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Tumor Biology |
Department of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany [J. Mo., S. H., G. K., I. K., L. S., S. W., A. P.]; Institute of Pathology, University Heidelberg, 69120 Heidelberg, Germany [B. H., H. F. O.]; Department of Immunology and Microbiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark [J. Ma., U. H.]; Institute of Pathology, Klinik am Eichert, 73035 Göppingen, Germany [K. S.]; and Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany [H-J. G.]
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ABSTRACT |
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5 kb. The stratified squamous epithelium of the esophagus is the only epithelium showing a constitutive targeting of DMBT1 to the extracellular matrix (ECM) suggestive of a role in epithelial differentiation. Squamous cell carcinomas of the esophagus show an early loss of DMBT1 expression. In contrast, adenocarcinomas of the esophagus commonly maintain higher DMBT1 expression levels. However, presumably subsequent to a transition from the lumenal secretion to a targeting to the ECM, a loss of DMBT1 expression also takes place in adenocarcinomas. Regarding DMBT1 as a mucin-like molecule is a new perspective that is instructive for its functions and its role in cancer. We conclude that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas. However, although DMBT1 originally has divergent functions in monolayered and multilayered epithelia, carcinogenesis possibly converges in a common pathway that requires an inactivation of its functions in the ECM. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DMBT1 encodes a large secreted glycoprotein with SRCR, CUB, and ZP domains and, thus, is exclusively composed of motives that are known to mediate protein-protein interactions. The repeated SRCR domains are separated by SIDs, small amino acid motives rich in serine, proline, and threonine (1 , 5) . The SRCR/SID region is frequently affected by deletions and other rearrangements in tumors but is also polymorphic in the normal population (1 , 5 , 6) .
By the mediation of protein-protein interactions, DMBT1 may participate in different processes. We have proposed that DMBT1 plays a role in the mucosal and cellular immune defense as well as in epithelial differentiation (6) . In particular, glycoprotein-340 has been identified as one of the isoforms encoded by DMBT1 (6 , 7) . DMBT1GP340 is secreted to the lumen of the respiratory tract, interacts with the defense collectins surfactant protein-D and -A (SP-D and SP-A), and is able to stimulate alveolar macrophages (8 , 9) . DMBT1 is additionally expressed by alveolar macrophages itself and by tumor-associated macrophages in the brain, pointing to a role in the cellular immune response (6, 7, 8) . In contrast, DMBT1 is secreted to the ECM in certain human fetal epithelia, and in the adult skin and its rabbit homologue, hensin, has been shown to trigger epithelial terminal differentiation when being polymerized in the ECM by the Mac-2 bp ligand galectin-3 (Mac-2; Refs. 6 , 10 , 11 ).
Reverse transcription-PCR analyses have demonstrated a loss or reduction of DMBT1 expression for 12.5% of the gastric, 17% of the colorectal, and 53.5% of the esophageal carcinomas (4) . However, to date the functions of DMBT1 in the human alimentary tract are poorly circumscribed. Accordingly, the mechanisms by which it participates in carcinogenesis are unknown. Previous analyses have revealed a supranuclear location of DMBT1 in colonocytes indicating that it is secreted to the lumen (6) . It is difficult to understand how the loss of the function of a lumenally secreted diffusible protein may aid tumorigenesis. One of the conceptual drawbacks is that adjacent cells would still provide secreted DMBT1 and, thus, would compensate for the loss of DMBT1 expression. This primarily makes both a role in tumor initiation and progression unlikely. Moreover, the 3–4-times higher prevalence of a loss of DMBT1 expression in esophageal carcinomas compared with gastric and colorectal carcinomas remains to be explained. We hypothesized that an improved understanding of the basic properties of DMBT1 would help to approach these problems. Thus, we carried out a systematic characterization of DMBT1 in the human alimentary tract and investigated its expression and location in squamous cell carcinomas and adenocarcinomas of the esophagus.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Isolation and Characterization of DMBT1 Full-Length cDNAs.
Poly(A)+ RNA from human adult small intestine (Clontech) was transcribed into cDNA with the Marathon cDNA kit (Clontech) and diluted 1:250. The primers and the PCR conditions for the subsequent amplification were the same as described before (7)
. PCR products were cloned with the TOPO XL PCR Cloning kit (Invitrogen), and the insert sizes of the clones were determined by NotI-HindIII digestion and subsequent separation on 0.8% agarose gels. The 5'-sequences up to SID1 and the 3'-sequences from SRCR12 up to the end of the 3'-utr were determined for all of the clones by sequencing via primer walking. Clone DMBT1/Int23 was sequenced to completion by applying the nested deletion technique (Nested Deletion kit; Amersham Pharmacia). All of the cDNA clones were additionally characterized by restriction mapping with the enzyme AccI.
Immunohistochemistry.
Human formalin-fixed tissue samples were analyzed for the expression and location of DMBT1 by immunohistochemistry using the monoclonal antibody anti-DMBT1h12. The immunohistochemical analyses were performed as described before (6)
except that a protease digest was carried out [20 min at room temperature with 0.05% Pronase in 10 mM Tris-Cl (pH 7.2), with 140 mM NaCl and 7.5 mM NaN3 (TBS), followed by two washes with PBS and one with PBS containing 0.1% Tween 20 for 5 min each] before the blocking of the endogenous peroxidase activity, and anti-DMBT1h12 was used at a concentration of 8 µg/ml. As standard negative control, anti-DMBT1h12 was substituted by equal amounts of normal mouse IgG (Santa Cruz Biotechnology). The relative amount of DMBT1-positive cells in the esophageal carcinomas was determined semiquantitatively by independent visual inspection of three investigators.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The Northern blot analyses revealed at least ten different DMBT1 transcripts that are expressed in a tissue-specific manner (Fig. 1, a and b)
. The fact that no tissue with a single transcript could be identified denied the possibility to establish simple structure-function relationships. However, these analyses suggested that the expression of DMBT1 was mainly confined to tissues with large epithelial surfaces, because repeatedly no signals were obtained for the adult liver and pancreas (Fig. 1, a and b
; data not shown). Tissues with monolayered epithelial surfaces displayed high expression levels and various transcripts within the size range of about 6–8 kb. The esophagus was the only tissue showing an additional smaller transcript of 5 kb (Fig. 1, a and b)
. Repeated efforts to isolate full-length cDNAs form the esophagus did not succeed. To determine the basis of the transcript diversity, full-length cDNAs were thus amplified from the adult small intestine, the tissue with the highest expression levels, cloned, and characterized. The 12 cDNA clones that were finally recovered could be subdivided in the three major size categories of 8.0, 7.5, and 6.0 kb. DMBT1/Int23 with an insert of 8 kb was sequenced to completion (GenBank accession no. AJ297935) and was found to be virtually identical to a transcript isolated previously from human adult trachea (DMBT1/8kb.2; GenBank accession no. AJ243212; Ref. 7
), with the lack of half of a SID (SID4b) being the only difference to the prototype sequence. The remaining 11 clones could be subdivided in 
5 different transcript species that exclusively displayed an alternative utilization of the SRCR and SID exons (Fig. 1c)
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, whereas DMBT1 was additionally expressed in the exocrine pancreas in 2 of 7 cases (Fig. 2b)
. Hepatocytes displayed no or a barely detectable DMBT1 expression in the 5 of 9 cases without major pathological changes (example in Fig. 2c
). In the remaining 4 cases, comprising 1 case with liver cirrhosis, 1 case with hepatic steatosis, and 2 cases with hepatocellular carcinomas, an up-regulation of DMBT1 was observed in the hepatocytes (example in Fig. 2d
).
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; Table 1
). At low prevalence DMBT1 was found to locate at a basal position in relation to the nucleus, diffusely distributed over the entire cytoplasm, or at the apical or basal periphery of the cells. These patterns were consistently observed for virtually every monolayered epithelium and gland (Table 1)
. However, commonly, DMBT1 was detected at a supranuclear location indicating a constitutive lumenal secretion to the mucus all along the alimentary tract. These expression and staining patterns closely resemble the patterns known from epithelial mucins (12, 13, 14)
.
The third group comprised the stratified squamous epithelium of the esophagus, the only epithelium that displayed a constitutive targeting of DMBT1 to the ECM. The DMBT1 expression was absent from the cells in the lower cell layers but started in the prickle cell layer (Fig. 2l)
.
To investigate the expression and location of DMBT1 in carcinomas arising from multilayered and monolayered epithelia, respectively, 8 cases each of squamous cell carcinomas and adenocarcinomas of the esophagus were analyzed by immunohistochemistry. The lesions contained within these sections comprised 6 epithelial dysplasias (including mild, moderate, and severe dysplasias), 2 carcinomata in situ, 2 moderately differentiated squamous cell carcinomas, 5 poorly differentiated squamous cell carcinomas, and 8 poorly differentiated adenocarcinomas. Five of the 6 epithelial dysplasias lacked DMBT1 expression, whereas DMBT1 was easily detectable in the flanking normal epithelium (example in Fig. 2m
). The remaining case (with severe dysplasia), as well as the 2 carcinomata in situ, showed significantly reduced DMBT1 levels. Only about 1–5% of the tumor cells maintained the expression. DMBT1 located to the ECM of the positive cells of the severe epithelial dysplasia (not shown). The location in the two carcinomata in situ could not be determined, but in one of these the DMBT1-positive cells displayed a more differentiated phenotype (not shown). Three of the 7 squamous cell carcinomas were totally devoid of DMBT1; 3 additional cases showed highly reduced DMBT1 levels with only about 1–10% of the tumor cells being positive, and the remaining case maintained DMBT1 expression in 50% of the tumor cells. However, in the two carcinomas that showed the highest DMBT1 expression levels, DMBT1-positive cells generally displayed a moderately or well-differentiated phenotype (example in Fig. 2n
). In contrast, none of the 8 adenocarcinomas totally lacked DMBT1 expression. Four of the 8 adenocarcinomas showed substantially reduced DMBT1 levels with about 1–10% of the tumor cells being positive. Two of these displayed a speckled perinuclear staining pattern that did not allow for the determination of the mode of DMBT1 secretion, whereas a basal or basolateral location of DMBT1 was observed in a subset of the tumor cells in the remaining two cases. Four adenocarcinomas maintained high DMBT1 expression levels. For 2 cases, with about 30 and 50% DMBT1-positive tumor cells, respectively, the staining pattern or morphology was not informative for the determination of the mode of secretion. The 2 adenocarcinomas with the highest DMBT1 expression levels (about 60% and 80% DMBT1 positive tumor cells, respectively) predominantly showed a lumenal secretion, but in subsets of the tumor cells a transition to a basal or basolateral secretion was noted (example in Fig. 2o
), and the DMBT1-positive cells generally displayed a more differentiated phenotype.
BGM Is the Cattle Homologue of DMBT1.
Its mucin-like expression pattern and its expression by the gallbladder epithelium led us to examine the relationship of DMBT1 to a protein known as BGM (15)
in more detail. A comparison between the two genes/proteins based on the two available cDNA sequences of BGM (GenBank accession nos. s78981 and s78869) identified BGM as the bovine homologue of DMBT1. Conceptual translation of these sequences demonstrated that BGM closely resembles the domain organization of DMBT1 (Fig. 3a)
. A crosswise sequence comparison additionally showed that BGM shares a higher homology with DMBT1 than with the other known DMBT1 homologues or with the next closest BGM relative in cattle, WC1 (Fig. 3b)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our studies indicate that within this organ system only tissues with large epithelial surfaces show significant steady state levels of DMBT1. Alternative splicing gives rise to a great variety of DMBT1 isoforms that differ in the utilization and order not only of the interfaces for protein-protein interactions, the SRCR domains, but also of the small spacer domains, the SIDs, which represent potential targets for O-glycosylation. Because transcripts can even differ in the utilization of the small SID exons that are only 30 bp in length, the true number of alternative splice products is assumed to exceed the number of transcripts resolved by the Northern blot analyses. If all of the possible permutations do occur, the theoretical number of DMBT1 isoforms equals 4 x 107, which is between the calculated diversities of complex cell adhesion molecules and antibodies, respectively. However, because DMBT1 shows deletion polymorphisms (6)
, it remains to be unraveled to what extent these VNTRs contribute to the apparent transcript diversity.
Quite diverse structures and cell types show DMBT1 expression, and its expression pattern is more complex than revealed by previous analyses, which, to the major part, relied on reverse transcription-PCR (1 , 4, 5, 6, 7) . Basically, the results of the Northern blot and immunohistochemical analyses strongly suggest that the expression of DMBT1 requires an induction in some cell types, e.g., in the cells of the exocrine pancreas and of the villus epithelium of the small intestine. Similar observations have been made for the human respiratory tract.4 The expression patterns in the human liver point to DMBT1 being up-regulated in response to liver damage. This is in agreement with the observation that the rat homologue of DMBT1, ebnerin, is up-regulated in response to liver damage induced by the tumor promoting agent 2-aminoacetylfluorene and subsequent partial hepatectomy (16) .
We have pointed recently to the fact that DMBT1 shares a set of features with the SRCR protein Mac-2 bp (6) . For example, both proteins distinguish from other SRCR proteins by their presumable capacity to participate in various different biological processes, such as tumor suppression, mucosal protection, and the cellular immune defense, as well as probably cell-cell and cell-ECM interactions (1, 2, 3, 4 , 6 , 7 , 17, 18, 19, 20, 21) . Furthermore, both are secreted proteins capable of interacting with lectins (8 , 9 , 19) . Support has been lent by recent studies on hensin, the rabbit homologue of DMBT1. These analyses have indicated that galectin-3 (Mac-2) may represent a ligand shared by DMBT1 and the Mac-2 bp (11) . The present data indicate that DMBT1 also shows extensive relationships to epithelial mucins. Glands, monolayered surface, and ductal epithelia within the human alimentary tract commonly show a lumenal secretion and transcripts within the size range of 6–8 kb. Thus, large DMBT1 isoforms are secreted to the mucus all along the human alimentary tract. In regard to its expression pattern, DMBT1 best compares to the mucins MUC1, MUC5B, and MUC6. We demonstrate that DMBT1 shows cell type-specific staining patterns. For example, parietal cells generally display a diffuse cytoplasmic staining, whereas other cell types within the gastric glands show supranuclear signals. The same differential reactivity of antibodies is observed when studying mucins where this effect is thought to arise from a cell type-specific glycosylation of the respective epitopes (12) . BGM represents the DMBT1 homologue in cattle, a relationship that has not been recognized over the past years. DMBT1 additionally compares to mucins by having a repetitive structure built up by serine-, proline-, and threonine-rich domains alternating with cysteine-rich domains (1 , 5) , though the cysteine-rich domains are dominating in DMBT1, whereas it is vice versa in mucins (14) . Because mucins are defined by their carbohydrate content and because the sites for potential O-glycosylation are fewer in DMBT1, it is appropriate to consider DMBT1 as a mucin-like molecule as has been proposed for Muclin (22) , which has turned out to correspond to CRP-ductin, the mouse homologue of DMBT1.
Mucins represent multifunctional proteins. Among other functions, they play a pivotal role in mucosal protection by hindering pathogen invasion (12, 13, 14)
. In the respiratory tract, DMBT1GP340 likely fulfills this function by indirect pathogen interaction via the collectins SP-D and SP-A (8
, 9)
. Our studies suggest that certain DMBT1 variants are secreted to the saliva. This is in agreement with the recent finding that SAG corresponds to one or more of the DMBT1 isoforms secreted to the oral cavity (23)
. DMBT1SAG directly interacts with various pathogens such as Streptococcus mutans and Helicobacter pylori and, therefore, likewise exerts protective functions (23)
. On the basis of these findings and its relationship to mucins, we propose that lumenally secreted DMBT1 participates in mucosal protection. In turn, the lumenal targeting can identify DMBT1 variants with this presumptive function. Combining the results of the Northern blot and immunohistochemical analyses we conclude that mucosal protection is predominantly mediated by large DMBT1 isoforms encoded by transcripts of 6–8 kb. This is supported by the fact that both DMBT1GP340 and DMBT1SAG are encoded by transcripts of 8 kb (6
, 7
, 23)
.
However, in the salivary ducts DMBT1 can also be secreted to the basal compartment indicating the existence of forms that are functionally distinct from DMBT1SAG. This also applies to other monolayered epithelia. The low prevalence of a basal targeting of DMBT1 in monolayered epithelia indicates that DMBT1 is unlikely to participate in constitutive processes of epithelial differentiation. Hensin can also trigger a reversal of cell polarity in kidney epithelial cells (24) . Therefore, switching the cell polarity could represent a candidate function for these DMBT1 forms. Pleiotropic effects of DMBT1 are additionally suggested by its relationship to BGM. Recombinantly expressed polypeptides containing the SRCR domains and SIDs of BGM have been shown to bind to cholesterol and to accelerate the nucleation of crystals (25) . Thus, BGM is thought to play a role in gallstone formation. Because the SRCR/SID region unequivocally is shared by the two proteins, the relationship to BGM suggests that interactions of DMBT1 may not be limited to protein ligands only.
The esophagus is the only tissue that shows both a lumenal secretion, by the esophageal glands and ducts, and a constitutive targeting of DMBT1 to the ECM, by the stratified squamous epithelium. Thus, the latter one is the only structure in which DMBT1 has the basic prerequisites to participate in constitutive epithelial differentiation. DMBT1 also locates to the ECM in fetal epithelia and in the adult skin (6) but is secreted to the lumen by the respiratory tract epithelium (8) . Taken together, these findings suggest that a principle subdivision can be made. Adult monolayered epithelia and glands predominantly show a lumenal secretion indicating a function of DMBT1 in mucosal protection. Fetal epithelia and adult multilayered epithelia secrete DMBT1 to the ECM suggestive of a role in epithelial differentiation.
If the concept that large DMBT1 variants are secreted to the lumen also applies to the esophagus, the 5-kb variant would code for the isoform(s) locating to the ECM. Under the assumption that this division of labor takes place and that a kind of minimal variant can maintain processes of differentiation, some of the intriguing features of DMBT1 would resolve. At first, VNTRs within DMBT1 would rather be predicted to interfere with its protective functions. Interestingly, the mucin genes MUC1 and MUC6 likewise show VNTRs within the normal population. Shortened alleles of MUC1 and MUC6 are thought to interfere with the protective functions of these mucins and have been linked to an increased risk for gastric cancer (13) . Secondly, because the degree of genomic instability directly depends on the length and the number of homologous sequences, a loss of expression would be predicted to represent a more efficient means to eliminate the function of a minimal DMBT1 variant. Mori et al. (4) have found a loss or reduction of DMBT1 expression in 53.5% of the esophageal carcinomas. Our immunohistochemical analyses support the view that a down-regulation of DMBT1 takes place in a substantial fraction of the esophageal squamous cell carcinomas. The data additionally indicate that a loss of expression occurs already at early stages of the formation of squamous cell carcinomas. Furthermore, if high DMBT1 levels are maintained, the expression appears to be confined to tumor cells showing a more differentiated phenotype. This is in agreement with both its putative role in epithelial differentiation in this particular tissue and the predictions resulting from the concepts of division of labor and the minimal variant. Also, it would be predicted that there primarily exists no selective pressure for a loss of DMBT1 expression during the genesis of tumors arising from monolayered epithelia. Accordingly, we observed that adenocarcinomas of the esophagus generally maintained higher DMBT1 expression levels compared with squamous cell carcinomas. However, in the 4 adenocarcinomas that allowed a distinction between the different modes of DMBT1 secretion, a transition from a lumenal targeting to a secretion to the ECM was noted. Thus, most probably attributable to a loss of cell polarity or to changes in the tissue architecture, DMBT1 can aberrantly be targeted to the ECM at later stages by carcinomas arising from monolayered epithelia. This is possibly associated with a change of function, because DMBT1 locating to the ECM may stimulate processes of differentiation depending on the presence of appropriate ligands. At these stages the initial situation in multilayered epithelia is resembled, and a loss of DMBT1 function has the capacity to contribute to carcinogenesis by aiding clonal selection. This mechanism may explain the patterns that are observed in esophageal adenocarcinomas in the present study. Results obtained from the analyses of carcinomas of the lung are in agreement with this model.4 The fact that similar changes of the expression and location in tumors have also been observed for MUC1 (14) enhances the view that DMBT1 is specifically related to this particular mucin.
In summary, our studies suggest that DMBT1 shows a complex alternative splicing, a complex regulation, and presumably has complex physiological functions. This is in line with its relationship to the Mac-2 bp and the mucins that represent multifunctional proteins playing a role in various biological processes such as cell-cell and cell-ECM interactions, differentiation, the cellular immune response, mucosal protection, cancer, metastasis, and acute and chronic inflammation. Assuming multifunctionality in turn points to a complex role of DMBT1 in tumorigenesis and indicates that reductionistical approaches are inappropriate. Accordingly, the present study suggests that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas, because DMBT1 must be anticipated to have divergent functions in monolayered and multilayered epithelia. However, carcinomas of the digestive tract possibly converge in a common pathway that requires an inactivation of the DMBT1 functions in the ECM. If this model is generally applicable, similar sequential changes are predicted for gastric and colorectal carcinomas, which are presently under investigation. This, in turn, would provide the molecular basis to explain the 3–4-times higher frequency of a loss of DMBT1 expression in squamous cell carcinomas of the esophagus compared with gastric and colorectal carcinomas.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Deutsche Krebshilfe Grant 10-1835-Mo1 (to J. Mo.) and by the Wilhelm Sander-Stiftung Grant 99.018.1 (to A. P.). 
2 To whom requests for reprints should be addressed, at Department of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-424746; Fax: 49-6221-423454.
3 The abbreviations used are: DMBT1, deleted in malignant brain tumors 1; BGM, bovine gallbladder mucin; CUB, C1r/C1s Uegf Bmp-1; ECM, extracellular matrix; Mac-2 bp, Mac-2 binding protein; SAG, salivary agglutinin; SID, SRCR interspersed domain; SRCR, scavenger receptor cysteine-rich; VNTR, variable number of tandem repeats; ZP, Zona pellucida.
4 J. Mollenhauer, unpublished observations.
Received 6/ 7/01. Accepted 10/15/01.
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REFERENCES |
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