Human PATHOLOGY VOLUME 22
April
NUMBER 4
d99q
Editorial Modulation of Oligosaccharide in Human Cancer Stnlc turd modifications to oligosa~~lr;~ride domains of cvll-surface glycoconjugatts occur during epitheli;4 otltogen) and oncogenesia.‘~” bl’ithin this group ot IINIICYules. man!- glycoproteins are recognired to 1)~ iiilportant mediators of‘ grobj th stimuli, and cellular atlhesion. In noncell-crll recc)gnitiori. (receptors) form nt.oplastic ti5suea, such molecules part ot rr;~llsrlleI7lhi-aile assemblies linking componrnts 01 thy extracellular environment with intracellular trdnsducrrs of the received iiifi)rrrl~ltioIi.:~ Disruption of’these receptor5 results in loss of. trarismemhrane cr)mnlutlicatiorl, which becomes apparent a5 a11 altered I-ea~wnse to growth factors and impaired adhesion 4)f crlls to the substratum. Oligosacc-haride domains t )t ~t~llular $ycoproteins and glvcolipids are s\,nthesi/ed by a series of hierarchically o&mized glycosvlt1-atlsf.~i-~i5t~ rnzpes within the regulated environment of (;olgi apparatus cisternar and associated mernhran~-t~o~~~~~i cvtoplasmic structures. ’ Although the precise t‘unctio;l of individual oligoaaccharide structures remains speculative, it is known that correct inrrac.~llular trafficking of ~mnv (although not all) glycopt-oteins, particularly to the plasma membraine, is critically dependent on expressioli of certain oligosaccharide determinants. For example, appropriate glyosylation of epidermal growth fctor rec.eptor proteins and erb-B:! oncogene protein is maildatory before these structures are correctly incorporated’into ~)lasma membranes. Furthermore, strong evidence no\\ indicates that structural modifications to cell-surfact* glvc.oconjugates occurring during oncyqent~5is affec-t tumor behavior.” In thy report h” l,ance and L,ev in rhis issue of I~L.MA:V l’..~I-IIOI.O(;I’.’ lectin histochemistry has been ustd tl, examine expression of two defined oligosacc.haridr determinants in conventionall~~ processed cotonic tissurs. ‘These latter comprised ~lormal epithepolvps. and ;tdeiioc.arcinonias. lium , ;rdenomatous ‘l’)pe I c,ligosaccharides (C;nlpl--t?C;(1(R~,4~,- ) lvere idrntiiied using the lcctin from .4771&\ hvf+ylrtc. ‘I‘er305
Determinants
minal oligosaccharide determinants ot. blood group A, structure (GcllNA~~al-9 3Go/N24~~) were identified M’ith the lectin from L)o/icho.~ ~$cJ).u.\. ‘[‘his study demonstrated &at no unmasked type I oligosacc.haride structures (C;cll~I--+?CuWAc - ) were expressed ty nonneoplastic colonic epithelium although these determinants wt’rv shown to be synthesized and expressed in sialvldted form. Nonsialylated tyl>e 1 oligosaccharides &re readily identified in colonic malignancies. Normal colonic mucosal cells r’xpressed at least a proportion of terminal blood group X, (;(111~,4~al~~Gal~~.4~ - structures in unmasked (nonsial~lated) form. However, following ~leuraminidase dIgestion to remo\‘e sialic acids and reveal previouslv masked blood group A, determinants, any difference in level of‘ expression hetween tlormal and neoplastic colonic epithelium was abolished. (:on\,ersely, expression ot ~~alN,4cc_wf-+ 3MN14r - structures was reduced irl colonic malignancies when compared with nonneoplastic mucosa. This difference was accentuated following desialylation. Lectin-hinding patterns of adenomatous colonic epithelium were both variable and intermediate between the patterns identified in normal and neoplastic tissues. ‘I‘he findings of this report support aspects of previous observations on the modulation of glycoconjugate oligosaccharides in colonic and other mali~nancies.x In particular, the data show differential slalvlation of oligosaccharide determinants to he a comin(;n event in normal as well as neoplastic tissues. Furthermore. sialylation is fount1 to affect different oligosaccharide structures in distinct and independent patterns, ie. alteration5 in gl~coprotein sialylation are not random. ‘I‘hesc observations provide useful data on the behavior of two oligosaccharide determinants in coIonic neoplasia. Nevertheless, one criticism of this report. which also applies to many other recent publications of similar tvpe, is the failure to approach the subject of cellular &gosaccharide structures in a sys-
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
tematic manner.The investigators base their work on earlier observations of another group, but they do not provide any substantive structural information defining their reasons for choosing the two particular unrelated oligosaccharide determinants for study. In addition, using the same technique of lectin histochemistry, but applying a more analytic approach, expression of type 2 oligosaccharide determinants could have been simultaneously examined through binding of the lectin from Eytkrincl cristagalli.These investigators have reported interesting phenomenology, the exact pathobiologic relevance of which is uncertain. Nevertheless, the adopted approach does not invalidate any of the obtained data, which are useful and appear to fit into the recognized developing patterns of oligosaccharide domain modulation in neoplasia. One important reason for defining the modulation of glycoconjugate oligosaccharides is the attempt to identify alterations in sugar structure related to specific changes in cellular behavior. Such changes might include an altered sensitivity to hormones, response to chemotherapeutic agents, or propensity to metastasize. The central role of cell-surface oligosaccharide determinants in the selective homing of lymphocyte populations has long been recognized.!’ The possibility (if not probability) that analogous mechanisms might pertain to the metastatic spread of nonlymphoid malignancies has not escaped consideration. However, the problem with immunohistochemical or lectin-histochemical studies of intact tissues is that they do not take account of the phenotypic heterogeneity that is inherent to all tumors. The natural tendency of such studies is to emphasize predominant trends in staining patterns, whereas the biologically significant events may be detected in only a very small proportion of cells in any primary mahgnancy and, hence, not be recognized. Recently, examination of cellular glycoconjugate oligosaccharide structures associated with metastasis of human malignancies has revealed increased GalNAcpl+ bMand+6Man~ branching (recognized by the lectin L-PHA) in asparagine-linked oligosaccharides.“’ Oligosaccharides containing this linkage appear to be required for effective metastatic spread of human cancer cells, including colonic. The current study by Lance and Le\T7 contributes useful additional observations to the field of oligosaccharide modulation in colonic neoplasia. Acquisition of accurate data identifying precise alterations in expression of glycoconjugate oligosaccharides is essential if the significance of sugar structures to the pathobiology of human malignancies is to be revealed.
Unfortunately, to be of real biologic (and, hence, pathologic) value, one of two additional pieces of information is simultaneously required: (1) knowledge of the protein moieties to which particular oligosaccharide determinants are attached would define whether the observed changes to sugar structures are either associated with or independent of modifications to specific transmembrane proteins; and (2) data on the relationship between the presence (or ahsence) of a specific oligosaccharide structure and the biologic behavior of a particular cell might indicate those sugar structures that are important ligands in cellular responses to external stimuli, including attachment or metastasis. During recent year-s, suitable model systems and highly purified preparations of selected glycosyl transferase enzymes have become available, with which such information has become obtainable. Using these novel tools, identification of oligosaccharide structures that are important in the pathobiology of human malignant disease (and definition of’ their individual roles in those diseases) is now becoming a reality. CHKISTOPHEH
S. FOSTER,
MD,
Royal Postgraduate Medical Hammersmith Hospital London, UK
PHD,
MRCPATH
School
REFERENCES I. ,]ohnsonLL’. (:alarco PC:: Mammalian preimplantation development. The cell surface. Anat Ret 196:201-2 19, 1981 2. Warren L. Buck CA, Tuszynski GP: Glycopeptide changes and malignant transformation. A possible role for carbohydrate in malignant behaviour. Biochim Biophvy Acta 5 16:97- 127. 197X 3. Norris WE: Evidence for a se&d class of membrane glycoprotein involved in cell adhesion. ,J Cell Sci Y3:63 l-640, 1WJ 4. Foster CS: Functional aspects of glycoprotein N-linked oligosaccharide processing by human turnours. Br,J Cancer Ci2:57-63 1990(suppl 10) 5. Carpenter C;: Receptorr for epidermal growth factor and other polypeptide mitogens. Ann Rev Biochem X1:881-914. 1987 6. Dennis JW, LafertC S: Tumor cell surface carbohydrates and the metastatic phenotype. Cancer Metastasis Rev 5: 185-204. 1987 7. Lance I’, Lcv R: GoIonic oligosaccharide structures deduced fi-om lectin-binding studies before and after desialylation. HUM PA.rHo[ 22:307-312. 1991 8. Schoentag R. Primus FJ, Kuhns W: ABH and Lewis blood group expression in colorectal carcinoma. Cancer Res 47: 1695. 1700, 1987 9. Rosen SD. Singer MS, Yednock ‘I‘A. et al: Involvement of sialic acid on endothelial cells in organ-specific lymphocyte recirculation. Science 22X: 1005-1007. 1985 IO. Fernandes B, Sagman C, Augur M, et al: @l-+6 Branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. Cancer Kes .5 1:7 18-723. 1991
306
April
NUMBER 4
d99q
Editorial Modulation of Oligosaccharide in Human Cancer Stnlc turd modifications to oligosa~~lr;~ride domains of cvll-surface glycoconjugatts occur during epitheli;4 otltogen) and oncogenesia.‘~” bl’ithin this group ot IINIICYules. man!- glycoproteins are recognired to 1)~ iiilportant mediators of‘ grobj th stimuli, and cellular atlhesion. In noncell-crll recc)gnitiori. (receptors) form nt.oplastic ti5suea, such molecules part ot rr;~llsrlleI7lhi-aile assemblies linking componrnts 01 thy extracellular environment with intracellular trdnsducrrs of the received iiifi)rrrl~ltioIi.:~ Disruption of’these receptor5 results in loss of. trarismemhrane cr)mnlutlicatiorl, which becomes apparent a5 a11 altered I-ea~wnse to growth factors and impaired adhesion 4)f crlls to the substratum. Oligosacc-haride domains t )t ~t~llular $ycoproteins and glvcolipids are s\,nthesi/ed by a series of hierarchically o&mized glycosvlt1-atlsf.~i-~i5t~ rnzpes within the regulated environment of (;olgi apparatus cisternar and associated mernhran~-t~o~~~~~i cvtoplasmic structures. ’ Although the precise t‘unctio;l of individual oligoaaccharide structures remains speculative, it is known that correct inrrac.~llular trafficking of ~mnv (although not all) glycopt-oteins, particularly to the plasma membraine, is critically dependent on expressioli of certain oligosaccharide determinants. For example, appropriate glyosylation of epidermal growth fctor rec.eptor proteins and erb-B:! oncogene protein is maildatory before these structures are correctly incorporated’into ~)lasma membranes. Furthermore, strong evidence no\\ indicates that structural modifications to cell-surfact* glvc.oconjugates occurring during oncyqent~5is affec-t tumor behavior.” In thy report h” l,ance and L,ev in rhis issue of I~L.MA:V l’..~I-IIOI.O(;I’.’ lectin histochemistry has been ustd tl, examine expression of two defined oligosacc.haridr determinants in conventionall~~ processed cotonic tissurs. ‘These latter comprised ~lormal epithepolvps. and ;tdeiioc.arcinonias. lium , ;rdenomatous ‘l’)pe I c,ligosaccharides (C;nlpl--t?C;(1(R~,4~,- ) lvere idrntiiied using the lcctin from .4771&\ hvf+ylrtc. ‘I‘er305
Determinants
minal oligosaccharide determinants ot. blood group A, structure (GcllNA~~al-9 3Go/N24~~) were identified M’ith the lectin from L)o/icho.~ ~$cJ).u.\. ‘[‘his study demonstrated &at no unmasked type I oligosacc.haride structures (C;cll~I--+?CuWAc - ) were expressed ty nonneoplastic colonic epithelium although these determinants wt’rv shown to be synthesized and expressed in sialvldted form. Nonsialylated tyl>e 1 oligosaccharides &re readily identified in colonic malignancies. Normal colonic mucosal cells r’xpressed at least a proportion of terminal blood group X, (;(111~,4~al~~Gal~~.4~ - structures in unmasked (nonsial~lated) form. However, following ~leuraminidase dIgestion to remo\‘e sialic acids and reveal previouslv masked blood group A, determinants, any difference in level of‘ expression hetween tlormal and neoplastic colonic epithelium was abolished. (:on\,ersely, expression ot ~~alN,4cc_wf-+ 3MN14r - structures was reduced irl colonic malignancies when compared with nonneoplastic mucosa. This difference was accentuated following desialylation. Lectin-hinding patterns of adenomatous colonic epithelium were both variable and intermediate between the patterns identified in normal and neoplastic tissues. ‘I‘he findings of this report support aspects of previous observations on the modulation of glycoconjugate oligosaccharides in colonic and other mali~nancies.x In particular, the data show differential slalvlation of oligosaccharide determinants to he a comin(;n event in normal as well as neoplastic tissues. Furthermore. sialylation is fount1 to affect different oligosaccharide structures in distinct and independent patterns, ie. alteration5 in gl~coprotein sialylation are not random. ‘I‘hesc observations provide useful data on the behavior of two oligosaccharide determinants in coIonic neoplasia. Nevertheless, one criticism of this report. which also applies to many other recent publications of similar tvpe, is the failure to approach the subject of cellular &gosaccharide structures in a sys-
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
tematic manner.The investigators base their work on earlier observations of another group, but they do not provide any substantive structural information defining their reasons for choosing the two particular unrelated oligosaccharide determinants for study. In addition, using the same technique of lectin histochemistry, but applying a more analytic approach, expression of type 2 oligosaccharide determinants could have been simultaneously examined through binding of the lectin from Eytkrincl cristagalli.These investigators have reported interesting phenomenology, the exact pathobiologic relevance of which is uncertain. Nevertheless, the adopted approach does not invalidate any of the obtained data, which are useful and appear to fit into the recognized developing patterns of oligosaccharide domain modulation in neoplasia. One important reason for defining the modulation of glycoconjugate oligosaccharides is the attempt to identify alterations in sugar structure related to specific changes in cellular behavior. Such changes might include an altered sensitivity to hormones, response to chemotherapeutic agents, or propensity to metastasize. The central role of cell-surface oligosaccharide determinants in the selective homing of lymphocyte populations has long been recognized.!’ The possibility (if not probability) that analogous mechanisms might pertain to the metastatic spread of nonlymphoid malignancies has not escaped consideration. However, the problem with immunohistochemical or lectin-histochemical studies of intact tissues is that they do not take account of the phenotypic heterogeneity that is inherent to all tumors. The natural tendency of such studies is to emphasize predominant trends in staining patterns, whereas the biologically significant events may be detected in only a very small proportion of cells in any primary mahgnancy and, hence, not be recognized. Recently, examination of cellular glycoconjugate oligosaccharide structures associated with metastasis of human malignancies has revealed increased GalNAcpl+ bMand+6Man~ branching (recognized by the lectin L-PHA) in asparagine-linked oligosaccharides.“’ Oligosaccharides containing this linkage appear to be required for effective metastatic spread of human cancer cells, including colonic. The current study by Lance and Le\T7 contributes useful additional observations to the field of oligosaccharide modulation in colonic neoplasia. Acquisition of accurate data identifying precise alterations in expression of glycoconjugate oligosaccharides is essential if the significance of sugar structures to the pathobiology of human malignancies is to be revealed.
Unfortunately, to be of real biologic (and, hence, pathologic) value, one of two additional pieces of information is simultaneously required: (1) knowledge of the protein moieties to which particular oligosaccharide determinants are attached would define whether the observed changes to sugar structures are either associated with or independent of modifications to specific transmembrane proteins; and (2) data on the relationship between the presence (or ahsence) of a specific oligosaccharide structure and the biologic behavior of a particular cell might indicate those sugar structures that are important ligands in cellular responses to external stimuli, including attachment or metastasis. During recent year-s, suitable model systems and highly purified preparations of selected glycosyl transferase enzymes have become available, with which such information has become obtainable. Using these novel tools, identification of oligosaccharide structures that are important in the pathobiology of human malignant disease (and definition of’ their individual roles in those diseases) is now becoming a reality. CHKISTOPHEH
S. FOSTER,
MD,
Royal Postgraduate Medical Hammersmith Hospital London, UK
PHD,
MRCPATH
School
REFERENCES I. ,]ohnsonLL’. (:alarco PC:: Mammalian preimplantation development. The cell surface. Anat Ret 196:201-2 19, 1981 2. Warren L. Buck CA, Tuszynski GP: Glycopeptide changes and malignant transformation. A possible role for carbohydrate in malignant behaviour. Biochim Biophvy Acta 5 16:97- 127. 197X 3. Norris WE: Evidence for a se&d class of membrane glycoprotein involved in cell adhesion. ,J Cell Sci Y3:63 l-640, 1WJ 4. Foster CS: Functional aspects of glycoprotein N-linked oligosaccharide processing by human turnours. Br,J Cancer Ci2:57-63 1990(suppl 10) 5. Carpenter C;: Receptorr for epidermal growth factor and other polypeptide mitogens. Ann Rev Biochem X1:881-914. 1987 6. Dennis JW, LafertC S: Tumor cell surface carbohydrates and the metastatic phenotype. Cancer Metastasis Rev 5: 185-204. 1987 7. Lance I’, Lcv R: GoIonic oligosaccharide structures deduced fi-om lectin-binding studies before and after desialylation. HUM PA.rHo[ 22:307-312. 1991 8. Schoentag R. Primus FJ, Kuhns W: ABH and Lewis blood group expression in colorectal carcinoma. Cancer Res 47: 1695. 1700, 1987 9. Rosen SD. Singer MS, Yednock ‘I‘A. et al: Involvement of sialic acid on endothelial cells in organ-specific lymphocyte recirculation. Science 22X: 1005-1007. 1985 IO. Fernandes B, Sagman C, Augur M, et al: @l-+6 Branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. Cancer Kes .5 1:7 18-723. 1991
306
