Oral leukoplakia-to treat or not to treat.

Various treatment modalities have been described for reducing or eliminating malignant development of oral leukoplakia, but no treatment has gained universal approval due to lack of randomized clinical studies. At present, it is uncertain whether we can do harm to the patients by treating or by not treating them. An essential aspect is the observation of cancer development even after surgical removal of the clinical lesions. Inadequate resection of the lesions or field cancerization may account for this phenomenon. Another challenge is whether surgical removal of the lesions in fact is associated with a cancer promotional effect resulting in increased risk of cancer. Moreover, unidentified existing cancer in non-suspicious oral leukoplakias may for diagnostic purposes imply that surgical removal is recommendable as well as serial section of all excised tissue. Intensive follow-up programmes for leukoplakias are important, independent of surgical intervention.

Molecular profiling of tumour budding implicates TGFß-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma.

Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFß signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFß signalling may prove useful in the treatment of OSCC.

TP53 mutations in clinically normal mucosa adjacent to oral carcinomas.

BACKGROUND: The tumour-suppressor protein p53 often accumulates in histologically normal epithelium adjacent to oral squamous cell carcinomas (OSCC). We investigated whether this was associated with mutations in TP53, the gene for p53, and might implicate impending malignancy. METHODS: Specimens from 18 human squamous cell carcinomas were stained with monoclonal p53 antibodies. Positive cells were microdissected with laser-captured microscopy from the tumour and adjacent normal and dysplastic epithelium. DNA was extracted, and exons 5-9 of the TP53 gene were amplified by PCR. Amplified products were separated by denatured gradient gel electrophoresis. Fragments with a deviant DGEE pattern were sequenced. RESULTS: TP53 mutations were found in six of 18 tumours. Fourteen specimens contained histologically normal mucosa adjacent to the tumour; 13 of these showed small clusters of p53 positive cells. Seven specimens contained both histological normal and dysplastic epithelial tissues adjacent to the tumour. A TP53 mutation was found in only one specimen; this mutation appeared in the normal mucosa, the adjacent tumour, and the epithelial dysplasia. CONCLUSION: We found that upregulation of p53 was a frequent event in histological normal mucosa adjacent to OSCC; however, it was rarely associated with a mutation in the TP53 gene.

Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement.

At a workshop coordinated by the WHO Collaborating Centre for Oral Cancer and Precancer in the United Kingdom issues related to potentially malignant disorders of the oral cavity were discussed by an expert group. The consensus views of the Working Group are presented in a series of papers. In this report, we review the oral epithelial dysplasia classification systems. The three classification schemes [oral epithelial dysplasia scoring system, squamous intraepithelial neoplasia and Ljubljana classification] were presented and the Working Group recommended epithelial dysplasia grading for routine use. Although most oral pathologists possibly recognize and accept the criteria for grading epithelial dysplasia, firstly based on architectural features and then of cytology, there is great variability in their interpretation of the presence, degree and significance of the individual criteria. Several studies have shown great interexaminer and intraexaminer variability in the assessment of the presence or absence and the grade of oral epithelial dysplasia. The Working Group considered the two class classification (no/questionable/ mild - low risk; moderate or severe - implying high risk) and was of the view that reducing the number of choices from 3 to 2 may increase the likelihood of agreement between pathologists. The utility of this need to be tested in future studies. The variables that are likely to affect oral epithelial dysplasia scoring were discussed and are outlined here; these need to be researched in longitudinal studies to explore the biological significance of a low-risk or high-risk dysplasia.

HGF is released from buccal fibroblasts after smokeless tobacco stimulation.

To investigate the effect of smokeless tobacco (ST) on (1) HGF, KGF and GM-CSF expression by buccal fibroblasts and (2) on keratinocyte and fibroblast proliferation. Buccal fibroblasts were stimulated with different concentrations of ST extracts in a double dilution from 0.50% w/v to 0.03% w/v. Supernatant was collected after 24/48/72/96 h and assayed for HGF, KGF, and GM-CSF by ELISA. The amount of RNA was used as an indicator of fibroblast cell number. Buccal epithelial cell proliferation was determined by CyQUANT proliferation assay. The amount of HGF and KGF in the supernatant was dependent on exposure time and on concentration of the tobacco extract. High concentration increased production of HGF 4-fold. KGF production was doubled when high concentration of tobacco was used, low concentration did not stimulate cells. GM-CSF production was low in both stimulated and non-stimulated cells. Keratinocytes and fibroblasts showed no increase in proliferation after stimulation with increased concentrations of ST. The results suggest that HGF and KGF may play an important role as a paracrine growth factor in epithelial hyperplasia in ST lesions.

ABO blood-group antigens in oral cancer.

Tumor progression is often associated with altered glycosylation of the cell-surface proteins and lipids. The peripheral part of these cell-surface glycoconjugates often carries carbohydrate structures related to the ABO and Lewis blood-group antigens. The expression of histo-blood-group antigens in normal human tissues is dependent on the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event is decreased expression of histo-blood-group antigens A and B. The mechanisms of aberrant expression of blood-group antigens are not clear in all cases. A relative down-regulation of the glycosyltransferase that is involved in the biosynthesis of A and B antigens is seen in oral carcinomas in association with tumor development. The events leading to loss of A transferase activity are related, in some instances, to loss of heterozygosity (LOH) involving chromosome 9q34, which is the locus for the ABO gene, and in other cases, to a hypermethylation of the ABO gene promoter. The fact that hypermethylation targets the ABO locus, but not surrounding genes, suggests that the hypermethylation is a specific tumor-related event. However, since not all situations with lack of expression of A/B antigens can be explained by LOH or hypermethylation, other regulatory factors outside the ABO promoter may be functional in transcriptional regulation of the ABO gene. Altered blood group antigens in malignant oral tissues may indicate increased cell migration. This hypothesis is supported by studies showing that normal migrating oral epithelial cells like malignant cells show lack of expression of A/B antigens, and by studies that target ABH antigens to key receptors controlling adhesion and motility, such as integrins, cadherins, and CD-44.

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma.

The DBCCR1 gene at chromosome 9q33 has been identified as a candidate tumour suppressor, which is frequently targeted by promoter hypermethylation in bladder cancer. Here, we studied the possible involvement of DBCCR1 in the development of oral squamous cell carcinoma. DNA from 34 tumours was examined for loss of heterozygosity (LOH) at three markers surrounding DBCCR1 and for hypermethylation of the DBCCR1 promoter, using methylation-specific PCR and methylation-specific melting-curve analysis. LOH was found in 10 of 31 cases (32%), and DBCCR1 hypermethylation was present in 15 of 34 cases (44%). Hypermethylation of DBCCR1 was also present in three of seven epithelial tissues adjacent to the tumours, including two hyperplastic and one histologically normal epithelia. Furthermore, of four oral leukoplakias with dysplasia, one showed LOH at 9q33 and two showed DBCCR1 hypermethylation. These data suggest that LOH at 9q33 and hypermethylation of the DBCCR1 promoter are frequent and possibly early events in oral malignant development.

The p53 molecule and its prognostic role in squamous cell carcinomas of the head and neck.

Despite intense research, the 5-year survival rate for patients with squamous cell carcinoma of the head and neck (SCCHN) is still low. Several different factors have been studied in the search for one or more factors that give important prognostic information at the time of diagnosis. Many recent studies have focused on the TP53 tumour suppressor gene, analysing its gene status and protein status. When looking at p53 protein expression, using immunohistochemistry, no correlation to patient outcome has been seen for the whole group of SCCHN. However, a significant association between p53 expression and poor patient outcome was found when looking only at patients with laryngeal squamous cell carcinomas. Also, in oral premalignant lesions, expression of p53-positive cells in the suprabasal layers of the epithelium has been seen as an indication of impending malignant development. Concerning the prognostic significance of mutations in the TP53 gene, results differ. But when restricting analysis to tumours with mutations causing an obvious change in protein, TP53 mutation was found to be a strong and independent variable for prognosticating survival. This review article gives an up-to-date overview of the p53 molecule and evaluates its possible prognostic role in SCCHN. Today it is clear that the p53 pathway is very important in SCCHN biology and potentially in its treatment. The function and importance of a few other cell cycle proteins connected to p53 are also discussed.

Tissue distribution of histo-blood group antigens.

The introduction of immunohistochemical techniques and monoclonal antibodies to specific carbohydrate epitopes has made it possible to study in detail the tissue distribution of histo-blood group antigens and related carbohydrate structures. The present paper summarizes the available data concerning the histological distribution of histo-blood group antigens and their precursor structures in normal human tissues. Studies performed have concentrated on carbohydrate antigens related to the ABO, Lewis, and TTn blood group systems, i.e. histo-blood group antigens carried by type 1, 2, and 3 chain carrier carbohydrate chains. Histo-blood group antigens are found in most epithelial tissues. Meanwhile, several factors influence the type, the amount, and the histological distribution of histoblood group antigens, i.e. the ABO, Lewis, and saliva-secretor type of the individual, and the cell- and tissue type. Oligosaccharides with blood-group specificity are synthesized by the stepwise action of specific gene-encoded glycosyltransferases. In general, this stepwise synthesis of histo-blood group antigens correlates with cellular differentiation. The H and the Se genes both encode an al-2fucosyltransferase, which is responsible for the synthesis of blood group antigen H from precursor disaccharides. A new model for the participation of the Se/H-gene-encoded glycosyl transferases in synthesis of terminal histo-blood group antigens in human tissues is proposed; the type and degree of differentiation rather than the embryologic origin determines whether it is the H or the Se gene-encoded transferases that influence expression of terminal histo-blood group antigens in tissues.

Blood-group-related carbohydrates are expressed in organotypic cultures of human skin and oral mucosa.

Cellular maturation and migration are usually associated with changes in cell-surface carbohydrates, but the relationship between these changes and cell behaviour is at present largely unknown. To investigate whether an organotypic culture system can be used as an in vitro model to study the function of cell-surface carbohydrates, we established organotypic cultures of skin and buccal mucosa. In these cultures, keratinocytes are grown at the air-liquid interface on a supporting matrix consisting of homologous fibroblasts embedded in a collagen type I gel. We examined the expression of blood-group-related carbohydrate structures, including Lewis x, sialylated Lewis x, Lewis y, Lewis a, and Lewis b, on the surface of epithelial cells in the cultures. We compared the results with the expression of more well-established markers, including cytokeratins, integrins, bullous pemphigoid antigen and laminin, in the same cultures. The organotypic skin and oral mucosa cultures showed a histological differentiation pattern analogous to that of normal skin and buccal mucosa, and a tissue-specific expression of carbohydrate structures and cytokeratins. However, both types of organotypic cultures also expressed markers which are normally seen during wound healing, including Lewis y, cytokeratin 16, and cytokeratin 19. We conclude that the organotypic cultures of oral mucosa and skin are suitable models for future studies of the function of cell-surface carbohydrates, although the expression of wound healing markers has to be taken into consideration.

Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-age dependent.

Several pathophysiologic mechanisms have been proposed to explain slow-healing leg ulcers, but little is known about the growth behavior of cells in these wounds. Platelet-derived growth factor-BB applied topically to chronic wounds has shown beneficial effects, although the effects have been less pronounced than would have been expected based on studies on acute wounds. The objective of this study was to compare fibroblasts in culture obtained from chronic wounds (non-healing chronic venous leg ulcers), acute wounds and normal dermis regarding growth, mitogenic response to platelet-derived growth factor-BB and levels ofplatelet-derived growth factor alpha-receptor and beta-receptor. Fibroblasts were obtained by an explant technique and expanded in vitro using fibroblast growth medium supplemented with 10% fetal bovine serum and used for the assays at their third passage. Growth of chronic wound fibroblasts (n = 8) was significantly (p < 0.05) decreased compared with those from acute wounds (n = 10) and normal dermis (n = 5). Fibroblasts from ulcers older than 3 y grew significantly (p < 0.01) slower than those from ulcers that had been present for less than 3 y. Morphology and size of fibroblasts from the oldest chronic wounds deviated substantially from those of acute wounds and normal dermis, and resembled in vitro aged or senescent fibroblasts. Mitogenic response of chronic wound fibroblasts to human recombinant platelet-derived growth factor-BB was also reduced with ulcer age. No significant differences were found in the amount of either platelet-derived growth factor alpha-receptor or beta-receptor among the three groups. The features decreased growth related to ulcer age, altered morphology, and reduced response to platelet-derived growth factor, indicating that fibroblasts in some chronic wounds have approached or even reached the end of their lifespan (phase III). This might provide one explanation for the non-healing state and therapy resistance to topical platelet-derived growth factor-BB of some venous leg ulcers.

Expression of polypeptide GalNAc-transferases in stratified epithelia and squamous cell carcinomas: immunohistological evaluation using monoclonal antibodies to three members of the GalNAc-transferase family.

Mucin-type O-glycosylation is initiated by a large family of UDP-GalNAc: polypeptide N -acetyl-galactosaminyltransferases (GalNAc-transferases). Individual GalNAc-transferases appear to have different functions and Northern analysis indicates that they are differently expressed in different organs. This suggests that O-glycosylation may vary with the repertoire of GalNAc-transferases expressed in a given cell. In order to study the repertoire of GalNAc-transferases in situ in tissues and changes in tumors, we have generated a panel of monoclonal antibodies (MAbs) with well defined specificity for human GalNAc-T1, -T2, and -T3. Application of this panel of novel antibodies revealed that GalNAc- transferases are differentially expressed in different cell lines, in spermatozoa, and in oral mucosa and carcinomas. For example, GalNAc-T1 and -T2 but not -T3 were highly expressed in WI38 cells, and GalNAc-T3 but not GalNAc-T1 or -T2 was expressed in spermatozoa. The expression patterns in normal oral mucosa were found to vary with cell differentiation, and for GalNAc-T2 and -T3 this was reflected in oral squamous cell carcinomas. The expression pattern of GalNAc-T1 was on the other hand changed in tumors to either total loss or expression in cytological poorly differentiated tumor cells, where the normal undifferentiated cells lacked expression. These results demonstrate that the repertoire of GalNAc-transferases is different in different cell types and vary with cellular differentiation, and malignant transformation. The implication of this is not yet fully understood, but it suggests that specific changes in sites of O-glycosylation of proteins may occur as a result of changes in the repertoire of GalNAc-transferases.

Altered expression of epithelial cell surface glycoconjugates and intermediate filaments at the margins of mucosal wounds.

Alterations in cell to cell adhesion are necessary to enable the type of cell movements that are associated with epithelial wound healing and malignant invasion. Several studies of transformed cells have related epithelial cell movement to changes in the cell surface expression of the carbohydrate structures represented by the ABO blood group antigens and, in particular, by Lewis antigens and their biosynthetic precursors. To study further the relationship between cell surface carbohydrates and keratinocyte cell movement, experimental wounds were created in human oral mucosa and examined by immunohistochemical methods for their expression of selected cytokeratins (K5, K16, K19), basement membrane components (laminin alpha5 and gamma2-chains, BP180, collagen IV and collagen VII), and blood group antigen precursor structures Le(x), sialosyl-Le(x), Le(y), H antigen, N-acetyllactosamine, and sialosyl-T antigen. The changes induced by wounding in the expression of collagen IV, laminin gamma2-chain (laminin-5), and laminin alpha5-chain were similar to those found in skin wounds and served to define the region of epithelial movement. This region was found to show a marked increase in staining for both Lewis antigen Y (Le(y)) and H blood group antigen, and decreased staining of Le(x), thus indicating an upregulation in wounded epithelium of the fucosyltransferases responsible for the synthesis of the H antigen. The changes in carbohydrate expression extended beyond the wound margin into the nonwounded epithelium, a pattern of expression similar to K16, which was also strongly upregulated in both the outgrowth and the adjacent nonwounded epithelium. These findings provide further support for an influence of such carbohydrate structures on the migratory behavior of epithelial cells.

Salivary gland carcinomas: prognostic significance of simple mucin-type carbohydrate antigens.

The prognosis of salivary gland carcinomas is difficult to assess. Simple mucin-type carbohydrates (T and sialosyl-T antigens, Tn and sialosyl-Tn antigens) have been shown to be of value in predicting prognosis for carcinomas in other locations. We studied the prognostic significance of the expression of these structures in a retrospective study of 133 patients with salivary gland carcinomas, using immunohistochemistry and a panel of well-defined monoclonal antibodies (MAbs) on formalin-fixed paraffin-embedded tissues. Sialosyl-Tn, T and sialosyl-T antigens were not correlated with prognosis. Univariate analyses showed no overall difference in survival or locoregional control between patients with Tn-positive and patients with Tn-negative tumours, but indicated that expression of the Tn antigen was associated with early locoregional recurrences and deaths. Tn was, however, not an independent prognostic factor by multivariate regression analysis.

Molecular biological aspects of acquired bullous diseases.

Bullous diseases of the oral mucosa and skin were originally classified on the basis of clinical and histological criteria. The discovery of autoantibodies in some of these patients and the introduction of molecular biology have resulted in a new understanding of the pathological mechanisms of many of the bullous lesions. In this article, updated topics of the immune-mediated bullous lesions which involve oral mucosa and skin are reviewed. Pemphigus antigens, which are desmosomal-associated proteins and belong to the cadherin superfamily of cell adhesion proteins, have been isolated, and their genes have been cloned. The antigens which react with autoantibodies from patients with bullous pemphigoid, cicatricial pemphigoid, acquired epidermolysis bullosa, and linear IgA disease are all proteins of the hemidesmosome basement membrane complex. Interestingly, most of the antigens also appear to be the target for mutations seen in patients with the inherited type of epidermolysis bullosa in which bullous lesions are a prominent clinical feature.

Can alterations in integrin and laminin-5 expression be used as markers of malignancy?

Development of squamous cell carcinomas (SCCs) involves alterations in the adhesive interactions in the epithelium and invasion through the basement membrane. Therefore, changes in the expression of receptors and ligands involved in cell-cell and cell-matrix adhesion may be essential for the transformation of a premalignant into a malignant lesion. The aim of this study was to examine if expression of specific cell adhesion molecules can be used as markers of malignant development. By immunohistochemistry, we examined the expression pattern of integrins alpha2beta1, alpha3beta1, alpha6beta4 and laminin-5 in biopsies from SCCs (n=18), premalignant lesions (leukoplakias, n=21) and non-premalignant tissue with chronic inflammation (n=11). In poorly differentiated SCCs, patchy loss of alpha3beta1, alpha6beta4 and laminin-5 expression was pronounced at the invasion front, whereas there was a tendency to increased expression of alpha2beta1. Analogous to the SCCs, biopsies from the leukoplakias and the non-premalignant inflammatory tissue showed alterations of the expression of alpha3beta1 and alpha6beta4 in the basal cell layers and of laminin-5. However, a characteristic finding in biopsies from leukoplakias was loss of alpha2beta1 and alpha3beta1 in the suprabasal cells. There was no unequivocal expression of the adhesion molecules distinguishing between inflammatory tissue, premalignant, and malignant lesions.

Differential expression of integrins and laminin-5 in normal oral epithelia.

beta 1 and beta 4 integrins are receptors on epithelial cells mediating cell-extracellular matrix adhesion. Furthermore, alpha 2 beta 1 and alpha 3 beta 1 contribute to cell-cell adhesion. Laminin-5 in epithelial basement membranes (BMs) is a ligand for alpha 6 beta 4 and alpha 3 beta 1. Expression of different integrins and laminin-5 was studied in oral epithelium to characterize regional variations in these adhesion molecules. Monoclonal antibodies directed against alpha 2-alpha 6 beta 1/alpha 6 beta 4 and laminin-5 were examined in cryopreserved biopsies of normal mucosa by immunohistochemistry. Laminin-5 was expressed as a line along the BMs. The junctional epithelium showed a unique phenotype: Laminin-5 was detected in the internal BM at the tooth surface and in the external BM, where excessive laminin-5 was seen in the stroma. alpha 6 beta 4 was expressed in all cells of the junctional epithelium. Integrins alpha 4 beta 1 and alpha 5 beta 1 were not detected in the epithelia, whereas alpha 2 beta 1 and alpha 3 beta 1 showed differential expression. Epithelia with well-developed rete pegs and connective tissue papillae showed polarized alpha 3 beta 1 expression along the BM in the rete pegs, in contrast to negative expression at the tips of the connective tissue papillae. A variation in the suprabasal distribution of alpha 2 beta 1 and alpha 3 beta 1 was observed between epithelia from different regions. alpha 2 beta 1 and alpha 3 beta 1 were detected in basal/parabasal cells in keratinized epithelia, whereas there was increased suprabasal expression in nonkeratinized mucosa. These results indicate inhomogeneity in the basal cell population of oral squamous epithelia and differential expression of integrins, which may reflect differences in the underlying stroma. Laminin-5 deposits in the stroma underneath the junctional epithelium may indicate subclinical gingival inflammation.

Expression of GLUT1 in stratified squamous epithelia and oral carcinoma from humans and rats.

Most cells express facilitative glucose transporters. Four isoforms (GLUT1-4) transporting D-glucose across the plasma membrane show a specific tissue distribution, which is the basis for tissue-specific patterns in glucose metabolism. GLUT1 is expressed at high levels in tissue barriers such as the blood-brain barrier, and this isoform has been suggested as an indicator of such barriers. GLUT1 has been found in basal layers of human epidermis where no such tissue barrier is present. To further clarify these issues, we examined the distribution of GLUT1 and GLUT4 in skin, different types of oral mucosa from rat and man, and a human oral carcinoma by indirect immunofluorescence microscopy. The results showed that GLUT1 was expressed in the basal and parabasal layers of the different stratified squamous epithelia, with some variations between keratinized and non-keratinized subtypes. GLUT1 was also expressed in ductal- and myoepithelial cells of minor salivary glands and perineural sheath located in the lamina propra, and furthermore in the cells of an oral carcinoma. GLUT4 was not expressed in any of the tissues examined. This distribution of GLUT1 does not fit with the idea of GLUT1 as a general indicator of tissue barriers. In contrast, our results support the prevailing, but limited knowledge of glucose metabolism in squamous stratified epithelia, a metabolism believed to depend mostly on glycolysis, especially in the basal layers. High-level expression seemed to be confined to keratinocytes without glycogen stores.

Loss of a novel mucin-like epithelial glycoprotein in oral and cervical squamous cell carcinomas.

Stratified squamous epithelia of oral and cervical mucosa express high levels of simple mucin-type O-linked carbohydrates, and these are known to undergo structural changes in relation to epithelial differentiation and neoplastic transformation. O-glycans in these epithelia are associated with the cell membrane, but the identity of the carrier molecule(s) remains largely unknown. We report here the identification of a membrane-bound M(r) 200,000-250,000 glycoprotein (gp230) that is expressed in stratified squamous epithelia of the oral cavity. Western blot analysis identified gp230 as a major carrier of simple-mucin type carbohydrate antigens in buccal nonkeratinized mucosal epithelium, suggesting that it may represent a mucin-like molecule. A monoclonal antibody PANH4 defining a protein epitope of gp230 was generated. The PANH4 epitope was localized by immunohistology to suprabasal cell layers of buccal epithelium and was also found in larynx, esophagus, vagina, and exocervix, but not in epidermis. Data showed that gp230 was distinct from MUC1 or CD44. It is interesting that in most cases gp230 was not expressed in squamous cell carcinomas of buccal and cervical mucosa. A few moderately differentiated carcinomas, mainly from cervix, expressed the gp230 epitope. The results suggest that a membrane-bound mucin-like molecule, gp230, is associated with the differentiated phenotype of normal mucosal stratified squamous epithelia and that expression of gp230 generally is lost in severe oral epithelial dysplasia and squamous cell carcinomas of oral and cervical mucosa.