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Breast Cancer Research and Treatment

, Volume 36, Issue 3, pp 307–313 | Cite as

Human mammary carcinomas express homologues of rat metastasis-associated variants of CD44

  • Hans-Peter Sinn
  • Karl-Heinz Heider
  • Petra Skroch-Angel
  • Gunter von Minckwitz
  • Manfred Kaufmann
  • Peter Herrlich
  • Helmut Ponta
Report

Summary

Splice variants of CD44 expressed in a metastasizing cell line derived from a rat pancreatic adenocarcinoma have been shown recently to confer metastatic potential onto non-metastasizing rat pancreatic carcinoma and sarcoma cell lines. Homologues of these variants have also been detected in a variety of human malignancies. Using antibodies raised against a bacterially expressed fusion protein containing variant CD44 sequences, we have explored the expression of variant CD44 glycoproteins on tumors of the female breast. The material examined included normal tissue, hyperplastic lesions, 103 primary invasive mammary carcinomas, 10in situ carcinomas, 12 local recurrences and 18 lymph node metastases. Using a polyclonal serum directed against several variant CD44 epitopes, normal mammary epithelia as well as ductal hyperplasias were negative for these splice variants, while the variant CD44 epitopes were detectable in all but six of the primary invasive carcinomas. From the reaction with various monoclonal antibodies and polyclonal sera specific for individual epitopes it is obvious that the tumors predominantly express CD44 variants encoded by exons v5 to v7. Interestingly, all investigated lymph node metastases reacted positively with the variant-specific antibodies, in contrast to primary tumors which reacted in 54% to 86% of the cases, depending on the antibody used. Statistical analysis revealed a significant correlation between expression of variant exons v3/v4 and v6 and increased tumor grade (p = 0.001 and p < 0.05, respectively; Fisher's exact test). Exon v6 is carried by the variants which confer metastatic capability in the rat. These results indicate that the expression of the CD44 variants is upregulated in mammary carcinomas and is closely linked to tumor anaplasia.

Key words

breast cancer CD44 variants metastasis tumor progression marker 

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References

  1. 1.
    Diel IJ, Kaufmann M, Goerner R, Costa SD, Kaul S, Bastert G: Detection of tumor cells in bone marrow of patients with primary breast cancer: A prognostic factor for distant metastasis. J Clin Oncol 10: 1534–1539, 1992Google Scholar
  2. 2.
    Fisher ER, Redmond C, Fisher B, Bass G: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Projects (BSABP). Prognostic discriminants for 8-year survival for node-negative invasive breast cancer patients. Cancer 65: 2121–2128, 1990Google Scholar
  3. 3.
    Breast Cancer Research, Special Report. Science 259: 612–632, 1993Google Scholar
  4. 4.
    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 65: 13–24, 1991Google Scholar
  5. 5.
    Herrlich P, Rudy P, Hofmann M, Arch R, Zöller M, Zawadzki V, Tölg C, Hekele A, Koopman G, Pals S, Heider K-H, Sleeman J, Ponta H: CD44 and splice variants of CD44 in normal differentiation and tumor progression. In: Hemler ME, Mihich E (eds) Cell Adhesion Molecules. Plenum Press, New York and London, 1993, pp 265–288Google Scholar
  6. 6.
    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 51: 5292–5297, 1991Google Scholar
  7. 7.
    Jackson DG, Buckley J, Bell JI: Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain. J Biol Chem 267: 4732–4739, 1992Google Scholar
  8. 8.
    Heider K-H, Hofmann M, Horst E, van den Berg F, Ponta H, Herrlich P, Pals ST: A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps. J Cell Biol 120: 227–233, 1993Google Scholar
  9. 9.
    Wielenga V, Heider K-H, Offerhaus JG, Adolf GR, van den Berg F, Ponta H, Herrlich P, Pals ST: Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res 53: 4754–4756, 1993Google Scholar
  10. 10.
    Heider K-H, Dämmrich J, Skroch-Angel P, Müller-Hermelink H-K, Vollmers HP, Herrlich P, Ponta H: Differential expression of CD44 splice variants in intestinal and diffuse type human gastric carcinoma and normal gastric mucosa. Cancer Res 53: 4197–4203, 1993Google Scholar
  11. 11.
    Koopman G, Heider K-H, Horst E, Adolf GR, van den Berg F, Ponta H, Herrlich P, Pals ST: Activated human lymphocytes and aggressive non-Hodgkin lymphomas express a homologue of the rat metastasis-associated variant of CD44. J Exp Med 177: 897–904, 1993Google Scholar
  12. 12.
    Hofmann M, Rudy W, Günthert U, Zimmer SG, Zawadzki V, Zöller M, Lichtner RB, 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 53: 1516–1521, 1993Google Scholar
  13. 13.
    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 53: 1262–1268, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Hans-Peter Sinn
    • 1
  • Karl-Heinz Heider
    • 2
  • Petra Skroch-Angel
    • 2
  • Gunter von Minckwitz
    • 3
  • Manfred Kaufmann
    • 3
  • Peter Herrlich
    • 2
  • Helmut Ponta
    • 2
  1. 1.Department of PathologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Forschungszentrum KarlsruheInstitute of GeneticsKarlsruheGermany
  3. 3.Womens HospitalUniversity of HeidelbergHeidelbergGermany

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