Skip to main content

Advertisement

SpringerLink
Log in

Role of HYAL1 expression in primary breast cancer in the formation of brain metastases

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

The incidence of brain metastases in breast cancer patients has increased in the last years. However, the knowledge about tumor cell invasion in the brain is still very limited. Based on our recent study on cDNA microarray data of breast cancer patients, we hypothesized that two enzymes involved in the hyaluronan metabolism, namely, hyaluronan synthase 2 (HAS2) and hyaluronidase 1 (HYAL1) are associated with brain metastases formation.

Methods

Protein expression levels of hyaluronan, HAS2, and HYAL1 were analyzed in primary breast cancer, and metastatic tissue samples from different localizations (brain, bone, skin, liver, and lung) were included in four different cohorts by immunohistochemistry. Correlations of expression levels with clinical and pathological parameters were performed within the individual cohorts.

Results

Higher HYAL1 expression was detected among primary tumors from patients with subsequent brain metastases compared with those without brain metastases (p = 0.011). Interestingly, brain metastatic tissue showed a significantly reduced HYAL1 expression compared with the corresponding primary tumor (p = 0.003). HYAL1 expression in brain metastases was also significantly lower than in skin, liver, and lung metastases. Further, hyaluronan staining in brain metastases was mainly located on the surface of the tumor cells, whereas in all other metastatic sites hyaluronan was only detected in the extracellular matrix. We could not show an association of HAS2 with the formation of brain metastases.

Conclusions

In conclusion, our results suggest that the enzyme HYAL1 plays a role in tumor dissemination and brain-specific colonization, rather than in subsequent metastatic out-growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BM:

Brain metastases

BC:

Breast cancer

BBB:

Blood–brain-barrier

ECM:

Extracellular matrix

HA:

Hyaluronan

HYAL-1:

Hyaluronidase 1

HAS2:

Hyaluronan synthase 2

HAbp:

HA-binding protein

References

  1. Asplund T, Versnel MA, Laurent TC, Heldin P (1993) Human mesothelioma cells produce factors that stimulate the production of hyaluronan by mesothelial cells and fibroblasts. Cancer Res 53:388–392

    CAS  PubMed  Google Scholar 

  2. Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, Hirvikoski P, Eskelinen M, Kosma VM (2000) Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156:529–536. doi:10.1016/S0002-9440(10)64757-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Csoka AB, Frost GI, Stern R (2001) The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 20:499–508

    Article  CAS  PubMed  Google Scholar 

  4. Frisk G, Svensson T, Backlund LM, Lidbrink E, Blomqvist P, Smedby KE (2012) Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden. Br J Cancer 106:1850–1853. doi:10.1038/bjc.2012.163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fuhrmann IK, Steinhagen J, Ruther W, Schumacher U (2015) Comparative immunohistochemical evaluation of the zonal distribution of extracellular matrix and inflammation markers in human meniscus in osteoarthritis and rheumatoid arthritis. Acta Histochem 117:243–254. doi:10.1016/j.acthis.2014.12.009

    Article  CAS  PubMed  Google Scholar 

  6. Fujisaki T, Tanaka Y, Fujii K, Mine S, Saito K, Yamada S, Yamashita U, Irimura T, Eto S (1999) CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Cancer Res 59:4427–4434

    CAS  PubMed  Google Scholar 

  7. Hagenfeld D, Kathagen N, Prehm P (2014) Adsorption of glycosaminoglycans to the cell surface is responsible for cellular donnan effects. J Cell Biochem 115:1334–1341. doi:10.1002/jcb.24791

    Article  CAS  PubMed  Google Scholar 

  8. Hunt LC, Gorman C, Kintakas C, McCulloch DR, Mackie EJ, White JD (2013) Hyaluronan synthesis and myogenesis: a requirement for hyaluronan synthesis during myogenic differentiation independent of pericellular matrix formation. J Biol Chem 288:13006–13021. doi:10.1074/jbc.M113.453209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y, Miyauchi S, Spicer AP, McDonald JA, Kimata K (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274:25085–25092

    Article  CAS  PubMed  Google Scholar 

  10. Knudson W, Biswas C, Toole BP (1984) Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc Natl Acad Sci U S A 81:6767–6771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kramer MW, Escudero DO, Lokeshwar SD, Golshani R, Ekwenna OO, Acosta K, Merseburger AS, Soloway M, Lokeshwar VB (2011) Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis. Cancer 117:1197–1209. doi:10.1002/cncr.25565

    Article  CAS  PubMed  Google Scholar 

  12. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP (2008) Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 113:2638–2645. doi:10.1002/cncr.23930

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL (2005) HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res 65:7782–7789. doi:10.1158/0008-5472.CAN-05-1022

    Article  CAS  PubMed  Google Scholar 

  14. Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406. doi:10.1083/jcb.201102147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McAtee CO, Barycki JJ, Simpson MA (2014) Chapter one—emerging roles for hyaluronidase in cancer metastasis and therapy. In: Melanie AS, Paraskevi H (eds) Advances in cancer research. Academic Press, Cambridge, pp 1–34

    Google Scholar 

  16. Milde-Langosch K, Karn T, Schmidt M, Zu Eulenburg C, Oliveira-Ferrer L, Wirtz RM, Schumacher U, Witzel I, Schutze D, Muller V (2014) Prognostic relevance of glycosylation-associated genes in breast cancer. Breast Cancer Res Treat 145:295–305. doi:10.1007/s10549-014-2949-z

    Article  CAS  PubMed  Google Scholar 

  17. Milde-Langosch K, Schutze D, Oliveira-Ferrer L, Wikman H, Muller V, Lebok P, Pantel K, Schroder C, Witzel I, Schumacher U (2015) Relevance of betaGal-betaGalNAc-containing glycans and the enzymes involved in their synthesis for invasion and survival in breast cancer patients. Breast Cancer Res Treat 151:515–528. doi:10.1007/s10549-015-3425-0

    Article  CAS  PubMed  Google Scholar 

  18. Oskarsson T (2013) Extracellular matrix components in breast cancer progression and metastasis. Breast 22(Suppl 2):S66–S72. doi:10.1016/j.breast.2013.07.012

    Article  PubMed  Google Scholar 

  19. Posey JT, Soloway MS, Ekici S, Sofer M, Civantos F, Duncan RC, Lokeshwar VB (2003) Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Res 63:2638–2644

    CAS  PubMed  Google Scholar 

  20. Prehm P (1984) Hyaluronate is synthesized at plasma membranes. Biochem J 220:597–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pukrop T, Dehghani F, Chuang HN, Lohaus R, Bayanga K, Heermann S, Regen T, Van Rossum D, Klemm F, Schulz M, Siam L, Hoffmann A, Trumper L, Stadelmann C, Bechmann I, Hanisch UK, Binder C (2010) Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58:1477–1489. doi:10.1002/glia.21022

    PubMed  Google Scholar 

  22. Schmaus A, Sleeman JP (2015) Hyaluronidase-1 expression promotes lung metastasis in syngeneic mouse tumor models without affecting accumulation of small hyaluronan oligosaccharides in tumor interstitial fluid. Glycobiology 25:258–268. doi:10.1093/glycob/cwu106

    Article  CAS  PubMed  Google Scholar 

  23. Schwertfeger KL, Cowman MK, Telmer PG, Turley EA, McCarthy JB (2015) Hyaluronan, inflammation, and breast cancer progression. Front Immunol 6:236. doi:10.3389/fimmu.2015.00236

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sierra A, Price JE, Garcia-Ramirez M, Mendez O, Lopez L, Fabra A (1997) Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest 77:357–368

    CAS  PubMed  Google Scholar 

  25. Simpson MA, Reiland J, Burger SR, Furcht LT, Spicer AP, Oegema TR Jr, McCarthy JB (2001) Hyaluronan synthase elevation in metastatic prostate carcinoma cells correlates with hyaluronan surface retention, a prerequisite for rapid adhesion to bone marrow endothelial cells. J Biol Chem 276:17949–17957. doi:10.1074/jbc.M010064200

    Article  CAS  PubMed  Google Scholar 

  26. Singleton PA (2014) Hyaluronan regulation of endothelial barrier function in cancer. Adv Cancer Res 123:191–209. doi:10.1016/B978-0-12-800092-2.00007-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma VM (2011) Hyaluronan in human malignancies. Exp Cell Res 317:383–391. doi:10.1016/j.yexcr.2010.11.017

    Article  CAS  PubMed  Google Scholar 

  28. Tammi RH, Kultti A, Kosma VM, Pirinen R, Auvinen P, Tammi MI (2008) Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 18:288–295. doi:10.1016/j.semcancer.2008.03.005

    Article  CAS  PubMed  Google Scholar 

  29. Tan JX, Wang XY, Li HY, Su XL, Wang L, Ran L, Zheng K, Ren GS (2011) HYAL1 overexpression is correlated with the malignant behavior of human breast cancer. Int J Cancer 128:1303–1315. doi:10.1002/ijc.25460

    Article  CAS  PubMed  Google Scholar 

  30. Tan JX, Wang XY, Su XL, Li HY, Shi Y, Wang L, Ren GS (2011) Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis. PLoS ONE 6:e22836. doi:10.1371/journal.pone.0022836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539. doi:10.1038/nrc1391

    Article  CAS  PubMed  Google Scholar 

  32. Udabage L, Brownlee GR, Nilsson SK, Brown TJ (2005) The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. Exp Cell Res 310:205–217. doi:10.1016/j.yexcr.2005.07.026

    Article  CAS  PubMed  Google Scholar 

  33. Witzel I, Oliveira-Ferrer L, Pantel K, Muller V, Wikman H (2016) Breast cancer brain metastases: biology and new clinical perspectives. Breast Cancer Res 18:8. doi:10.1186/s13058-015-0665-1

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wu M, Cao M, He Y, Liu Y, Yang C, Du Y, Wang W, Gao F (2015) A novel role of low molecular weight hyaluronan in breast cancer metastasis. FASEB J 29:1290–1298. doi:10.1096/fj.14-259978

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful for the excellent technical assistance of Maila Rossberg and Kathrin Eylmann.

Funding

This work was funded by the Hamburger Krebsgesellschaft (Grant Number HKG 4048).

Author information

Author notes

    Authors and Affiliations

    1. Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

      Isabell Witzel, Anna K. Marx, Volkmar Müller, Elena Laakmann, Barbara Schmalfeldt, Karin Milde-Langosch & Leticia Oliveira-Ferrer

    2. Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Harriet Wikman

    3. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Jakob Matschke

    4. Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Udo Schumacher & Christine Stürken

    5. Institute of Physiological Chemistry and Pathobiochemistry, University Medical Center, Münster, Germany

      Peter Prehm

    Authors
    1. Isabell Witzel
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Anna K. Marx
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Volkmar Müller
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Harriet Wikman
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jakob Matschke
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Udo Schumacher
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Christine Stürken
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Peter Prehm
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Elena Laakmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Barbara Schmalfeldt
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Karin Milde-Langosch
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Leticia Oliveira-Ferrer
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Isabell Witzel.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Additional information

    Isabell Witzel and Anna K. Marx have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    10549_2017_4135_MOESM1_ESM.pptx

    Supplementary material 1 (PPTX 1096 kb)

    Fig. 1S: HA-binding protein staining pattern of tumor and stroma in breast cancer metastases of various locations. (A) Brain metastasis with HA-binding protein negative to positive tumor-associated staining (T), HA-binding protein negative to positive tumor microenviroment (TME) and HA-binding protein negative to positive blood vessels (BV) (20x, IRS 0-8). (B) Brain metastasis with HA-binding protein positive tumor cells (T) and HA-binding protein positive TME. All tumor cells show HA-binding protein expression in the membrane and some in the cytoplasm (20 × , IRS 2-8 and IRS 6-10). (C) Bone metastasis with HA-binding protein negative tumor cells (T), HA-binding protein positive TME, and HA-binding protein positive blood vessels (BV) (20 × , IRS 0 and IRS 11-12). (D) Skin metastasis with HA-binding protein positive tumor cells (T) and HA-binding protein positive adipocytes (A) (20 × IRS 4-8 and IRS 10-12). (E) Liver metastasis with HA-binding protein negative and weakly stained tumor cells (T) and HA-binding protein positive TME (20 × , IRS 0-4, and 10-12). (F) Lung metastasis with HA-binding protein negative to positive tumor cells (T) and HA-binding protein positive TME (20 × , IRS 0-4 and IRS 8-12)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Witzel, I., Marx, A.K., Müller, V. et al. Role of HYAL1 expression in primary breast cancer in the formation of brain metastases. Breast Cancer Res Treat 162, 427–438 (2017). https://doi.org/10.1007/s10549-017-4135-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10549-017-4135-6

    Keywords

    Search

    Navigation