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Pathology

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Many modifications in glycosylation of cell surface glycoconjugates have been described in cancer (1, 2). For the most part, the biological roles of these alterations are not well defined. Thus the expression of ABH antigens is subject to considerable variations on malignant transformation, and its significance is unclear (3).

A loss of A and B antigens is observed in most types of carcinomas, such as carcinomas from the buccal epithelium, stomach, proximal colon, pancreas, larynx, lung, endometrium, ovary, prostate, urinary bladder, and breast. However, these antigens appear on carcinomas derived from some tissues where they are normally not present, such as the colorectal epithelium, liver parenchyme, and thyroid. The loss of A and B antigens is associated with a poor prognosis in carcinomas of the lung, urinary bladder, and head and neck. Inversely, in the case of colorectal carcinomas, it is their presence that is a sign of unfavorable outcome (4). In addition, a higher incidence of various types of carcinomas is observed for blood group A and B individuals compared with blood group O individuals (5, 6, 7, 8, 9,10, 11, 12,13).

Transfection of the A or B enzymes’ cDNA or selection of A-positive subpopulations of human colorectal carcinoma cell lines showed that the presence of the A and B antigens was associated with a reduced motility on matrigel. These observations may explain why the loss of A and B antigens is associated with a bad prognosis in some types of carcinomas because the A and B antigens would decrease the cells metastatic potential. However, they cannot account for the increased frequency of cancers in blood group A and B individuals or for the meaning of the appearance of A and B antigens from the early stages of colorectal carcinoma development.[1]

Abstracts

Blood group antigens as tumor markers, parasitic/bacterial/viral receptors, and their association with immunologically important proteins

Immunol Invest. 1995 Jan-Feb;24(1-2):213-32.

Garratty G.

Research Department, American Red Cross Blood Services, Los Angeles, CA 90006, USA.

  • Blood group antigens (BGAs) are chemical moieties on the red blood cell (RBC) membrane. Some BGAs (e.g., A, B, H, Lewis, P, I) are widely distributed throughout the body and may not be primarily erythroid antigens. Statistical correlations with ABO blood groups and disease have been made for years and have been highly controversial. It is not known if BGAs have a biological function. There are increasing reports of BGAs [e.g., Le(x) (an isomer of Le(a)), Le(y) (an isomer of Le(b)), T, Tn, "A-like"] appearing as "new" antigens on malignant tissue. Their presence and membrane density appears to correlate with the metastatic potential of the tumor. This often parallels loss of normal BGAs (e.g., ABH) from the tissue. Some of these antigens have been shown to influence the humoral and cellular response and have been used in assays to determine preclinical cancer, and in tumor immunotherapy. Interactions of some parasites and bacteria with human cells have been shown to depend on the presence of certain BGAs. P. vivax malarial parasites only enter human RBCs when the Fy6 Duffy blood group protein is present on the RBCs. Certain E. coli will only attach to the epithelial cells of the urinary tract if P or Dr BGAs are present in the epithelial cells. The P antigen is also the RBC receptor for Parvovirus B19. Leb has recently been found to be the receptor for H. pylori in the gastric tissue. The high frequency BGA, AnWj, is the RBC receptor for H. influenzae. BGAs have been shown to be associated closely with some important complement proteins. Ch/Rg BGAs have been found not to be true BGAs but are RBC-bound C4 (C4d). Knops/McCoy/York BGAs have been located on the C3b/C4b receptor (CR1). The high frequency BGAs of the Cromer (Cr) system are located on decay accelerating factor (DAF or CD55). Cartwright (Yt) BGAs are located on RBC acetylcholinesterase molecules. DAF and acetylcholinesterase are on phosphatidylinositol-glycan (PIG) linked proteins. When the PIG anchor is missing from RBCs, as in paroxysmal nocturnal hemoglobinuria, the affected RBCs lack all Cr, Yt, JMH, Hy/Gy, Do and Emm BGAs. The most important ligand for P, E and L selectins is sialyl-Le(x). This interaction is the tethering stage that start the leukocytes' journey from the circulation into the tissue. It appears that malignant cells may move through tissue in a similar way and may explain the close association of Le(x) with metastasis. Thus, there are increasing data suggesting a biological role for BGAs unrelated to the RBC.
Tumor-associated carbohydrate antigens related to blood group carbohydrates

Gan To Kagaku Ryoho. 1986 Apr;13(4 Pt 2):1395-401. Hirohashi S.

  • Biochemical studies have revealed the alteration of carbohydrate structures of cell membrane glycolipids, glycoproteins and cell secretory products associated with neoplastic transformation. Immunohistochemical examination of the blood group carbohydrate antigens in various cancer tissues have revealed the following results. 1) Incomplete synthesis of carbohydrate chains (e.g. loss of ABO antigens) 2) accumulation of precursor carbohydrates (e.g. accumulation of I antigen which is one of the precursors of ABO) 3) synthesis of new carbohydrates (e.g. expression of A-like antigens in cancer of O & B hosts). Many monoclonal antibodies raised against cancer cells have been shown to react with these, or modified, blood group carbohydrates. Monoclonal antibodies NCC-LU-35, or-81 obtained by immunizing with lung cancer reacted with the Tn antigen (GalNAc directly linked to serine or threonine), which is formed by incomplete synthesis of mucin-type carbohydrates including MN blood group antigens. These antibodies against Tn antigen cross-reacted with A glycolipids, since Tn antigen and A glycolipids share terminal GalNAc. Therefore, Tn antigen was concluded to be an A-like antigen in a broad sense. Tn antigen is expressed in many cancers and some hyperplastic lesions but is undetectable in various normal tissues. These studies indicate that alterations of blood group-related carbohydrates may be good markers for diagnosis and treatment of cancers.
Distribution of blood group antigens and CA 19-9 in gastric cancers and non-neoplastic gastric mucosa.

Gann. 1984 Jun;75(6):540-7. Hirohashi S, Shimosato Y, Ino Y, Tome Y, Watanabe M, Hirota T, Itabashi M.

  • The distribution of blood group ABH antigens, their precursor I(Ma) antigen, Lewis a antigen and monoclonal antibody-defined tumor-associated antigen CA 19-9 in gastric cancers and their surrounding non-neoplastic mucosa was studied by using immunohistochemical methods. ABH antigens were localized in the foveolar epithelium except for a few cases presumed to be non-secretors, but ABH antigens were lost focally from metaplastic mucosa. In contrast, Lewis a and I(Ma) antigens were present in the foveolar epithelium of non-secretors and metaplastic mucosa where ABH antigens were not detected. Gastric cancers also showed focal loss of ABH antigens and gain of Lewis a and I(Ma) antigens, and the cancer cells showed marked heterogeneity in antigen expression compared with non-neoplastic mucosa. Expression of incompatible blood group antigen (A-like antigen) reactive with monoclonal anti-A antibody was also detected in cancer cells of blood group O and B cases. CA 19-9 (sialylated-Lewis a) was detected in 62% of gastric cancers and in the restricted areas of gastric mucosa where Lewis a was positive.
Expression of the blood group antigens A and B in carcinoma of the urinary bladder

Tichy M, Jansa P, Student V, Ticha V, Vanak J. Bratisl Lek Listy. 1992 Aug;93(8):415-20. Katedra patologicke anatomie LF Univerzity Palackeho, Olomouci.

  • In 21 patients with transitional cell carcinoma of the urinary bladder expression of A and B blood group antigens was studied by means of monoclonal antibodies on using indirect immunoperoxide reaction. Expression of the investigated antigens was found to be dependent on the degree of histological differentiation of the tumor tissue. In well-defined carcinomas mostly pronounced expression of A and B blood group antigens was observed. Middle and low-differentiated carcinomas were characterized by reduction or even total deletion of expression. The expected favorable prognosis in transitional cell carcinomas expressing A and B blood group antigens failed to be confirmed. The expression of incompatible A-like antigens in 0 and B blood group patients with carcinoma is discussed.
A further case of Tn-polyagglutination

Folia Haematol Int Mag Klin Morphol Blutforsch. 1979;106(3):426-34. Lahmann N.

  • Another case of Tn-polyagglutination is described where for 6 years those responses have been observed which are typical of the acquired erythrocyte changes, viz. mixed-field polyagglutination by normal adult sera of all blood groups, no response with anti-TAh, agglutination of a certain part of erythrocytes by anti-TnSs, anti-ADb, anti-AHP, agglomeration of the other part by protamin sulfate and A-like specificity. Papain treatment eliminates polyagglutination by human sera of adults. Sera of new-borns did not agglutinate Tn-erythrocytes. Mrs. B. B. 38 years old belongs to blood group 0 and shows latent signs of haemolysis as well as permanently lowered leukocyte and thrombocyte numbers. The difficulties in blood group serology in connection with polyagglutination are referred too.
Isoantigenic expression of Forssman glycolipid in human gastric and colonic mucosa: Its possible identity with “A-like antigen” in human cancer

Proc Natl Acad Sci U S A. 1977 July; 74(7): 3023–3027. S. Hakomori, S.-M. Wang, and W. W. Young, Jr.

  • The heterogenetic Forssman antigen is a glycosphingolipid, a ceramide pentasaccharide with the structure GalNAcα1→3GalNAcβ1→3Galα1→4Galβ1→4Glc→ceramide. Forssman-positive animals are capable of synthesizing this compound in tissues or in erythrocytes, in contrast to the Forssman-negative species, including humans, which are incapable of adding the last carbohydrate in the sequence of the Forssman antigen, namely αGalNAc. The Forssman glycolipid and its precursor globoside were examined in twenty-one samples of surgically extirpated gastrointestinal mucosa and tumors derived therefrom. The results revealed that a few patients had chemically and immunologically detectable levels of the Forssman glycolipid as a normal component of their gastrointestinal mucosa (F+ population); in contrast, the majority of patients did not contain this glycolipid in their normal mucosa (F- population). Whereas the F- population included blood groups A, B, and O, the F+ population did not correspond to blood group A. The Forssman status in tumors taken from the F+ or F- population showed the following striking features: (i) all tumors derived from F- mucosa possessed Forssman glycolipid, whereas (ii) none of the tumors originating in F+ mucosa 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 expression of Forssman antigen in gastrointestinal mucosa appears akin to that of an isoantigen. Furthermore, the Forssman antigen that appears in tumors of the F- population could represent a human tumor-associated antigen. In view of the strong crossreactivity of Forssman antigen with blood group A determinants, the appearance of Forssman antigen in human tumors could be related to the “A-like antigen” (or “neo-A antigen”) of human tumors reported previously.
Tn-polyagglutinability of red blood cells and acquired A-like specificity

Transfusion. 1977 May-Jun;17(3):272-6. Related Articles, Links

Kourteva BT, Manolova VR, Mitova DK.

  • A woman whose red blood cells are polyagglutinable due to Tn-activation is reported. The true blood group of the patient is B but her cells have an acquired A-like specificity. The importance of the lectins, especially of Salvia sclarae extract, for the identification of Tn-polyagglutinability is demonstrated. The possibilities of A-like specificity of Tn-activated group B red blood cells is discussed.
A-like specificity in Tn-activated erythrocytes of blood group B

Kurteva B. Folia Haematol Int Mag Klin Morphol Blutforsch. 1977;104(2):277-82.

  • A Tn-polyagglutinability was observed in a 35 years old female patient with metrorrhagia. The A-like specificity of Tn-activated erythrocytes found simultaneously is especially significant, because this patient belonged to the blood group B, up till now, however, A-like findings have been described only for blood group O.
The blood group A-like site on the carcinoembryonic antigen

Cancer Res. 1973 Nov;33(11):2821-4. Gold JM, Gold P.

Links


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2. Kim, Y.J. and Varki, A. (1997) Perspective on the significance of altered glycosylation in cancer. Glycoconj. J., 14, 569–576

3. Hakomori, S. (1999) Antigen structure and genetic basis of histo-blood groups A, B and O: their changes associated with human cancer. Biochim. Biophys. Acta, 1473, 247–266.

4. Le Pendu, J., Marionneau, S., Cailleau-Thomas, A., Rocher, J., Le Moullac-Vaydie, B., and Clément, M. (2001) ABH and Lewis histo-blood group antigens in cancer. APMIS, 109, 9–31

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7. Henderson, J., Seagroat, V., and Goldacre, M. (1993) Ovarian cancer and ABO blood groups. J. Epidemiol. Comm. Health, 47, 287–289.

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9. Mourant, A.E., Kopec, A.C., and Domaniewska-Sobczak, K. (1978) Blood groups and diseases. A study of associations of diseases with blood groups and other polymorphisms. Oxford: Oxford University Press.

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11. Su, M., Lu, S.M., Tian, D.P., Zhao, H., Li, X.Y., Li, D.R., and Zheng, Z.C. (2001) Relationship between ABO blood groups and carcinoma of the esophagus and cardia in Chaoshan inhabitants of China. World J. Gastroenterol., 7, 657–661.

12. Vioque, J. and Walker, A.M. (1991) Pancreatic cancer and ABO blood types: a study of cases and control. Med. Clin., 96, 761–764

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