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. 1991 Mar;138(3):741–750.

Expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in normal mucosa and adenomas of the colon, and in colon carcinomas and their liver metastases.

K Koretz 1, P Schlag 1, L Boumsell 1, P Möller 1
PMCID: PMC1886279  PMID: 2000944

Abstract

'Very late antigen' (VLA) proteins are members of the integrin superfamily with cell-surface receptor function and are involved in the cell-cell matrix interaction. They are heterodimers with a common beta 1 chain and different alpha chains counted through VLA-1 to VLA-6. The VLA-2 complex (alpha 2/beta 1) was found to act as collagen receptor on platelets and the VLA-6 complex (alpha 6/beta 1) as laminin receptor. Using monoclonal antibodies and an indirect immunoperoxidase method, we investigated the expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in 20 normal colonic mucosa samples, in 20 colonic adenomas, and in 96 carcinomas together with 10 accompanying liver metastases. All three proteins were expressed throughout the colonic epithelium, except for VLA-alpha 2, which was present in the cryptic gland but was absent on the mucosal surface in some cases. In general, adenomas were strongly positive for the VLA proteins but 3 of 20 cases showed focal VLA-alpha 2-negative areas. The carcinomas revealed considerable heterogeneity of VLA-alpha 2 expression; ie, 59 tumors were completely positive, 35 tumors revealed a focal loss of antigen, and 2 cases were negative. This reduced antigen expression was statistically associated with Dukes' stage C/D (P = 0.003). VLA-alpha 6 was expressed throughout in all tumors. VLA-beta 1 was found extensively expressed in 77 carcinomas, partially expressed in 17 carcinomas, and was absent in 2 carcinomas. As compared to their primary tumors, liver metastases showed roughly corresponding patterns of antigen expression. The down regulation/loss of VLA proteins in a subset of epithelial colon tumors might cause a disturbed cell-cell/cell-matrix interaction that might augment the invasive property of their cells.

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  1. Albini A., Aukerman S. L., Ogle R. C., Noonan D. M., Fridman R., Martin G. R., Fidler I. J. The in vitro invasiveness and interactions with laminin of K-1735 melanoma cells. Evidence for different laminin-binding affinities in high and low metastatic variants. Clin Exp Metastasis. 1989 Jul-Aug;7(4):437–451. doi: 10.1007/BF01753664. [DOI] [PubMed] [Google Scholar]
  2. Amiot M., Bernard A., Tran H. C., Leca G., Kanellopoulos J. M., Boumsell L. The human cell surface glycoprotein complex (gp 120,200) recognized by monoclonal antibody K20 is a component binding to phytohaemagglutinin on T cells. Scand J Immunol. 1986 Jan;23(1):109–118. doi: 10.1111/j.1365-3083.1986.tb01948.x. [DOI] [PubMed] [Google Scholar]
  3. Chang W. W., Leblond C. P. Renewal of the epithelium in the descending colon of the mouse. I. Presence of three cell populations: vacuolated-columnar, mucous and argentaffin. Am J Anat. 1971 May;131(1):73–99. doi: 10.1002/aja.1001310105. [DOI] [PubMed] [Google Scholar]
  4. Cheresh D. A., Smith J. W., Cooper H. M., Quaranta V. A novel vitronectin receptor integrin (alpha v beta x) is responsible for distinct adhesive properties of carcinoma cells. Cell. 1989 Apr 7;57(1):59–69. doi: 10.1016/0092-8674(89)90172-4. [DOI] [PubMed] [Google Scholar]
  5. Choy M. Y., Richman P. I., Horton M. A., MacDonald T. T. Expression of the VLA family of integrins in human intestine. J Pathol. 1990 Jan;160(1):35–40. doi: 10.1002/path.1711600109. [DOI] [PubMed] [Google Scholar]
  6. Cierniewski C. S., Swiatkowska M., Poniatowski J., Niewiarowska J. Anti-(Arg-Gly-Asp-Ser) antibody and its interaction with fibronectin, fibrinogen and platelets. Eur J Biochem. 1988 Oct 15;177(1):109–115. doi: 10.1111/j.1432-1033.1988.tb14350.x. [DOI] [PubMed] [Google Scholar]
  7. Coller B. S., Beer J. H., Scudder L. E., Steinberg M. H. Collagen-platelet interactions: evidence for a direct interaction of collagen with platelet GPIa/IIa and an indirect interaction with platelet GPIIb/IIIa mediated by adhesive proteins. Blood. 1989 Jul;74(1):182–192. [PubMed] [Google Scholar]
  8. DUKES C. E., BUSSEY H. J. The spread of rectal cancer and its effect on prognosis. Br J Cancer. 1958 Sep;12(3):309–320. doi: 10.1038/bjc.1958.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dedhar S., Saulnier R. Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol. 1990 Feb;110(2):481–489. doi: 10.1083/jcb.110.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dunn S. M., Hillam A. J., Stomski F., Jin B. Q., Lucas C. M., Boyd A. W., Krissansen G. W., Burns G. F. Leukocyte adhesion molecules involved in inflammation. Transplant Proc. 1989 Feb;21(1 Pt 1):31–34. [PubMed] [Google Scholar]
  11. Eastwood G. L. Gastrointestinal epithelial renewal. Gastroenterology. 1977 May;72(5 Pt 1):962–975. [PubMed] [Google Scholar]
  12. Elices M. J., Hemler M. E. The human integrin VLA-2 is a collagen receptor on some cells and a collagen/laminin receptor on others. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9906–9910. doi: 10.1073/pnas.86.24.9906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freed E., Gailit J., van der Geer P., Ruoslahti E., Hunter T. A novel integrin beta subunit is associated with the vitronectin receptor alpha subunit (alpha v) in a human osteosarcoma cell line and is a substrate for protein kinase C. EMBO J. 1989 Oct;8(10):2955–2965. doi: 10.1002/j.1460-2075.1989.tb08445.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Garcia-Pardo A., Wayner E. A., Carter W. G., Ferreira O. C., Jr Human B lymphocytes define an alternative mechanism of adhesion to fibronectin. The interaction of the alpha 4 beta 1 integrin with the LHGPEILDVPST sequence of the type III connecting segment is sufficient to promote cell attachment. J Immunol. 1990 May 1;144(9):3361–3366. [PubMed] [Google Scholar]
  15. Guan J. L., Hynes R. O. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 1990 Jan 12;60(1):53–61. doi: 10.1016/0092-8674(90)90715-q. [DOI] [PubMed] [Google Scholar]
  16. Gullberg D., Terracio L., Borg T. K., Rubin K. Identification of integrin-like matrix receptors with affinity for interstitial collagens. J Biol Chem. 1989 Jul 25;264(21):12686–12694. [PubMed] [Google Scholar]
  17. Hall D. E., Reichardt L. F., Crowley E., Holley B., Moezzi H., Sonnenberg A., Damsky C. H. The alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers mediate cell attachment to distinct sites on laminin. J Cell Biol. 1990 Jun;110(6):2175–2184. doi: 10.1083/jcb.110.6.2175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hemler M. E. Adhesive protein receptors on hematopoietic cells. Immunol Today. 1988 Apr;9(4):109–113. doi: 10.1016/0167-5699(88)91280-7. [DOI] [PubMed] [Google Scholar]
  19. Hemler M. E., Crouse C., Sonnenberg A. Association of the VLA alpha 6 subunit with a novel protein. A possible alternative to the common VLA beta 1 subunit on certain cell lines. J Biol Chem. 1989 Apr 15;264(11):6529–6535. [PubMed] [Google Scholar]
  20. Hemler M. E., Crouse C., Takada Y., Sonnenberg A. Multiple very late antigen (VLA) heterodimers on platelets. Evidence for distinct VLA-2, VLA-5 (fibronectin receptor), and VLA-6 structures. J Biol Chem. 1988 Jun 5;263(16):7660–7665. [PubMed] [Google Scholar]
  21. Hemler M. E., Glass D., Coblyn J. S., Jacobson J. G. Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation. J Clin Invest. 1986 Sep;78(3):696–702. doi: 10.1172/JCI112629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hemler M. E., Huang C., Schwarz L. The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight beta subunit. J Biol Chem. 1987 Mar 5;262(7):3300–3309. [PubMed] [Google Scholar]
  23. Hemler M. E., Huang C., Takada Y., Schwarz L., Strominger J. L., Clabby M. L. Characterization of the cell surface heterodimer VLA-4 and related peptides. J Biol Chem. 1987 Aug 25;262(24):11478–11485. [PubMed] [Google Scholar]
  24. Hemler M. E., Jacobson J. G., Brenner M. B., Mann D., Strominger J. L. VLA-1: a T cell surface antigen which defines a novel late stage of human T cell activation. Eur J Immunol. 1985 May;15(5):502–508. doi: 10.1002/eji.1830150515. [DOI] [PubMed] [Google Scholar]
  25. Holzmann B., Weissman I. L. Peyer's patch-specific lymphocyte homing receptors consist of a VLA-4-like alpha chain associated with either of two integrin beta chains, one of which is novel. EMBO J. 1989 Jun;8(6):1735–1741. doi: 10.1002/j.1460-2075.1989.tb03566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hynes R. O. Integrins: a family of cell surface receptors. Cell. 1987 Feb 27;48(4):549–554. doi: 10.1016/0092-8674(87)90233-9. [DOI] [PubMed] [Google Scholar]
  27. Ignatius M. J., Large T. H., Houde M., Tawil J. W., Barton A., Esch F., Carbonetto S., Reichardt L. F. Molecular cloning of the rat integrin alpha 1-subunit: a receptor for laminin and collagen. J Cell Biol. 1990 Aug;111(2):709–720. doi: 10.1083/jcb.111.2.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kadagidze Z. G., Tupitsyn N. N., Baryshnikov A. J., Kadyrov K. P., Blinov V. M., Bernard A., Amiot M., Boumsell L. K20 and ICO-10 monoclonal antibodies (gp120/200; Thy-1): immunophenotyping of human solid tumours. Br J Cancer. 1990 Feb;61(2):215–217. doi: 10.1038/bjc.1990.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kajiji S., Tamura R. N., Quaranta V. A novel integrin (alpha E beta 4) from human epithelial cells suggests a fourth family of integrin adhesion receptors. EMBO J. 1989 Mar;8(3):673–680. doi: 10.1002/j.1460-2075.1989.tb03425.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kaufmann R., Frösch D., Westphal C., Weber L., Klein C. E. Integrin VLA-3: ultrastructural localization at cell-cell contact sites of human cell cultures. J Cell Biol. 1989 Oct;109(4 Pt 1):1807–1815. doi: 10.1083/jcb.109.4.1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kramer R. H., McDonald K. A., Vu M. P. Human melanoma cells express a novel integrin receptor for laminin. J Biol Chem. 1989 Sep 15;264(26):15642–15649. [PubMed] [Google Scholar]
  32. LIPKIN M. CELL REPLICATION IN THE GASTROINTESTINAL TRACT OF MAN. Gastroenterology. 1965 May;48:616–624. [PubMed] [Google Scholar]
  33. Languino L. R., Gehlsen K. R., Wayner E., Carter W. G., Engvall E., Ruoslahti E. Endothelial cells use alpha 2 beta 1 integrin as a laminin receptor. J Cell Biol. 1989 Nov;109(5):2455–2462. doi: 10.1083/jcb.109.5.2455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Liotta L. A., Rao C. N., Wewer U. M. Biochemical interactions of tumor cells with the basement membrane. Annu Rev Biochem. 1986;55:1037–1057. doi: 10.1146/annurev.bi.55.070186.005133. [DOI] [PubMed] [Google Scholar]
  35. Liotta L. A., Rao N. C., Barsky S. H., Bryant G. The laminin receptor and basement membrane dissolution: role in tumour metastasis. Ciba Found Symp. 1984;108:146–162. doi: 10.1002/9780470720899.ch10. [DOI] [PubMed] [Google Scholar]
  36. Lorenzsonn V., Trier J. S. The fine structure of human rectal mycosa. The epithelial lining of the base of the crypt. Gastroenterology. 1968 Jul;55(1):88–101. [PubMed] [Google Scholar]
  37. Martin G. R., Timpl R. Laminin and other basement membrane components. Annu Rev Cell Biol. 1987;3:57–85. doi: 10.1146/annurev.cb.03.110187.000421. [DOI] [PubMed] [Google Scholar]
  38. Mould A. P., Wheldon L. A., Komoriya A., Wayner E. A., Yamada K. M., Humphries M. J. Affinity chromatographic isolation of the melanoma adhesion receptor for the IIICS region of fibronectin and its identification as the integrin alpha 4 beta 1. J Biol Chem. 1990 Mar 5;265(7):4020–4024. [PubMed] [Google Scholar]
  39. Oz O. K., Campbell A., Tao T. W. Reduced cell adhesion to fibronectin and laminin is associated with altered glycosylation of beta 1 integrins in a weakly metastatic glycosylation mutant. Int J Cancer. 1989 Aug 15;44(2):343–347. doi: 10.1002/ijc.2910440226. [DOI] [PubMed] [Google Scholar]
  40. Piotrowicz R. S., Orchekowski R. P., Nugent D. J., Yamada K. Y., Kunicki T. J. Glycoprotein Ic-IIa functions as an activation-independent fibronectin receptor on human platelets. J Cell Biol. 1988 Apr;106(4):1359–1364. doi: 10.1083/jcb.106.4.1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pischel K. D., Bluestein H. G., Woods V. L., Jr Platelet glycoproteins Ia, Ic, and IIa are physicochemically indistinguishable from the very late activation antigens adhesion-related proteins of lymphocytes and other cell types. J Clin Invest. 1988 Feb;81(2):505–513. doi: 10.1172/JCI113348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pischel K. D., Hemler M. E., Huang C., Bluestein H. G., Woods V. L., Jr Use of the monoclonal antibody 12F1 to characterize the differentiation antigen VLA-2. J Immunol. 1987 Jan 1;138(1):226–233. [PubMed] [Google Scholar]
  43. Pytela R., Pierschbacher M. D., Ruoslahti E. Identification and isolation of a 140 kd cell surface glycoprotein with properties expected of a fibronectin receptor. Cell. 1985 Jan;40(1):191–198. doi: 10.1016/0092-8674(85)90322-8. [DOI] [PubMed] [Google Scholar]
  44. Ruoslahti E. Fibronectin and its receptors. Annu Rev Biochem. 1988;57:375–413. doi: 10.1146/annurev.bi.57.070188.002111. [DOI] [PubMed] [Google Scholar]
  45. Ruoslahti E., Pierschbacher M. D. New perspectives in cell adhesion: RGD and integrins. Science. 1987 Oct 23;238(4826):491–497. doi: 10.1126/science.2821619. [DOI] [PubMed] [Google Scholar]
  46. Santoro S. A., Rajpara S. M., Staatz W. D., Woods V. L., Jr Isolation and characterization of a platelet surface collagen binding complex related to VLA-2. Biochem Biophys Res Commun. 1988 May 31;153(1):217–223. doi: 10.1016/s0006-291x(88)81211-7. [DOI] [PubMed] [Google Scholar]
  47. Sonnenberg A., Janssen H., Hogervorst F., Calafat J., Hilgers J. A complex of platelet glycoproteins Ic and IIa identified by a rat monoclonal antibody. J Biol Chem. 1987 Jul 25;262(21):10376–10383. [PubMed] [Google Scholar]
  48. Sonnenberg A., Modderman P. W., Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature. 1988 Dec 1;336(6198):487–489. doi: 10.1038/336487a0. [DOI] [PubMed] [Google Scholar]
  49. Staatz W. D., Rajpara S. M., Wayner E. A., Carter W. G., Santoro S. A. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J Cell Biol. 1989 May;108(5):1917–1924. doi: 10.1083/jcb.108.5.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Straus A. H., Carter W. G., Wayner E. A., Hakomori S. Mechanism of fibronectin-mediated cell migration: dependence or independence of cell migration susceptibility on RGDS-directed receptor (integrin). Exp Cell Res. 1989 Jul;183(1):126–139. doi: 10.1016/0014-4827(89)90423-0. [DOI] [PubMed] [Google Scholar]
  51. Takada Y., Huang C., Hemler M. E. Fibronectin receptor structures in the VLA family of heterodimers. Nature. 1987 Apr 9;326(6113):607–609. doi: 10.1038/326607a0. [DOI] [PubMed] [Google Scholar]
  52. Tomaselli K. J., Damsky C. H., Reichardt L. F. Interactions of a neuronal cell line (PC12) with laminin, collagen IV, and fibronectin: identification of integrin-related glycoproteins involved in attachment and process outgrowth. J Cell Biol. 1987 Nov;105(5):2347–2358. doi: 10.1083/jcb.105.5.2347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tomaselli K. J., Damsky C. H., Reichardt L. F. Purification and characterization of mammalian integrins expressed by a rat neuronal cell line (PC12): evidence that they function as alpha/beta heterodimeric receptors for laminin and type IV collagen. J Cell Biol. 1988 Sep;107(3):1241–1252. doi: 10.1083/jcb.107.3.1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wayner E. A., Carter W. G. Identification of multiple cell adhesion receptors for collagen and fibronectin in human fibrosarcoma cells possessing unique alpha and common beta subunits. J Cell Biol. 1987 Oct;105(4):1873–1884. doi: 10.1083/jcb.105.4.1873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wayner E. A., Carter W. G., Piotrowicz R. S., Kunicki T. J. The function of multiple extracellular matrix receptors in mediating cell adhesion to extracellular matrix: preparation of monoclonal antibodies to the fibronectin receptor that specifically inhibit cell adhesion to fibronectin and react with platelet glycoproteins Ic-IIa. J Cell Biol. 1988 Nov;107(5):1881–1891. doi: 10.1083/jcb.107.5.1881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zutter M. M., Santoro S. A. Widespread histologic distribution of the alpha 2 beta 1 integrin cell-surface collagen receptor. Am J Pathol. 1990 Jul;137(1):113–120. [PMC free article] [PubMed] [Google Scholar]

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