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Isoantigenic Expressionof Forssman Glycolipid in Human Gastric and Colonic Mucosa

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Isoantigenic Expressionof Forssman Glycolipid in Human Gastric and Colonic Mucosa Proc. Natl. Acad. Sci. USA Vol. 74, No. 7, pp. 3023-3027, July 1977 Medical Sciences Isoantigenic expression of Forssman glycolipid in human gastric and colonic mucosa: Its possible identity with "A-like antigen" in human cancer (Forssman-positive and Forssman-negative populations/tumor/globoside/blood group) S. HAKOMORI, S.-M. WANG, AND W. W. YOUNG, JR. Division of Biochemical Oncology, Fred Hutchinson Cancer Research Center; and Departments of Pathobiology and Microbiology, University of Washington, Seattle, Washington 98104 Communicated by Philip Levine, May 4, 1977 ABSTRACT The heterogenetic Forssman antigen is a gly- and blood group A antigens (5, 6), the A-like activity observed cosphingolipid, a ceramide pentasaccharide with the structure in those studies could have been due to the presence of a GalNAcal-s-3GalNAc,1-a3Galal---4Gal,1--.4Glc-.ceramide. Forssman antigen. In fact, Kawanami (7) described the presence Forssman-positive animals are capable of synthesizing this compound in tissues or in erythrocytes, in contrast to the of Forssman glycolipid in one case of gastric cancer although Forssman-negative species, including humans, which are in- the glycolipid composition of normal mucosa was not examined. capable of adding the last carbohydrate in the sequence of the Consequently, a thorough study has been undertaken using the Forssman antigen, namely aGalNAc. The Forssman glycolipid surgical samples collected by one of the authors (S.M.W.) in and its precursor globoside were examined in twenty-one sam- Taiwan, where there is a high incidence of gastric cancer. ples of surgically extirpated gastrointestinal mucosa and tumors derived therefrom. The results revealed that a few patients had The heterogenetic Forssman antigen (8) is a glycosphingo- chemically and immunologically detectable levels of the lipid (9, 10) whose structure was identified as GalN- Forssman glycolipid as a normal component of their gastroin- Acal1-3GalNAc/ll-3Gala1-'"4Galfll1-'4Glc--ceramide (11, testinal mucosa (F+ population); in contrast, the majority of 12). Forssman-positive animals, irrespective of species, are patients did not contain this glycolipid in their normal mucosa characterized by having a glycolipid of this structure (13-16),* (F- population). Whereas the F- population included blood whereas Forssman-negative animals, including humans,t are groups A, B, and 0, the F+ population did not correspond to bloo group A. The Forssman status in tumors taken from the considered to be unable to complete the carbohydrate structure, F+ or F- population showed the following striking features: (i) although they can synthesize the immediate precursor of the all tumors derived from F- mucosa possessed Forssman gly- Forssman antigen, which has been identified as globoside colipid, whereas (ii) none of the tumors originating in F+ mu- (11). cosa contained Forssman glycolipid. Globoside, the immediate precursor of Forssman antigen, was distributed equally among F+ and F- mucosa and the tumors derived therefrom. Thus, the MATERIALS AND METHODS expression of Forssman antigen in gastrointestinal mucosa ap- Tissues. Normal mucosa and cancer tissues from gastric and pears akin to that of an isoantigen. Furthermore, the Forssman antigen that appears in tumors of the F- population could rep- colonic mucosa were obtained from surgically extirpated resent a human tumor-associated antigen. In view of the strong specimens obtained in the National Taiwan University Hospital crossreactivity of Forssman antigen with blood group A deter- and its associated hospitals. All cases were diagnosed by histo- minants, the appearance of Forssman antigen in human tumors logical examination, and the ABO blood group of patients was could be related to the "A-like antigen" (or "neo-A antigen") of determined by standard procedures. Immediately after the human tumors reported previously [Hakomori, S., Koscielak, specimens were extirpated, the tissues were cleaned by rinsing J., Black, K. J. & Jeanloz, R. W. (1967) J. Immunol. 98, 31-38; with saline and frozen in dry ice and stored at -70°. The Hakkinen, I. (1970) J. Nat]. Cancer Inst. 44, 1183-11931. samples were shipped to this institute in dry ice. After thawing, The appearance of incompatible blood group antigens foreign the tumor tissues and normal mucosa were carefully separated to the host may occur in some human tumors. In 1951 Levine and weighed. et al. (1, 2) reported a case which suggested the synthesis of P Preparation of Glycolipid Fractions, Including Ceramide and PI antigen in gastric cancer tissue of a rare p individual. Tetra- and Pentasaccharide. The total glycolipid fraction was A possible conversion of blood group 0 or B to an A-like antigen prepared from the weighed tissue by the acetylation procedure in human gastrointestinal tumor was suggested by two inde- ("procedure A") (19), and was further separated into neutral pendent studies: (a) rabbit antiserum directed against a "human glycolipids and gangliosides by DEAE-Sephadex A-25 ac- tumor glycolipid" fraction agglutinated blood group A eryth- cording to the procedure of Yu and Ledeen (20). The total rocytes more strongly than 0 or B erythrocytes although the glycolipid was prepared from the tumor of a patient of blood * The immunodeterminant of Forssman antigen must reside on the group 0 (ref. 3; see also Discussion in the present paper); and terminal disaccharide GaINAcal -c3GalNAcB1 - R, because a (b) Hakkinen (4) described the presence of A-like antigen in ceramide tetrasaccharide with GalNAcal - 3GaINAcfil - 3Galal stomach cancers from patients whose blood group status was 4Galf,1 - ceramide of hamster fibroblast is equally as active as group 0 or B. The active fraction was described as a the ceramide pentasaccharide (17), and a polysaccharide of Strep- "sulfo- tococcus type C containing the terminal disaccharide is Forssman- glycoprotein." active (18). In view of the extensive crossreaction between the Forssman t In the early literature, reviewed by Buchbinder in 1935 (6), most primates were Forssman-negative in erythrocytes and tissues. Abbreviations: TLC, thin-layer chromatography; CTT, ceramide te- However, humans of blood groups A and AB were found by immu- trasaccharide; CP, ceramide pentasaccharide; F+ and F-, positive and nological means to be Forssman-reactive, but these results could have negative for the presence of Forssman antigen. been due to crossreactions with blood group A structures. 3023 Downloaded by guest on October 1, 2021 3024 Medical Sciences: Hakomori et al. Froc. Natl. Acad. sci. USA 74 (1977) neutral glycolipid fraction was further separated into various from globoside liposomes (both preparations containing 25 MAg classes of glycolipids by a small column (15 X 0.8 cm) of porous of glycolipid pert mol of sphingomyelin). In contrast, rabbit silica gel (latrobeads, latron Co., Tokyo) eluted with a chloro- anti-sheep hemolysin reacts more extensively with globoside form/methanol/water system of increasing polarity (21). liposomes (27). The liposomes prepared for the lysis assay were Ceramide tetrasaccharides were mainly eluted with chloro- used also for inhibition of sheep erythrocyte hemolysis by form/methanol/water 70:30:2.5 (vol/vol) (fraction 5) and the anti-Forssman antibody. Twenty-five microliters of each ceramide pentasaccharides, with chloroform/methanol/water liposome suspension were diluted in a 2-fold series in a micro- 66:34:3.0 (fraction 6). Because these fractions slightly over- titer plate. The liposomes were incubated with 25 Ml of three lapped, aliquots of fraction 5 and 6 were combined for immu- hemolysis doses (about 1:500 dilution) of the anti-Forssman nological assay, but chemical analysis was carried out on sep- antiserum for 1 hr. Then the mixture was incubated with 25 Ml arate fractions. each of complement (1:60 diluted guinea pig serum) and 1% Separation of Forssman Glycolipid and Its Identification. sheep erythrocytes. The extent of hemolysis was determined Because the iorssman glycolipid in the free state was not sep- after 1 hr. arable by thin-layer chromatography from the other ceramide pentasaccharides of fraction 6, the fraction was acetylated in RESULTS pyridine/acetic anhydride. Excellent separation of the acety- lated Forssman glycolipid was accomplished on TLC using Isoantigenic expression of Forssman glycolipid in solvent 1,2-dichloroethane/acetone (55:45, vol/vol). Under gastric and colonic mucosa: Distinction of F+ and F- these conditions the other ceramide pentasaccharides ran much mucosa faster than Forssman glycolipid (see Fig. 1). Following this The results of hemolysis inhibition and liposome lysis assays of purification step, the Forssman glycolipid was deacetylated. the ceramide tetra- and pentasaccharide fractions of 21 samples An aliquot was degraded by a-N-acetylgalactosaminidase of of normal mucosae indicated a clear-cut distinction of two pig liver (22) according to the procedure previously described human populations: one group showed positive Forssman ac- (9). Another portion was methylated (23) and identified by tivity while the other lacked Forssman activity (designated F+ electron impact mass fragmentography (16) using a Finnigan and F-, respectively; Tables 1 and 2). Sixteen of the twenty-one 3300 mass spectrometer. patients were F-; this group encompassed all ABO blood Immunological Analysis. Preliminary analysis of the total groups, while four of the five F+ patients were from blood glycolipid fraction failed to demonstrate any Forssman reac- group 0. Because samples
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