Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Esophagogastric  Junction
 Barrett's
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Diagnosis
 

What is the meaning of "mosaic" sucrase-isomaltase staining found in Barrett's epithelium?

D.G. Beer, H.D. Appelman (Ann Arbor)

Sucrase-isomaltase is an intestinal brush border disaccharidase which is found primarily in small intestinal enterocytes [1]. This enzyme was also demonstrated by Wu et al. [2], using both immunohistochemical and reverse-transcription polymerase chain reaction techniques, to be abundantly expressed in the specialized Barrett's epithelium. Sucraseisomaltase was localized to the apical cell surface and the cytoplasm and was detected in 88% (15/17) of the cases of Barrett's mucosa. Similarly, 82% (9/11) of the esophageal adenocarcinomas expressed sucrase-isomaltase, however, approximately half of these tumors showed only cytoplasmic localization of sucrase-isomaltase. The mechanism underlying the predominantly cytoplasmic localization of sucrase-isomaltase in these tumors is unknown, but may potentially result from the loss of an intact brush-border which is required for insertion of the sucrase-isomaltase protein, or alterations in the transport of sucrase-isomaltase from the cytoplasm to the cell membrane. In a limited subset of Barrett's mucosa and in some containing areas of dysplastic epithelium, a heterogeneous pattern of sucrase-isomaltase expression showing both apical and cytoplasmic cellular staining was detected. In addition, an interesting "mosaic" pattern was observed in which sucraseisomaltase immunoreactive cells were located directly adjacent to negative staining cells [2].

The mechanisms underlying the "mosaic" expression pattern of sucrase-isomaltase in Barrett's mucosa are also unknown, but may potentially result from either the loss of positive-acting factors which induce sucrase-isomaltase transcription, or genetic alterations at or near the sucrase-isomaltase gene locus that influence gene dosage. The genetic instability associated with dysplastic Barrett's development may increase the probability that these alterations occur. The expression of sucrase-isomaltase in the intestine is known to demonstrate a complex pattern of developmental and spacial regulation [3, 4]. The induction of sucrase-isomaltase is also an important intestinal differentiation event leading to the acquisition of the functional ability to digest carbohydrates in the diet. Doell and Kretchmer [5] demonstrated that glucocorticoids can induce sucrase-isomaltase in intestinal cells located in the upper crypt and villus base 24 hours after administration of this steroid. Thus, both dietary and hormonal agents, such as glucocorticoids and thyroxine, can regulate sucrase-isomaltase expression.

The cloning of the sucrase-isomaltase gene [6], and the characterization of the sucraseisomaltase promoter region [7], has identified a complex set of factors which can influence sucrase-isomaltase transcription. Tissue specificity for sucrase-isomaltase expression was shown to be contained within the 324 bases of the start of sucrase-isomaltase gene transcription [6]. At least three novel DNA binding proteins were found to interact within this promoter region and act as positive cis-acting elements for sucrase-isomaltase transcription [7]. These authors demonstrated that these nuclear DNA-binding proteins showed tissue and cell specificity, indicating that some of the selectivity for sucraseisomaltase expression may result from co-expressed trans-activating factors. The presence of an intestinal-specific homeobox gene, Cdx2, also appears to be an important transcriptional regulator of sucrase-isomaltase expression [8]. The abundant expression of sucrase-isomaltase in Barrett's epithelium [2] indicates the presence of at least some of these positive-acting factors, although the specific factors present have yet to be determined for this metaplastic tissue.

Recent studies have indicated that sucrase-isomaltase expression can be induced by administration of glucagon-like peptide-2 in rats [9], and that the state of cell proliferation and/or differentiation may strongly influence sucrase-isomaltase expression [10, 11]. The involvement of the mitogen-activated protein (MAP) kinase pathway in intestinal cell differentiation was shown in in vitro studies using long-term treatment of HT-29 subclones with the MAP kinase (MEK) inhibitor PD98059. The cells demonstrated induction of a number of differentiation marker proteins, including sucrase-isomaltase, as well as showed evidence of gland formation, goblet cell appearance and mucin production [11]. Similar results were observed in Caco-2/15 human colon cancer cells following treatment with this compound [10]. The MAP kinase pathway appears to play an important role in stimulating cell proliferation and a reduction or direct inhibition of this pathway correlates with G1 arrest, cell differentiation and increased expression of sucrase-isomaltase. It is therefore possible that a "mosaic' pattern of expression of the sucrase-isomaltase protein in Barrett's mucosa may refect cells with distinct cell proliferation or differentiation states within the same glandular structure.

In addition to these positive-acting factors, however, two HNF-1 (hepatocyte nuclear factor-1) binding sites have been identified in the sucrase-isomaltase promoter which mediate repression of sucrase-isomaltase transcription by glucose [12]. Similarly, the negative regulation of sucrase-isomaltase gene in human intestinal epithelial cells by inflammatory cytokines has been reported [13]. Both interleukin-6 and interferon gamma decreased sucrase-isomaltase synthesis in these cells. Interestingly, tumor necrosis factor-alpha showed a slight ability to increase sucrase-isomaltase in these studies. In human colon adenocarcinoma cell lines epidermal growth factor receptor (EGF) was observed to inhibit sucrase-isomaltase expression [14]. Low concentrations (20 ng/ml) EGF appears to influence sucrase-isomaltase by affecting it's processing in the endoplasmic reticulum and/or increase it's degradation. At higher concentrations (200 ng/ml), EGF reduced sucrase-isomaltase mRNA and protein biosynthesis. It is therefore possible that induction, perhaps by an autocrine mechanism, of one or more negative regulators may be responsible for the very selective, or "mosaic" sucrase-isomaltase expression pattern observed in some Barrett's mucosa. The exact role of these negative-acting factors in regulating sucraseisomaltase expression in Barrett's esophagus, however, remains unknown.

The expression of sucrase-isomaltase has also been reported in chronic ulcerative colitis, colitic dysplasia, adenomatous polyps and colonic adenocarcinomas [15, 16]. Interestingly, a similar pattern of strong sucrase-isomaltase staining areas adjacent to negative areas was also noted in tubulovillous colonic adenomas [16], which indicates that a potentially similar process responsible for the "mosaic" pattern in Barrett's esophagus occurs in colonic neoplasms. During the development of dysplasia in Barrett's esophagus a high frequency of gene alterations are observed [17, 18]. It is unknown whether the alterations in genes such as CDNK2 or p53, which occur early in the neoplastic development of Barrett's esophagus, directly influence the expression of differentiated cell markers such as sucrase-isomaltase. It is known, however, that the chromosomal region of 3q25-ter which includes the location of the sucrase-isomaltase gene, demonstrates gene amplification in some cancers [19], and that allelic losses on 3q near this locus have also been reported [20]. This chromosomal region may be a target for genomic alterations which might result in the loss of one or more allele of 3q, thus reducing or eliminating sucraseisomaltase gene expression. If a clonal expansion of these cells in the Barrett's epithelium were to occur, a region of cells lacking sucrase-isomaltase expression might be observed. Loss of the 3q26 region in the Barrett's mucosa demonstrating loss of sucrase-isomaltase expression has not been reported. Silencing of the sucrase-isomaltase promoter by methylation is another mechanism which may influence expression of this gene although this possibility has not been investigated.

At the present time, the exact cause or meaning of “mosaic” expression of sucraseisomaltase in Barrett’s epithelium remains unknown. Because the regulation of the sucraseisomaltase enzyme is complex, with many positive and negative-acting factors and a relationship between sucrase-isomaltase expression and differentiation, there may be multiple mechanisms to create this unique expression pattern. Further, given the known genetic instability associated with development of dysplastic Barrett’s mucosa, the "mosaic" sucrase-isomaltase expression pattern may be linked to one or more specific genetic alterations.

References

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2. Wu GD, Beer DG, Moore JH, Orringer MB, Appelman HD, Traber PG. Sucrase-isomaltase gene expression in Barrett's esophagus and adenocarcinoma. Gastroenterology 1993;105:837-844.

3. Henning SJ. Functional development of the gastrointestinal tract. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven Press, 1987:285-300.

4. Traber PG, Yu L, Wu G, Judge T. Sucrase-isomaltase gene expression along the crypt-villus axis of human small intestine is regulated at the level of mRNA abundance. Am J Physiol 1992;262:G123-130.

5. Doell RG, Rosen G, Kretchmer N. Immunocytochemical studies of intestinal disaccharidases during normal and precocious development. Proc Natl Acad Sci USA 1965;54:1268-1273.

6. Wu GD, Wang W, Traber PG. Isolation and characterization of the human sucrase-isomaltase gene and demonstration of intestine-specific transcriptional elements. J Biol Chem 1992;267:7863-870.

7. Traber PG, Wu GD, Wang W. Novel DNA-binding proteins regulate intestine-specific transcription of the sucraseisomaltase gene. Mol Cell Biol 1992;12:3614-3627.

8. Traber PG, Silberg DG. Intestine-specific gene transcription. Annu Rev Physiol 1996;58:275-297.

9. Kitchen PA, Fitzgerald AJ, Goodlad RA, Barley NF, Ghatei MA, Legon S, Bloom SR, Price A, Walters JR, Forbes A. Glucagon-like peptide-2 increases sucrase-isomaltase but not caudal-related homeobox protein-2 gene expression. Am J Physiol Gastrointest Liver Physiol 2000;278:G425-428.

10. Aliaga JC, Deschenes C, Beaulieu JF, Calvo EL, Rivard N. Requirement of the MAP kinase cascade for cell cycle progression and differentiation of human intestinal cells. Am J Physiol 1999;277:G631-641.

11. Taupin D, Podolsky DK. Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology 1999;116:1072-1080.

12. Rodolosse A, Carriere V, Rousset M, Lacasa M. Two HNF-1 binding sites govern the glucose repression of the human sucrase-isomaltase promoter. Biochem J 1998;336:115-123.

13. Ziambaras T, Rubin DC, Perlmutter DH. Regulation of sucrase-isomaltase gene expression in human intestinal epithelial cells by inflammatory cytokines. J Biol Chem 1996;271:1237-1242.

14. Cross HS, Quaroni A. Inhibition of sucrase isomaltase expression by EGF in the human colon adenocarcinoma cells Caco-2. Am J Physiol 1991;261:C1173-1183.

15. Andrews CW, Ohara CJ, Goldman H, Mercurio AM, Silverman ML, Steele GD. Sucrase-isomaltase expression in chronic ulcerative colitis and dysplasia. Hum Pathol 1992;23:774-779.

16. Wiltz O, Ohara CJ, Steele GD, Mercurio AM. Sucrase-isomaltase: a marker associated with progression of adenomatous polyps to adenocarcinomas. Surgery 1990;108:269-276.

17. Galipeau PC, Prevo LJ, Sanchez CA, Longton GM, Reid BJ. Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue. J Natl Cancer Inst 1999;91:2087-2095.

18. Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, Rabinovitch PS, Reid BJ. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 1999;22:106-109.

19. Brass N, Racz A, Heckel D, Remberger K, Sybrecht GW, Meese EU. Amplification of the genes BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung. Cancer Res 1997;57:2290-2294.

20. Hammond ZT, Kaleem Z, Cooper JD, Sundaresan SR, Patterson GA, Goodfellow PJ. Allelotype analysis of esophageal adenocarcinomas: evidence for the involvement of sequences on the long arm of chromosome 4. Cancer Res 1996;56:4409-4402.


Publication date: August 2003 OESO©2015