[CANCER RESEARCH 48. 181-187, January 1, 1988]
Structural Variations of Blood Group A Antigens in Human Normal
Colon and Carcinomas1
Erik Dabelsteen, Niels Graem, Henrik Clausen, and Sen-itiroh Hakomori
Department of Oral Diagnosis, Royal Dental College ¡E.D., H. C.J, Pathological-Anatomical Institute, Kommunehospitalet [N. G.J, and Laboratory of Paediatric
Pathology, Rigshospitalet [N. G.J, Copenhagen, Denmark; and Department of Pathobiology, University of Washington and The Biomembrane Institute, Seattle,
Washington 98119 [H. C., S. H.]
ABSTRACT
The blood group A determinant is carried by four basic carrier carbo
hydrate chains. This paper reports the expression of blood group A
variants, as determined by immunohistology with highly specific mono
clonal anti-A antibodies, in 18 adenocarcinomas of the distal colon, 4
specimens of normal proximal mucosa from group A persons, and 5
specimens of fetal colonie mucosa. Monoclonal antibodies directed to
type 1 chain A, type 1 chain Al ,<•'',
type 2 chain A, type 2 chain ALey,
and type 3 chain A (repetitive A) were used. In normal mucosa, type 1
chain A and ALeb were expressed in proximal regions. Type 1 chain A
was expressed in columnar cells, whereas type 1 chain ALeb was found
in goblet cells. Type 2 and type 3 chain A structures were not found in
normal adult mucosa. All types of A antigens were detected in adenocar
cinomas from the distal colon as well as in normal fetal mucosa. In fetal
mucosa, type I chain A and ALeb antigens and type 3 chain A antigens
were expressed in columnar cells, whereas type 2 chain A and Le' and
type 1 chain ALeb antigens were found in goblet cells. The results indicate
that blood group A antigens with type 1, 2, and 3 carriers are present in
fetal mucosa and adenocarcinomas of distal colon, while epithelial mucosa
of normal adult colon is characterized by the exclusive expression of type
1 chain A antigens.
INTRODUCTION
Blood group ABO(H) antigens are the major human alloantigens expressed not only in erythrocytes but also in many other
cell types and in tissue and secretions throughout the body,
particularly in gastrointestinal, colorectal, urogenital, and bronchopneumonal epithelia and their secretions ( 1). In the digestive
tract, they are present in the cell membranes of oral mucosal
and esophageal squamous epithelia, whereas in the mucosa of
the stomach, small intestine, and proximal part of the colon,
they are mainly present in the goblet cells and the cytoplasm of
the columnar epithelial cells (2, 3). During neoplastic transfor
mation, blood group antigen expression changes profoundly
(4). Thus, neoplastic cells may "lose" certain blood group
structures, see Table 1) (4,6, 7). Second, modifications through
fucosylation and sialylation have been shown to affect expres
sion of blood group antigens and to generate most of the known
tumor-associated carbohydrate antigens. Typical examples of
tumor-associated antigens in gastrointestinal and colorectal
lesions are fucosylated mono- and multimene Le", Ley (4, 812), and sialylated Le" and Le" structures (4, 8-12).
Blood group ABH antigen expression in colonie epithelia
and tumors has been extensively investigated (12-15). These
studies have shown that the antigens are present only in the
proximal part of normal adult colon, whereas they are found
throughout fetal colon. Generally, blood group antigen expres
sion is maintained in adenocarcinomas of the colon and, im
portantly, tumors originating from the distal part have been
found to reexpress ABH antigens, thus suggestive of the ap
pearance of oncodevelopmental antigens. As it is unknown
whether the ABH antigens of malignant cells are of the same
structural variety as those found in fetal and/or normal adult
cells, it is of special interest to determine the structure of the
ABH antigens reexpressed in distal colon tumors.
With the use of a set of monoclonal antibodies directed to
various structural variants of blood group A antigens (Table 1),
we were able to study A antigen polymorphism in detail, in
cluding carrier chain differences and modifications through
fucosylation. In the present paper, we describe an immunohistological study of normal adult colon, fetal colon, and adeno
carcinomas of the distal colon using this set of well-defined
monoclonal antibodies. The results show that blood group A
antigens reexpressed in tumors from the distal colon are struc
turally similar to those from fetal colon, but distinctly different
from those of normal adult proximal colon.
MATERIALS AND METHODS
antigens that are expressed by their normal counterparts, or
they may acquire new antigens that are not normally expressed
(4,5).
Most studies of blood group antigen expression in tissue have
been performed with conventional polyclonal blood group test
sera or monoclonal antibodies with wide specificity that do not
provide detailed structural information of the antigens (4, 6).
Increasing evidence, obtained both by chemical and immunochemical means, points to the significance of two major factors
influencing the expression of blood group antigens. First,
changes in core or carrier chain assembly are associated with
development and transformation; branching status (blood group
II), and carrier chains of type 1 and 2 are good examples (foi
Received 5/11/87; revised 9/22/87; accepted 9/28/87.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This investigation was supported by Grant CA42S05 from the NIH, and by
grants from the Danish Cancer Society (Project 84-124) (N. (..). Ingeborg og Leo
Dannins Fonden, Vera og Carl Johan Michaelsens Legat (E. D., H. C.), and
Arkitekt Holger Hjortenberg og hustru, Dagmar Hjortenbergs fond (H. C.).
Patients and Tissue. Tissue from a consecutive series of 18 patients
belonging to blood group A (9 men and 9 women; mean age, 71.2 years)
who had undergone surgery' for adenocarcinoma of the sigmoid colon
(9 patients) and rectum (9 patients) at Kommunehospitalet, Copen
hagen, during the period 1976-1979, were studied. Lewis and secretor
blood group status was not available. In the selection of the Tiledparaffin
blocks, special attention was paid to obtain representation of both
normal colonie mucosa (resection line) and adenocarcinoma from each
patient. The study also included normal mucosa from the cecum of
four blood group A individuals (mean age, 64 years) treated for nonmalignant diseases, and fetal colonie tissue from five blood group A
fetuses aborted at 8-12 weeks of gestation. The five were selected from
14 after positive staining with anti-A antibodies. In specimens of fetal
colon, distinction between proximal and distal colon was not possible,
and blood group information was not available. All tissues were placed
in 10% (w/v) formaldehyde in 0.1 M sodium phosphate buffer, pH 7.2,
immediately after removal and fixed for 24 h, followed by embedding
in paraffin by routine histológica!methods. Fetal tissues were removed
at 1-24 h after abortion.
Antibodies and Staining Method. Blood group A antigen was dem
onstrated in the tissue by an indirect immunofluorescence staining
technique. Five monoclonal anti-A antibodies with different specificities
were used as primary antibodies: (a) AH21 recognizes only monofucosylated blood group antigen A with type 1 chain structure (16); (ft)
181
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BLOOD GROUP A ANTIGENS IN COLORECTAL CANCER
Table 1 Structure of A variants with regard to carrier carbohydrates, and the specific antibodies defining each structure
A
variant
Structure
Type 1 chain
GalNAcnl—3Gal/31—3GlcNAc/31-.3Gal01-»R
2
Monoclonal
antibodies
defining
the structure
Ref.
ALe-
AH21 IgM
16
ALe"
HH3IgG2a
17
Unbranched A
(fetal A)
HH4 IgG3
18
ALe'
HH2 IgG3
17
Branched A
(adult A)
HH4 IgG3
18
TH1 IgG2a
HN5 IgM
19
18
HH5 IgM
18
ÃŽ
Fucal
GaIN Aca 1—3Gal01—3GlcNAc/31—3Gal01-»R
2
4
T
ÃŽ
Fucal
Fucal
Type 2 chain
GaIN Aco 1-.3Ga 101--»[GlcNAc/31-.3Gall.il l—R
2
ÃŽ
Fucal
n = 1, 2, or 3
GaIN Aca l—3Gal/31-«»GlcN
Ac/31—3Gal/31—R
2
3
T
ÃŽ
Fucal
Fucal
GaIN Aca 1-.3Gal/31 --tGlcN Ac/31
2
"ÃŽ
*
Fucal
Gal/31-«4GlcNAc/31->R
3
GalNAcal-.3|Gal/3l—4GlcNAcl./31
2
T
Fucal
n = 1 or 2
Type 3 chain A (A, specific)
GaIN Aca 1—3Gal01-»3GalNAca 1->3Gal/31 -*»[GlcNAc/31-.3Gall./31 ->R
2
2
f
t
n = 1 or 2
Fucal
Fucal
A
A
Type 4 chain A
GaIN Aca 1-»3Gal01-OGalN Ac/31-.3Galn 1->4Gal/31-»R
2
ÃŽ
Fucal
Table 2 Staining pattern ofcolorectal tissue and adenocarcinomas of distal colon
Typel
Tissues
ALe(AH21)
ALe"
(HH3)
Type
„. 2
A
ALe'
(HH4) (HH2)
Type3
A
(TH1)
(18/18)
(18/18)
(4/18)
(7/18)
Fetal columnar cells
Fetal goblet cells
Adult proximal columnar cells
Adult proximal goblet cells
Adult distal (resection line)
Adenocarcinoma (distal part)
Summary
(11/18)
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
" Symbols in parentheses, weakly and partially positive.
Fig. 1. Normal proximal adult colonie mucosa with diffuse staining of monofucosylated type 1 chain A antigen in columnar absorptive cells. Bar, 50 (/ni
Stained with AH2I antibody, x 160.
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BLOOD GROUP A ANTIGENS IN COLORECTAL CANCER
staining procedures have been described elsewhere (20). In brief, rehydrated paraffin sections were incubated with the primary antibody for
20 h at 4°C,washed three times for 5 min in phosphate-buffered saline,
pH 7.2, and incubated with fluorescein-conjugated rabbit anti-serum to
mouse immunoglobulin (Dako) for l h at 20°C.To allow comparison
between staining reactions, serial sections of each specimen were stained
with different monoclonal antibodies. Control reactions consisted of
(a) staining with conjugate alone; (/»)
substitution of the primary antisera with culture supernatant from the myeloma cell line (SP/2-0) used
for hybridization; (<•)
substitution with mouse monoclonal antibody of
irrelevant specificity (OKT4); and (d) substitution of primary antibody
with antibody to blood group B.
RESULTS
The control reactions did not result in any staining. All untiA antibodies stained enterocytes, and considerable differences
in binding patterns were observed. A survey of the staining is
shown in Table 2.
Normal Adult Proximal Colon
Type 1 Chain A. AH21, which recognizes monofucosyl type
1 chain A, showed a diffuse cytoplasm it- staining of columnar
(absorptive) cells, but not of goblet cells (Fig. 1) in normal adult
mucosa from the cecum. HH3, which recognizes difucosyl type
1 chain A, stained goblet cells, with only a slight granular
staining in the cytoplasm of columnar (absorptive) cells (Fig.
2). Thus, a distinct difference in distribution of mono- and
difucosylated type 1 chain A antigens in normal proximal colon
was found.
Type 2 and 3 Chain A. The antibodies HH4 (defining mono
fucosyl type 2 chain) and HH2 (defining difucosyl type 2 chain)
did not stain any of these cells, indicating the absence of type
2 chain A antigens in normal adult colon. Likewise, no staining
of these cells was found with antibody TH1, which reacts with
extended A structure (type 3 chain A).
Fig. 2. Difucosylated type I chain A antigen in goblet cells of normal proximal
adult colonie mucosa. Bar, 50 /im. Stained with HH3 antibody; x 160.
Normal Adult Distal Colon
Colonie mucosa of specimens from sigmoid colon and rectum
showed no staining with any of the antibodies.
Adenocarcinomas of Distal Colon
Fig. 3. Adenocarcinoma of distal colon with diffuse staining of monofucosylated type 1 chain A antigen. Bar, SOi<\\\.Stained with AH21 antibody. X 100.
A detailed summary of the staining of adenocarcinomas is
shown in Table 2.
Type 1 Chain A. Antibody AH21 (defining monofucosyl type
1 chain) showed diffuse staining of cytoplasm and no staining
of mucus in goblet-like cells similar to normal proximal epithe
lium (Fig. 3). HH3 (defining difucosyl type 1 chain) stained
only a few tumor cells in some specimens, but stained groups
of cells in other tumors (Fig. 4). Mucus in tumor cells was also
stained.
Type 2 and 3 Chain A. In general, the antibodies HH4
(defining monofucosyl type 2 chain) and HH2 (defining difu
cosyl type 2 chain) stained cells which were stained with HH3,
although HH3 stained more cells (Figs. 5 and 6). In most areas,
a fine evenly distributed granular staining of the cytoplasm was
seen, but in some areas an intense fluorescence was also ob
served at the cell membranes. Positive staining with TH1 (which
recognizes type 3 chain A) appeared as a granular staining in
the cytoplasm (Fig. 7). Adenocarcinomas from distal colon
were therefore found to express type 1, 2, and 3 chain A
antigens, in contrast to normal adult proximal colon.
HH3 recognizes difucosyl blood group A antigen with type 1 chain
structure (17); (e) HH4 recognizes monofucosylated type 2 chain A,
but cross-reacts to some degree with difucosylated type 2 chain A (18);
(</)HH2 recognizes difucosyl blood group A antigen with type 2 chain
structure (17); and (e) TH1 recognizes type 3 chain A (repetitive A
antigen), which is essentially an A antigen extended from a type 2 chain
A structure (19). The chemical structures of these antigens are shown
in Table 1. Production and characterization of these antibodies have
previously been described (16-19).
The secondary antibody was a rabbit anti-mouse immunoglobulin
conjugated with fluorescein isothiocyanate (Dako, Copenhagen). The
183
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BLOOD GROUP A ANTIGENS IN COLORECTAL CANCER
Fig. 4. Difucosylated type 1 chain A antigen at the plasma membranes or cells
of an adenocarcinoma of the distal colon. Bar, 50 firn. Stained with HH3 antibody,
x 160.
Fig. 6. Difucosylated type 2 chain A antigen in an adenocarcinoma of the
distal colon (neighboring section to that shown in Fig. 5). Bar, 50 urn. Stained
with HH2 antibody, x 160.
Fig. S. Monofucosylated type 2 chain A antigen in an adenocarcinoma of the
distal colon. Bar, 50 urn. Stained with HH4 antibody, x 160.
Fig. 7. Adenocarcinoma of the distal colon with granular cytoplasmic staining
of type 3 chain antigen A. Bar, 50 urn. Stained with TH1 antibody, x 100.
Fetal Colon
agreement with other authors who have found no major regional
variation in the distribution of type 1 and type 2 chain struc
tures, namely, Le", Leb, Le", and Ley structures (8, 12, 21-23).
Staining of fetal tissue was evident in 5 of the 14 cases, and
these were regarded as blood group A individuals. Except for
TH1, all antibodies stained only scattered group of cells. The
positive cases were stained with all five anti-A antibodies.
Proximal and distal fetal colon could not be distinguished, but
serial sections through the entire embedded material showed
no variation in staining with the different antibodies. This is in
Type 1 Chain A. AH21 (defining monofucosyl type 1 chain)
produced a fine granular perinuclear staining as well as a
distinct cell membrane staining, but did not stain goblet cells
(Fig. 8). HH3 (defining difucosyl type 1 chain) produced a focal
and discrete cytoplasmic staining of columnar cells and goblet
cells (Fig. 9).
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BLOOD GROUP A ANTIGENS IN COLORECTAL CANCER
colon in contrast to normal adult colon but similar to adenocarcinomas.
DISCUSSION
Fig. 8. Felal colonie mucosa with distinct staining of monofucosy lated type 1
chain A antigen at the luminal cell membrane. Bar, 50 ,mi Stained AH21
antibody, x 160.
The blood group A determinant
is a trisaccharide
GalNAcal->3(Fucal->2)Gal|31-»R
(24) that is carried by dif
ferent basic core structures as shown in Table 1. Differences in
carrier core structure, but not in the antigen determinant itself,
provide the basis for the presence of structurally and immunologically distinct variants of A antigens investigated in the
present study. The antibodies were selected to differentiate A
determinants carried by different lacto-series structures: (a) type
1 chain, Gal01->3GlcNAc; (b) type 2 chain, Gal/3l-»4GlcNAc;
and (c) type 3 chain, which is type 2 chain A with a repetitive
A epitope (Table 1). These are believed to be the main carriers
of ABH antigens in gastrointestinal tissue, although other
carrier types exist, such as O-linked type 3 chain (munii type)
and type 4 chain (globo series) (25, 26).
Tissue-specific expression of carbohydrate carrier chains has
been well documented (7). The present study supports previous
findings (7, 27) that blood group antigens in normal adult
colonie mucosa are primarily carried on type 1 chain structures,
since neither type 2 or type 3 (repetitive) structures were found.
Several studies have indicated regional variation in expres
sion of blood group antigens in normal adult colonie mucosa
(2, 12, 13, 23). In the present study, we have shown that there
are distinct differences in cellular distribution of monofucosylated and difucosylated type 1 chain A structures. Whereas
monofucosylated type 1 chain A antigen was evident in colum
nar cells but not in goblet cells, difucosylated type 1 chain A
(ALeb) was found primarily in goblet cells. As the internal
fucosylation of the ALeb structure is thought to be catalyzed by
the Lewis gene-encoded fucosyltransferase, it is likely that
goblet cells and columnar cells differ in the expression or
activation of this transferase. Interestingly, tumor tissue ap
peared to maintain the differentiation-dependent expression of
type 1 chain A structures. Another difference between columnar
and goblet cells was observed in fetal colon, in which type 2
chain A antigens were found only in goblet cells, in contrast to
type 3 chain A (extended type 2 chain A), which was only found
in columnar cells.
The distribution of mono- and difucosylated type 2 chain A
antigens in the tumor tissue was similar to that of ALeb,
although there were more cells expressing ALeb. The expression
of type 2 chain A antigen in tumor tissue, but not in normal
colon, may represent a change in the core structure of the
carbohydrates in relationship to tumor development. This cor
relates with previous findings that type 2 chain structures such
as Le", Ley, and sialylated Le" are highly accumulated in colonie
adenocarcinomas and essentially absent in normal adult epithe
lium, although recent immunohistochemical studies have indi
cated detectable type 2 chain Ley in normal proximal colonie
epithelium, particularly of the crypt area (4, 8, 12, 23). The
Type 2 and 3 Chain A. HH4 (defining monofucosyl type 2 absence of type 2 chain A antigens in this epithelium is probably
chain) and HH2 (defining difucosyl type 2 chain) stained only due to lack of type 2 chain H precursor substances, since neither
goblet cells, which showed weak granular staining (Fig. 10). Le" nor Ley are good substrates for the A enzyme.
Changes in certain cell surface carbohydrate structures during
This staining was, however, more pronounced with HH3 than
with HH4 and HH2. TH1 (which defines extended A) stained embryonic development have been clearly established (2, 21,
all columnar cells with comma-shaped fluorescent granules in 22), and many of these structures, minimally expressed in adult
the cytoplasm and did not stain goblet cells, in contrast to other tissue, have been found to be coexpressed in fetal and tumor
tissue (21, 22, 28, 29); thus, these antigens have been described
type 2 chain A structures (Fig. 11). These results clearly indicate
the presence of all type 1, 2, and 3 chain A antigens in fetal as oncodevelopmental antigens as classically defined (30).
185
Fig. 9. Fetal colonie mucosa with focal staining of difucosylated type 1 chain
A antigen in goblet cells. Bar, SO i.ni. Stained with HH3 antibody, x 160.
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BLOOD GROUP A ANTIGENS IN COLORECTAL CANCER
Fig. 10. Fetal colonie mucosa with staining
of monofucosylated type 2 chain A antigen in
goblet cells. Bar, 50 ,im. Stained with HH4
antibody, x 160.
Fig. 11. Fetal colonie mucosa with staining
of type 3 chain A antigen in comma-shaped
supranuclear granules. Bar, SO /im. Stained
with TH1 antibody, x 160.
Therefore, in the present work, we correlated the expression of
blood group A structures in adenocarcinomas of the colon with
the expression of the same structures in fetal colonie mucosa.
We found the same blood group A variant antigens, defined by
monoclonal antibodies AH21, HH3, HH4, HH2, and TH1, in
fetal colon as well as in tumors, although the histological
distribution of type 1 chain monofucosylated A was limited in
adult normal mucosa! cells. The basis for this change in expres
sion of carrier chains in normal adult colon and in fetal colon
and tumors is not clear. These differences could be in the
synthesis of the respective carrier chains; however, carrier
chains could also be modified by other glycosyltransferases,
especially sialyltransferases (8). In summary, the present study
has established the differential expression of blood group A
variants in the distal region of normal adult colonie epithelia
as compared with that of fetal colonie epithelia and colonie
carcinomas, and showed clear structural characteristics of the
reexpressed blood group A antigens in carcinomas of the distal
colon. The study also provides evidence that this reexpression
can be regarded as an oncodevelopmental change.
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Structural Variations of Blood Group A Antigens in Human
Normal Colon and Carcinomas
Erik Dabelsteen, Niels Graem, Henrik Clausen, et al.
Cancer Res 1988;48:181-187.
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