Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Aug;74(3):342–351. doi: 10.1038/bjc.1996.364

Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.

D C Gotley 1, J Fawcett 1, M D Walsh 1, J A Reeder 1, D L Simmons 1, T M Antalis 1
PMCID: PMC2074640  PMID: 8695347

Abstract

Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression.

Full text

PDF
342

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antalis T. M., Dickinson J. L. Control of plasminogen-activator inhibitor type 2 gene expression in the differentiation of monocytic cells. Eur J Biochem. 1992 Apr 1;205(1):203–209. doi: 10.1111/j.1432-1033.1992.tb16769.x. [DOI] [PubMed] [Google Scholar]
  2. Aruffo A., Stamenkovic I., Melnick M., Underhill C. B., Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. doi: 10.1016/0092-8674(90)90694-a. [DOI] [PubMed] [Google Scholar]
  3. Brown T. A., Bouchard T., St John T., Wayner E., Carter W. G. Human keratinocytes express a new CD44 core protein (CD44E) as a heparan-sulfate intrinsic membrane proteoglycan with additional exons. J Cell Biol. 1991 Apr;113(1):207–221. doi: 10.1083/jcb.113.1.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Dall P., Heider K. H., Sinn H. P., Skroch-Angel P., Adolf G., Kaufmann M., Herrlich P., Ponta H. Comparison of immunohistochemistry and RT-PCR for detection of CD44v-expression, a new prognostic factor in human breast cancer. Int J Cancer. 1995 Feb 8;60(4):471–477. doi: 10.1002/ijc.2910600408. [DOI] [PubMed] [Google Scholar]
  6. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  7. Finke L. H., Terpe H. J., Zörb C., Haensch W., Schlag P. M. Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. Lancet. 1995 Mar 4;345(8949):583–583. [PubMed] [Google Scholar]
  8. Fox S. B., Fawcett J., Jackson D. G., Collins I., Gatter K. C., Harris A. L., Gearing A., Simmons D. L. Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. Cancer Res. 1994 Aug 15;54(16):4539–4546. [PubMed] [Google Scholar]
  9. Guo Y., Ma J., Wang J., Che X., Narula J., Bigby M., Wu M., Sy M. S. Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody. Cancer Res. 1994 Mar 15;54(6):1561–1565. [PubMed] [Google Scholar]
  10. Günthert U., Hofmann M., Rudy W., Reber S., Zöller M., Haussmann I., Matzku S., Wenzel A., Ponta H., Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991 Apr 5;65(1):13–24. doi: 10.1016/0092-8674(91)90403-l. [DOI] [PubMed] [Google Scholar]
  11. Hart I. R., Birch M., Marshall J. F. Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Rev. 1991 Jun;10(2):115–128. doi: 10.1007/BF00049409. [DOI] [PubMed] [Google Scholar]
  12. Heider K. H., Dämmrich J., Skroch-Angel P., Müller-Hermelink H. K., Vollmers H. P., Herrlich P., Ponta H. Differential expression of CD44 splice variants in intestinal- and diffuse-type human gastric carcinomas and normal gastric mucosa. Cancer Res. 1993 Sep 15;53(18):4197–4203. [PubMed] [Google Scholar]
  13. Heider K. H., Hofmann M., Hors E., van den Berg F., Ponta H., Herrlich P., Pals S. T. A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps. J Cell Biol. 1993 Jan;120(1):227–233. doi: 10.1083/jcb.120.1.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hofmann M., Rudy W., Günthert U., Zimmer S. G., Zawadzki V., Zöller M., Lichtner R. B., Herrlich P., Ponta H. A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. Cancer Res. 1993 Apr 1;53(7):1516–1521. [PubMed] [Google Scholar]
  15. Hofmann M., Rudy W., Zöller M., Tölg C., Ponta H., Herrlich P., Günthert U. CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res. 1991 Oct 1;51(19):5292–5297. [PubMed] [Google Scholar]
  16. Jackson D. G., Buckley J., Bell J. I. Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain. J Biol Chem. 1992 Mar 5;267(7):4732–4739. [PubMed] [Google Scholar]
  17. Jalkanen S., Jalkanen M., Bargatze R., Tammi M., Butcher E. C. Biochemical properties of glycoproteins involved in lymphocyte recognition of high endothelial venules in man. J Immunol. 1988 Sep 1;141(5):1615–1623. [PubMed] [Google Scholar]
  18. Jalkanen S., Joensuu H., Söderström K. O., Klemi P. Lymphocyte homing and clinical behavior of non-Hodgkin's lymphoma. J Clin Invest. 1991 May;87(5):1835–1840. doi: 10.1172/JCI115205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jamal H. H., Cano-Gauci D. F., Buick R. N., Filmus J. Activated ras and src induce CD44 overexpression in rat intestinal epithelial cells. Oncogene. 1994 Feb;9(2):417–423. [PubMed] [Google Scholar]
  20. Kim H., Yang X. L., Rosada C., Hamilton S. R., August J. T. CD44 expression in colorectal adenomas is an early event occurring prior to K-ras and p53 gene mutation. Arch Biochem Biophys. 1994 May 1;310(2):504–507. doi: 10.1006/abbi.1994.1199. [DOI] [PubMed] [Google Scholar]
  21. Koopman G., Heider K. H., Horst E., Adolf G. R., van den Berg F., Ponta H., Herrlich P., Pals S. T. Activated human lymphocytes and aggressive non-Hodgkin's lymphomas express a homologue of the rat metastasis-associated variant of CD44. J Exp Med. 1993 Apr 1;177(4):897–904. doi: 10.1084/jem.177.4.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Matsumura Y., Tarin D. Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet. 1992 Oct 31;340(8827):1053–1058. doi: 10.1016/0140-6736(92)93077-z. [DOI] [PubMed] [Google Scholar]
  23. Mulder J. W., Wielenga V. J., Polak M. M., van den Berg F. M., Adolf G. R., Herrlich P., Pals S. T., Offerhaus G. J. Expression of mutant p53 protein and CD44 variant proteins in colorectal tumorigenesis. Gut. 1995 Jan;36(1):76–80. doi: 10.1136/gut.36.1.76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rudy W., Hofmann M., Schwartz-Albiez R., Zöller M., Heider K. H., Ponta H., Herrlich P. The two major CD44 proteins expressed on a metastatic rat tumor cell line are derived from different splice variants: each one individually suffices to confer metastatic behavior. Cancer Res. 1993 Mar 15;53(6):1262–1268. [PubMed] [Google Scholar]
  25. Screaton G. R., Bell M. V., Bell J. I., Jackson D. G. The identification of a new alternative exon with highly restricted tissue expression in transcripts encoding the mouse Pgp-1 (CD44) homing receptor. Comparison of all 10 variable exons between mouse, human, and rat. J Biol Chem. 1993 Jun 15;268(17):12235–12238. [PubMed] [Google Scholar]
  26. Screaton G. R., Bell M. V., Jackson D. G., Cornelis F. B., Gerth U., Bell J. I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12160–12164. doi: 10.1073/pnas.89.24.12160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Seiter S., Arch R., Reber S., Komitowski D., Hofmann M., Ponta H., Herrlich P., Matzku S., Zöller M. Prevention of tumor metastasis formation by anti-variant CD44. J Exp Med. 1993 Feb 1;177(2):443–455. doi: 10.1084/jem.177.2.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Southgate J., Trejdosiewicz L. K., Smith B., Selby P. J. Patterns of splice variant CD44 expression by normal human urothelium in situ and in vitro and by bladder-carcinoma cell lines. Int J Cancer. 1995 Aug 9;62(4):449–456. doi: 10.1002/ijc.2910620415. [DOI] [PubMed] [Google Scholar]
  29. Stamenkovic I., Amiot M., Pesando J. M., Seed B. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell. 1989 Mar 24;56(6):1057–1062. doi: 10.1016/0092-8674(89)90638-7. [DOI] [PubMed] [Google Scholar]
  30. Sy M. S., Guo Y. J., Stamenkovic I. Distinct effects of two CD44 isoforms on tumor growth in vivo. J Exp Med. 1991 Oct 1;174(4):859–866. doi: 10.1084/jem.174.4.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Takada M., Yamamoto M., Saitoh Y. The significance of CD44 in human pancreatic cancer: I. High expression of CD44 in human pancreatic adenocarcinoma. Pancreas. 1994 Nov;9(6):748–752. doi: 10.1097/00006676-199411000-00013. [DOI] [PubMed] [Google Scholar]
  32. Terpe H. J., Stark H., Prehm P., Günthert U. CD44 variant isoforms are preferentially expressed in basal epithelial of non-malignant human fetal and adult tissues. Histochemistry. 1994 Feb;101(2):79–89. doi: 10.1007/BF00269353. [DOI] [PubMed] [Google Scholar]
  33. Wielenga V. J., Heider K. H., Offerhaus G. J., Adolf G. R., van den Berg F. M., Ponta H., Herrlich P., Pals S. T. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res. 1993 Oct 15;53(20):4754–4756. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES