed. This immunohistochemical study was carried out to analyze the expression of MUC2 and MUC5AC in neoplastic and non-neoplastic glandular lesions of the cervix. Monoclonal antibodies were used on paraffin-embedded sections from 41 adenocarcinomas, 2 adenosquamous carcinomas, 13 adenocarcinomas in situ (ACIS), 3 glandular dysplasias, 8 endometrioses, 5 tubal metaplasias, 17 squamous metaplasias, 3 microglandular hyperplasias and normal tissue of the endocervix, endometrium and fallopian tube. The patterns of expression of MUC2 and MUC5AC were different and in principle contrary. Focal MUC2 expression was observed almost exclusively in neoplastic lesions (36%) and not in normal epithelia and non-neoplastic lesions, the one notable exception being immature metaplasia. In contrast, strong expression of MUC5AC was observed in both normal endocervical epithelium (100%) and neoplastic lesions (73%). The expression of MUC5AC, however, was diminished in most neoplastic glandular lesions. Co-expression of MUC2 and MUC5AC was consistently documented in the lesions with intestinal differentiation. In contrast, cases of tubal metaplasia and endometriosis were negative for MUC2 and MUC5AC. These results indicate that discrimination of mucin gene expression may be helpful in discriminating lesions of the cervix.

Columnar epithelium-lined esophagus (Barrett's esophagus) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Columnar epithelium resembling intestinal metaplasia (IM) is especially important, since it is considered to be a premalignant condition. The aim of this study was to define the sulfated carbohydrate chain of mucin and its core peptide profile in Barrett's esophagus (BE) and to compare it with the profile in Barrett's adenocarcinoma and lower esophageal adenocarcinoma. The sulfated carbohydrate chain was not expressed in 16 specimens of normal esophageal epithelium, but in BE, it was expressed in 50% (8/16) of the specimens. This chain was detected in 100% (7/7) of esophageal adenocarcinoma specimens, including four cases of Barrett's adenocarcinoma. These data suggest that the sulfated carbohydrate chain may be associated with malignant phenotype of the esophagus. MUC1 core peptide was positive in 87% (13/15) of BE specimens and in 29% (2/7) of the esophageal adenocarcinoma specimens. MUC2 core peptide was present in 57% (8/14) and 43% (3/7) of these specimens, respectively. These data suggest that Barrett's epithelium, which is similar to IM, but not normal esophageal epithelium, expresses the sulfated sugar chain which is known to be present in gastric IM and colonic mucosa. However, there was no significant correlation between the expression of the sulfated sugar chain and the expression of either mucin core peptide MUC1 or MUC2. Thus, this carbohydrate chain may be expressed on as yet unidentified core proteins, other than MUC1 or MUC2 core peptide, in BE and esophageal adenocarcinoma. Identification of these proteins may be very important in helping to detect premalignant status in BE.