Abstract
Most monoclonal antibodies that have been raised to human epithelial tumours bind to only some of the cells in a tumour, showing that tumour cells are very heterogeneous in their expression of antigens. Normal epithelia show the same heterogeneity of antigen expression, as also do cell lines and clones of epithelial cells in culture. It is not related to the mitotic cell cycle. Many, probably most of the antigenic determinants to which the antibodies bind are carbohydrate structures. It is not clear whether variations in antigen expression reflect variations in the differentiated state of the cells or merely variations in the carbohydrate structures on otherwise identical cells, nor is ir clear whether antibodies could be made that bind to all tumour cells by avoiding antibodies to carbohydrate structures. The normal and apparently reversible nature of this heterogeneity of antigen expression conflicts with conventional views that heterogeneity among cells of a tumour is due to permanent genetic change. The heterogeneity within normal clones suggests that cloning is not an adequate way to study heterogeneity in tumour cells. The implications of heterogeneous expression of antigens within tumours for therapeutic and diagnostic application of antibodies are discussed.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abe K., McKibbin J. M., Hakomori S. The monoclonal antibody directed to difucosylated type 2 chain (Fuc alpha 1 leads to 2Gal beta 1 leads to 4[Fuc alpha 1 leads to 3]GlcNAc; Y Determinant). J Biol Chem. 1983 Oct 10;258(19):11793–11797. [PubMed] [Google Scholar]
- Arends J. W., Verstynen C., Bosman F. T., Hilgers J., Steplewski Z. Distribution of monoclonal antibody-defined monosialoganglioside in normal and cancerous human tissues: an immunoperoxidase study. Hybridoma. 1983;2(2):219–229. doi: 10.1089/hyb.1983.2.219. [DOI] [PubMed] [Google Scholar]
- Arklie J., Taylor-Papadimitrious J., Bodmer W., Egan M., Millis R. Differentiation antigens expressed by epithelial cells in the lactating breast are also detectable in breast cancers. Int J Cancer. 1981 Jul 15;28(1):23–29. doi: 10.1002/ijc.2910280105. [DOI] [PubMed] [Google Scholar]
- Brockhaus M., Magnani J. L., Blaszczyk M., Steplewski Z., Koprowski H., Karlsson K. A., Larson G., Ginsburg V. Monoclonal antibodies directed against the human Leb blood group antigen. J Biol Chem. 1981 Dec 25;256(24):13223–13225. [PubMed] [Google Scholar]
- Burchell J., Durbin H., Taylor-Papadimitriou J. Complexity of expression of antigenic determinants, recognized by monoclonal antibodies HMFG-1 and HMFG-2, in normal and malignant human mammary epithelial cells. J Immunol. 1983 Jul;131(1):508–513. [PubMed] [Google Scholar]
- Cahan L. D., Irie R. F., Singh R., Cassidenti A., Paulson J. C. Identification of a human neuroectodermal tumor antigen (OFA-I-2) as ganglioside GD2. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7629–7633. doi: 10.1073/pnas.79.24.7629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Canevari S., Fossati G., Balsari A., Sonnino S., Colnaghi M. I. Immunochemical analysis of the determinant recognized by a monoclonal antibody (MBr1) which specifically binds to human mammary epithelial cells. Cancer Res. 1983 Mar;43(3):1301–1305. [PubMed] [Google Scholar]
- Capone P. M., Papsidero L. D., Chu T. M. Relationship between antigen density and immunotherapeutic response elicited by monoclonal antibodies against solid tumors. J Natl Cancer Inst. 1984 Mar;72(3):673–677. [PubMed] [Google Scholar]
- Carrel S., Schreyer M., Schmidt-Kessen A., Mach J. P. Reactivity spectrum of 30 monoclonal antimelanoma antibodies to a panel of 28 melanoma and control cell lines. Hybridoma. 1982;1(4):387–397. doi: 10.1089/hyb.1.1982.1.387. [DOI] [PubMed] [Google Scholar]
- Chang S. E., Taylor-Papadimitriou J. Modulation of phenotype in cultures of human milk epithelial cells and its relation to the expression of a membrane antigen. Cell Differ. 1983 Mar;12(3):143–154. doi: 10.1016/0045-6039(83)90004-0. [DOI] [PubMed] [Google Scholar]
- Colcher D., Hand P. H., Nuti M., Schlom J. A spectrum of monoclonal antibodies reactive with human mammary tumor cells. Proc Natl Acad Sci U S A. 1981 May;78(5):3199–3203. doi: 10.1073/pnas.78.5.3199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daar A. S., Fabre J. W. The membrane antigens of human colorectal cancer cells: demonstration with monoclonal antibodies of heterogeneity within and between tumours and of anomalous expression of HLA-DR. Eur J Cancer Clin Oncol. 1983 Feb;19(2):209–220. doi: 10.1016/0277-5379(83)90419-4. [DOI] [PubMed] [Google Scholar]
- Damjanov I., Knowles B. B. Biology of disease. Monoclonal antibodies and tumor-associated antigens. Lab Invest. 1983 May;48(5):510–525. [PubMed] [Google Scholar]
- Easty G. C., Easty D. M., Monaghan P., Ormerod M. G., Neville A. M. Preparation and identification of human breast epithelial cells in culture. Int J Cancer. 1980 Nov 15;26(5):577–584. doi: 10.1002/ijc.2910260509. [DOI] [PubMed] [Google Scholar]
- Edwards P. A., Brooks I. M. Antigenic subsets of human breast epithelial cells distinguished by monoclonal antibodies. J Histochem Cytochem. 1984 May;32(5):531–537. doi: 10.1177/32.5.6371134. [DOI] [PubMed] [Google Scholar]
- Edwards P. A. Differential cell adhesion may result from nonspecific interactions between cell surface glycoproteins. Nature. 1978 Jan 19;271(5642):248–249. doi: 10.1038/271248a0. [DOI] [PubMed] [Google Scholar]
- Edwards P. A. Some properties and applications of monoclonal antibodies. Biochem J. 1981 Oct 15;200(1):1–10. doi: 10.1042/bj2000001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ellis I. O., Robins R. A., Elston C. W., Blamey R. W., Ferry B., Baldwin R. W. A monoclonal antibody, NCRC-11, raised to human breast carcinoma. 1. Production and immunohistological characterization. Histopathology. 1984 May;8(3):501–516. doi: 10.1111/j.1365-2559.1984.tb02360.x. [DOI] [PubMed] [Google Scholar]
- Fidler I. J., Hart I. R. Biological diversity in metastatic neoplasms: origins and implications. Science. 1982 Sep 10;217(4564):998–1003. doi: 10.1126/science.7112116. [DOI] [PubMed] [Google Scholar]
- Fleming K. A., McMichael A., Morton J. A., Woods J., McGee J. O. Distribution of HLA class 1 antigens in normal human tissue and in mammary cancer. J Clin Pathol. 1981 Jul;34(7):779–784. doi: 10.1136/jcp.34.7.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Foster C. S., Dinsdale E. A., Edwards P. A., Neville A. M. Monoclonal antibodies to the human mammary gland. II. Distribution of determinants in breast carcinomas. Virchows Arch A Pathol Anat Histol. 1982;394(3):295–305. doi: 10.1007/BF00430672. [DOI] [PubMed] [Google Scholar]
- Foster C. S., Edwards P. A., Dinsdale E. A., Neville A. M. Monoclonal antibodies to the human mammary gland. I. Distribution of determinants in non-neoplastic mammary and extra mammary tissues. Virchows Arch A Pathol Anat Histol. 1982;394(3):279–293. doi: 10.1007/BF00430671. [DOI] [PubMed] [Google Scholar]
- Fox N., Damjanov I., Knowles B. B., Solter D. Immunohistochemical localization of the mouse stage-specific embryonic antigen 1 in human tissues and tumors. Cancer Res. 1983 Feb;43(2):669–678. [PubMed] [Google Scholar]
- Gatter K. C., Mason D. Y. The use of monoclonal antibodies for histopathologic diagnosis of human malignancy. Semin Oncol. 1982 Dec;9(4):517–525. [PubMed] [Google Scholar]
- Gooi H. C., Uemura K., Edwards P. A., Foster C. S., Pickering N., Feizi T. Two mouse hybridoma antibodies against human milk-fat globules recognise the I(Ma) antigenic determinant beta-D-Galp-(1 leads to 4)-beta-D-GlcpNAc-(1 leads to 6). Carbohydr Res. 1983 Aug 16;120:293–302. doi: 10.1016/0008-6215(83)88023-9. [DOI] [PubMed] [Google Scholar]
- Greaves M., Delia D., Sutherland R., Rao J., Verbi W., Kemshead J., Hariri G., Goldstein G., Kung P. Expression of the OKT monoclonal antibody defined antigenic determinants in malignancy. Int J Immunopharmacol. 1981;3(3):283–299. doi: 10.1016/0192-0561(81)90022-9. [DOI] [PubMed] [Google Scholar]
- Hand P. H., Nuti M., Colcher D., Schlom J. Definition of antigenic heterogeneity and modulation among human mammary carcinoma cell populations using monoclonal antibodies to tumor-associated antigens. Cancer Res. 1983 Feb;43(2):728–735. [PubMed] [Google Scholar]
- Heppner G. H. Tumor heterogeneity. Cancer Res. 1984 Jun;44(6):2259–2265. [PubMed] [Google Scholar]
- Hilkens J., Buijs F., Hilgers J., Hageman P., Calafat J., Sonnenberg A., van der Valk M. Monoclonal antibodies against human milk-fat globule membranes detecting differentiation antigens of the mammary gland and its tumors. Int J Cancer. 1984 Aug 15;34(2):197–206. doi: 10.1002/ijc.2910340210. [DOI] [PubMed] [Google Scholar]
- Houghton A. N., Brooks H., Cote R. J., Taormina M. C., Oettgen H. F., Old L. J. Detection of cell surface and intracellular antigens by human monoclonal antibodies. Hybrid cell lines derived from lymphocytes of patients with malignant melanoma. J Exp Med. 1983 Jul 1;158(1):53–65. doi: 10.1084/jem.158.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huang L. C., Brockhaus M., Magnani J. L., Cuttitta F., Rosen S., Minna J. D., Ginsburg V. Many monoclonal antibodies with an apparent specificity for certain lung cancers are directed against a sugar sequence found in lacto-N-fucopentaose III. Arch Biochem Biophys. 1983 Jan;220(1):318–320. doi: 10.1016/0003-9861(83)90417-4. [DOI] [PubMed] [Google Scholar]
- Iwaki Y., Kasai M. K., Terasaki P. I., Bernoco D., Park M. S., Cicciarelli J., Heintz R., Saxton R. E., Burk M. W., Morton D. L. Monoclonal antibody against A1 Lewis d antigen produced by the hybridoma immunized with a pulmonary carcinoma. Cancer Res. 1982 Feb;42(2):409–411. [PubMed] [Google Scholar]
- Kerbel R. S. Implications of immunological heterogeneity of tumours. Nature. 1979 Aug 2;280(5721):358–360. doi: 10.1038/280358a0. [DOI] [PubMed] [Google Scholar]
- Klein J. The major histocompatibility complex of the mouse. Science. 1979 Feb 9;203(4380):516–521. doi: 10.1126/science.104386. [DOI] [PubMed] [Google Scholar]
- Kufe D. W., Nadler L., Sargent L., Shapiro H., Hand P., Austin F., Colcher D., Schlom J. Biological behavior of human breast carcinoma-associated antigens expressed during cellular proliferation. Cancer Res. 1983 Feb;43(2):851–857. [PubMed] [Google Scholar]
- Lampert I. A., Suitters A. J., Chisholm P. M. Expression of Ia antigen on epidermal keratinocytes in graft-versus-host disease. Nature. 1981 Sep 10;293(5828):149–150. doi: 10.1038/293149a0. [DOI] [PubMed] [Google Scholar]
- Levy R., Miller R. A. Biological and clinical implications of lymphocyte hybridomas: tumor therapy with monoclonal antibodies. Annu Rev Med. 1983;34:107–116. doi: 10.1146/annurev.me.34.020183.000543. [DOI] [PubMed] [Google Scholar]
- Lloyd K. O., Larson G., Strömberg N., Thurin J., Karlsson K. A. Mouse monoclonal antibody F-3 recognizes the difucosyl type-2 blood group structure. Immunogenetics. 1983;17(5):537–541. doi: 10.1007/BF00696877. [DOI] [PubMed] [Google Scholar]
- Magnani J. L., Steplewski Z., Koprowski H., Ginsburg V. Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. Cancer Res. 1983 Nov;43(11):5489–5492. [PubMed] [Google Scholar]
- Mason D. W., Dallman M., Barclay A. N. Graft-versus-host disease induces expression of Ia antigen in rat epidermal cells and gut epithelium. Nature. 1981 Sep 10;293(5828):150–151. doi: 10.1038/293150a0. [DOI] [PubMed] [Google Scholar]
- McDowell E. M., Wilson T. S., Trump B. F. Atypical endocrine tumors of the lung. Arch Pathol Lab Med. 1981 Jan;105(1):20–28. [PubMed] [Google Scholar]
- McGee J. O., Woods J. C., Ashall F., Bramwell M. E., Harris H. A new marker for human cancer cells, 2 immunohistochemical detection of the Ca antigen in human tissues with the Ca1 antibody. Lancet. 1982 Jul 3;2(8288):7–10. doi: 10.1016/s0140-6736(82)91151-5. [DOI] [PubMed] [Google Scholar]
- Mènard S., Tagliabue E., Canevari S., Fossati G., Colnaghi M. I. Generation of monoclonal antibodies reacting with normal and cancer cells of human breast. Cancer Res. 1983 Mar;43(3):1295–1300. [PubMed] [Google Scholar]
- Natali P. G., Giacomini P., Bigotti A., Imai K., Nicotra M. R., Ng A. K., Ferrone S. Heterogeneity in the expression of HLA and tumor-associated antigens by surgically removed and cultured breast carcinoma cells. Cancer Res. 1983 Feb;43(2):660–668. [PubMed] [Google Scholar]
- Neri A., Nicolson G. L. Phenotypic drift of metastatic and cell-surface properties of mammary adenocarcinoma cell clones during growth in vitro. Int J Cancer. 1981 Dec;28(6):731–738. doi: 10.1002/ijc.2910280612. [DOI] [PubMed] [Google Scholar]
- Neville A. M., Foster C. S., Moshakis V., Gore M. Monoclonal antibodies and human tumor pathology. Hum Pathol. 1982 Dec;13(12):1067–1081. doi: 10.1016/s0046-8177(82)80241-4. [DOI] [PubMed] [Google Scholar]
- Newman R. A., Ormerod M. G., Greaves M. F. The presence of HLA-DR antigens on lactating human breast epithelium and milk fat globule membranes. Clin Exp Immunol. 1980 Sep;41(3):478–486. [PMC free article] [PubMed] [Google Scholar]
- Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
- Nudelman E., Hakomori S., Kannagi R., Levery S., Yeh M. Y., Hellström K. E., Hellström I. Characterization of a human melanoma-associated ganglioside antigen defined by a monoclonal antibody, 4.2. J Biol Chem. 1982 Nov 10;257(21):12752–12756. [PubMed] [Google Scholar]
- Ormerod M. G., Steele K., Westwood J. H., Mazzini M. N. Epithelial membrane antigen: partial purification, assay and properties. Br J Cancer. 1983 Oct;48(4):533–541. doi: 10.1038/bjc.1983.226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Papsidero L. D., Croghan G. A., Wang M. C., Kuriyama M., Johnson E. A., Valenzuela L. A., Chu T. M. Monoclonal antibody (F5) to human prostate antigen. Hybridoma. 1983;2(2):139–147. doi: 10.1089/hyb.1983.2.139. [DOI] [PubMed] [Google Scholar]
- Peterson J. A., Ceriani R. L., Blank E. W., Osvaldo L. Comparison of rates of phenotypic variability in surface antigen expression in normal and cancerous human breast epithelial cells. Cancer Res. 1983 Sep;43(9):4291–4296. [PubMed] [Google Scholar]
- Poste G. Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev. 1982;1(2):141–199. doi: 10.1007/BF00048224. [DOI] [PubMed] [Google Scholar]
- Pukel C. S., Lloyd K. O., Travassos L. R., Dippold W. G., Oettgen H. F., Old L. J. GD3, a prominent ganglioside of human melanoma. Detection and characterisation by mouse monoclonal antibody. J Exp Med. 1982 Apr 1;155(4):1133–1147. doi: 10.1084/jem.155.4.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ramaekers F., Huysmans A., Moesker O., Kant A., Jap P., Herman C., Vooijs P. Monoclonal antibody to keratin filaments, specific for glandular epithelia and their tumors. Use in surgical pathology. Lab Invest. 1983 Sep;49(3):353–361. [PubMed] [Google Scholar]
- Rognum T. O., Brandtzaeg P., Thorud E. Is heterogeneous expression of HLA-dr antigens and CEA along with DNA-profile variations evidence of phenotypic instability and clonal proliferation in human large bowel carcinomas? Br J Cancer. 1983 Oct;48(4):543–551. doi: 10.1038/bjc.1983.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rougon G., Deagostini-Bazin H., Hirn M., Goridis C. Tissue- and developmental stage-specific forms of a neural cell surface antigen linked to differences in glycosylation of a common polypeptide. EMBO J. 1982;1(10):1239–1244. doi: 10.1002/j.1460-2075.1982.tb00019.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shevinsky L. H., Knowles B. B., Damjanov I., Solter D. Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells. Cell. 1982 Oct;30(3):697–705. doi: 10.1016/0092-8674(82)90274-4. [DOI] [PubMed] [Google Scholar]
- Shimizu M., Yamauchi K. Isolation and characterization of mucin-like glycoprotein in human milk fat globule membrane. J Biochem. 1982 Feb;91(2):515–524. doi: 10.1093/oxfordjournals.jbchem.a133724. [DOI] [PubMed] [Google Scholar]
- Sloane J. P., Ormerod M. G. Distribution of epithelial membrane antigen in normal and neoplastic tissues and it value in diagnostic tumor pathology. Cancer. 1981 Apr 1;47(7):1786–1795. doi: 10.1002/1097-0142(19810401)47:7<1786::aid-cncr2820470711>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
- Stoker M., Perryman M., Eeles R. Clonal analysis of morphological phenotype in cultured mammary epithelial cells from human milk. Proc R Soc Lond B Biol Sci. 1982 May 22;215(1199):231–240. doi: 10.1098/rspb.1982.0039. [DOI] [PubMed] [Google Scholar]
- Thompson J. J., Herlyn M. F., Elder D. E., Clark W. H., Steplewski Z., Koprowski H. Use of monoclonal antibodies in detection of melanoma-associated antigens in intact human tumors. Am J Pathol. 1982 Jun;107(3):357–361. [PMC free article] [PubMed] [Google Scholar]
- Weiss L., Holmes J. C., Ward P. M. Do metastases arise from pre-existing subpopulations of cancer cells? Br J Cancer. 1983 Jan;47(1):81–89. doi: 10.1038/bjc.1983.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss M. A., Michael J. G., Pesce A. J., DiPersio L. Heterogeneity of beta 2-microglobulin in human breast carcinoma. Lab Invest. 1981 Jul;45(1):46–57. [PubMed] [Google Scholar]
- Wilkinson M. J., Howell A., Harris M., Taylor-Papadimitriou J., Swindell R., Sellwood R. A. The prognostic significance of two epithelial membrane antigens expressed by human mammary carcinomas. Int J Cancer. 1984 Mar 15;33(3):299–304. doi: 10.1002/ijc.2910330304. [DOI] [PubMed] [Google Scholar]
- Willison K. R., Karol R. A., Suzuki A., Kundu S. K., Marcus D. M. Neutral glycolipid antigens as developmental markers of mouse teratocarcinoma and early embryos: an immunologic and chemical analysis. J Immunol. 1982 Aug;129(2):603–609. [PubMed] [Google Scholar]
- Woodruff M. F. Cellular heterogeneity in tumours. Br J Cancer. 1983 May;47(5):589–594. doi: 10.1038/bjc.1983.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wright G. L., Jr, Beckett M. L., Starling J. J., Schellhammer P. F., Sieg S. M., Ladaga L. E., Poleskic S. Immunohistochemical localization of prostate carcinoma-associated antigens. Cancer Res. 1983 Nov;43(11):5509–5516. [PubMed] [Google Scholar]
- Zagury D., Morgan D. A., Fouchard M. Production of human T-lymphocyte clones. I. monoclonal culture and functional cytotoxic maturation. J Immunol Methods. 1981;43(1):67–78. doi: 10.1016/0022-1759(81)90037-5. [DOI] [PubMed] [Google Scholar]