Showing papers by "Anthony P. Corfield published in 2001"

Mucins in the gastrointestinal tract in health and disease.

Abstract: Mucins form part of the dynamic, interactive mucosal defensive system active at the mucosal surface of the gastrointestinal tract. They are carbohydrate rich glycoproteins with unique molecular structure and chemical properties. The family of mucin (MUC) genes has 13 members that can be divided into secreted and membrane-associated forms each with characteristic protein domains and tissue specific glycosylation. Biosynthetic pathways have been described for the secreted and membrane-associated mucins and their eventual degradation and turnover. Mucins are present at all mucosal surfaces throughout the body in typical combinations and relate to the demands of organ function. Patterns of MUC gene expression with gastrointestinal site specific glycosylation are clearly important but are not yet well defined. Mucin production during fetal development shows distinct patterns that may correlate in many cases with neoplastic expression in adult life. An increasing number of protective proteins have been identified that appear in the adherent mucus layer at the mucosal surface. These proteins are co-secreted with mucins in some cases, interact with mucins at a molecular level through peptide and carbohydrate sites or benefit from the viscoelastic, aqueous environment afforded by the mucus gel to effect their defensive roles. The mechanism of many of these interaction remains to be elucidated but is clearly part of an integrated innate and adaptive mucosal defensive system relying on the mucins as an integral component to provide a mucus gel. Recent improvements in the description of MUC gene expression and mature mucin synthesis in the healthy gastrointestinal tract has formed a basis for assessment of mucosal disease at sites throughout the tract. Pathological patterns of mucin expression in disease appear to follow tissue phenotype, so that gastric and intestinal types can be defined and appear in metaplasia in e.g. esophagus and stomach. Adaptation of previous mucin based, histochemical classification of intestinal metaplasia to assess MUC gene expression has proved helpful and promises greater value if reliably combined with mucin linked glycosylation markers. Few changes in MUC gene expression or polymorphism have been detected in inflammatory bowel diseases in contrast to malignant transformation. Glycosylation changes however, are evident in both types of disease and appear to be early events in disease pathogenesis. Review of the major mucosal diseases affecting the gastrointestinal tract in childhood reveals parallel patterns to those found in adult pathology, but with some novel conditions arising through the developmental stages at lactation and weaning. The impact of bacterial colonization and nutrition at these stages of life are important in the evaluation of mucosal responses in pediatric disease.

Mucinases and sialidases: their role in the pathogenesis of sexually transmitted infections in the female genital tract

Abstract: Background: Mucinases and sialidases contribute to the process of invasion and colonisation in many conditions and infections of the female reproductive tract by degrading the protective cervical mucus. The role of hydrolytic enzymes in the pathogenesis of sexually transmitted diseases and their eVect on cervical mucus are discussed in this review. Methods: Articles were searched for using the keywords “sialidase,” “mucinase,” “protease,” and “sexually transmitted infections.” As well as review and other articles held by our group, searches were conducted using PubMed, Grateful Med, and the University of Bath search engine, BIDS. Results: Numerous publications were found describing the production of hydrolytic enzymes in sexually transmitted diseases. Because the number of publications exceeded the restrictions imposed on the size of the review, the authors selected and discussed those which they considered of the most relevance to sexually transmitted infections. (Sex Transm Inf 2001;77:402‐408)

Differential expression of the chromosome 11 mucin genes in colorectal cancer.

Abstract: The four secretory mucin genes clustered on chromosome 11, MUC2, MUC5AC, MUC5B and MUC6, were screened in 37 patients with cancers in the left hemi-colon or rectum and 10 normal rectal controls. The mucin genes were detected by in situ hybridization using oligonucleotide probes to the variable number tandem repeat (VNTR) sequences, while the proteins were stained with non-VNTR (MUC2, MUC5AC and MUC5B) or VNTR (MUC6) antibodies. Low levels of MUC2 mRNA were detected in non-mucinous adenocarcinomas (5/27) while a higher proportion of mucinous carcinomas (4/9) was positive. All 25 cases of adjacent normal tissue expressed MUC2 mRNA. No transcripts for MUC5AC, MUC5B or MUC 6 were detected in any of these specimens. MUC2 protein product was detected immunohistochemically in 34/36 carcinoma specimens, with no change from normal controls. There was de novo expression of MUC5AC in 23/36 carcinomas. No MUC5B or MUC6 protein was detected. No difference in MUC2 and MUC5AC protein was found between mucinous and non-mucinous carcinomas. The level of MUC2 was increased in moderately differentiated cancers compared with normal controls and decreased in the poorly differentiated group. Decreased MUC2 was found in poorly differentiated compared with moderately differentiated tumours. More MUC5AC protein was detected in well and moderately differentiated tumours than in poorly differentiated tumours and in all tumours relative to controls. The pattern of MUC2 staining in cancers was different from control tissue, with strong staining in the perinuclear region and none in goblet cell vesicles. MUC5AC staining was mainly detected in the cytoplasm. Poor detection of MUC2 and MUC5AC mRNA and associated strong staining for the total protein suggests altered biosynthesis and processing, leading to the characteristic subcellular distribution. Hence, change in the synthesis of MUC2 and the de novo appearance of MUC5AC in colorectal carcinomas may be significant events in the adenoma-carcinoma sequence, with possible implications for tumour prognosis.

Abnormal subcellular distribution of mature MUC2 and de novo MUC5AC mucins in adenomas of the rectum: immunohistochemical detection using non-VNTR antibodies to MUC2 and MUC5AC peptide.

Abstract: Anti-mucin variable number tandem repeat (VNTR) antibodies have been used previously to demonstrate the de novo presence of MUC5AC and MUC6 mucin in colorectal adenomas and increased synthesis of MUC2, the major secreted mucin in normal colorectal mucosa. Here we examined secreted mucins in tubular, tubulovillous and villous adenomas of the rectum using non-VNTR antibodies designed to assess mature mucin. Mucin gene messenger RNAs were detected by in situ hybridization. The anti-MUC2 non-VNTR antibody in the goblet cells of adenomas revealed a staining pattern of increased cytoplasmic, Golgi and membrane staining with no change in goblet vesicle reactivity compared with normal controls. In addition, blank goblet cell vesicle immunostaining for MUC2 was found in the transitional mucosa adjacent to all types of adenoma. Although a trend to overexpression of MUC2 was observed with in situ hybridization this was not detected with immunohistology. De novo synthesis of MUC5AC, but not MUC5B or MUC6 mucin was seen in all adenomas and transitional mucosa using immunohistochemistry. There was no correlation of MUC2 or MUC5AC mucin with polyp size or the grade of dysplasia using the non-VNTR antibodies. This study demonstrates that anti-mucin non-VNTR antibodies reveal a different subcellular-localization in rectal adenomas compared with normal colorectal mucosa. Further, this pattern is in contrast to that reported for anti-mucin VNTR antibodies. Combined use of these reagents may benefit future assessment of these cancers.