Skip to main content

Advertisement

SpringerLink
Log in

Differential expression and clinical relevance of MUC1 in renal cell carcinoma metastasis

  • Original Article
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

Purpose

To determine the differential expression patterns and prognostic relevance of Mucin-1 (MUC1) expression in clear cell renal cell carcinoma (RCC) metastasis.

Methods

Tissue microarrays (TMA) from samples of 151 RCC metastases, 61 primary RCCs and corresponding benign renal tissues were immunohistochemically stained for MUC1 and semi-quantitatively evaluated by immunoreactivity scores (IRS). MUC1 differential expression in metastasis, primary RCC and normal tissue were comparatively analyzed. Patient characteristics and clinical follow-up for patients with metastatic RCC (mRCC) were recorded. Correlations of MUC1 expression with mRCC survival were determined.

Results

Median cytoplasmic expression was highest in benign tissue (IRS = 1.04). Primary RCC (0.50) and metastasis (0.12) showed significantly lower cytoplasmic staining intensity. Membranous expression in benign tissue was, however, significantly lower (0.21) compared with primary RCC (0.59) and metastasis (0.57). Notable differences of MUC1 cytoplasmic and membranous expression were observed between different metastasis sites. Significantly higher (P = 0.014) membranous expression was observed in pulmonary versus non-pulmonary lesions, while no significant differences of cytoplasmic MUC1 expression were observed. The prognostic relevance of MUC1 expression in metastatic RCC was limited.

Conclusions

MUC1 is differentially expressed in benign renal tissue, primary RCC and RCC metastasis. Membranous MUC1 expression was significantly elevated in pulmonary metastases compared to non-pulmonary lesions, which may reflect individual biology and putative response to MUC1-based anti-cancer therapy.

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

Similar content being viewed by others

References

  1. Bouillez A, Gnemmi V, Gaudelot K, Hemon B, Ringot B, Pottier N, Glowacki F, Butruille C, Cauffiez C, Hamdane M, Sergeant N, Van Seuningen I, Leroy X, Aubert S, Perrais M (2014) MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway. Oncotarget 5(3):754–763

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kufe DW (2013) MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 32(9):1073–1081. doi:10.1038/onc.2012.158

    Article  CAS  PubMed  Google Scholar 

  3. Horm TM, Schroeder JA (2013) MUC1 and metastatic cancer: expression, function and therapeutic targeting. Cell Adhes Migr 7(2):187–198. doi:10.4161/cam.23131

    Article  Google Scholar 

  4. Cowey CL, Rathmell WK (2009) VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Current Oncol Rep 11(2):94–101

    Article  CAS  Google Scholar 

  5. Aubert S, Fauquette V, Hemon B, Lepoivre R, Briez N, Bernard D, Van Seuningen I, Leroy X, Perrais M (2009) MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor progression. Cancer Res 69(14):5707–5715. doi:10.1158/0008-5472.CAN-08-4905

    Article  CAS  PubMed  Google Scholar 

  6. Deguchi T, Tanemura M, Miyoshi E, Nagano H, Machida T, Ohmura Y, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Ito T, Mori M, Doki Y, Sawa Y (2010) Increased immunogenicity of tumor-associated antigen, mucin 1, engineered to express alpha-gal epitopes: a novel approach to immunotherapy in pancreatic cancer. Cancer Res 70(13):5259–5269. doi:10.1158/0008-5472.CAN-09-4313

    Article  CAS  PubMed  Google Scholar 

  7. Deng J, Wang L, Chen H, Li L, Ma Y, Ni J, Li Y (2013) The role of tumour-associated MUC1 in epithelial ovarian cancer metastasis and progression. Cancer Metastasis Rev 32(3–4):535–551. doi:10.1007/s10555-013-9423-y

    Article  CAS  PubMed  Google Scholar 

  8. Lakshmanan I, Ponnusamy MP, Macha MA, Haridas D, Majhi PD, Kaur S, Jain M, Batra SK, Ganti AK (2015) Mucins in lung cancer: diagnostic, prognostic, and therapeutic implications. J Thorac Oncol 10(1):19–27. doi:10.1097/JTO.0000000000000404

    Article  CAS  PubMed  Google Scholar 

  9. Liu S, Ruan M, Li S, Wang L, Yang W (2014) Increased expression of MUC1 predicts poor survival in salivary gland mucoepidermoid carcinoma. J Cranio-Maxillo-Fac Surg 42(8):1891–1896. doi:10.1016/j.jcms.2014.07.008

    Article  Google Scholar 

  10. Shibahara H, Higashi M, Koriyama C, Yokoyama S, Kitazono I, Kurumiya Y, Narita M, Kuze S, Kyokane T, Mita S, Arai T, Kato T, Yuasa N, Yamaguchi R, Kubota H, Suzuki H, Baba S, Rousseau K, Batra SK, Yonezawa S (2014) Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer. Plos One 9(4):e86111. doi:10.1371/journal.pone.0086111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fujita K, Denda K, Yamamoto M, Matsumoto T, Fujime M, Irimura T (1999) Expression of MUC1 mucins inversely correlated with post-surgical survival of renal cell carcinoma patients. Br J Cancer 80(1–2):301–308. doi:10.1038/sj.bjc.6690355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kraus S, Abel PD, Nachtmann C, Linsenmann HJ, Weidner W, Stamp GW, Chaudhary KS, Mitchell SE, Franke FE, el Lalani N (2002) MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis. Hum Pathol 33(1):60–67

    Article  CAS  PubMed  Google Scholar 

  13. Langner C, Ratschek M, Rehak P, Schips L, Zigeuner R (2004) Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases. Mod Pathol 17(2):180–188. doi:10.1038/modpathol.3800032

    Article  CAS  PubMed  Google Scholar 

  14. Leroy X, Zerimech F, Zini L, Copin MC, Buisine MP, Gosselin B, Aubert JP, Porchet N (2002) MUC1 expression is correlated with nuclear grade and tumor progression in pT1 renal clear cell carcinoma. Am J Clin Pathol 118(1):47–51. doi:10.1309/1F99-BPDY-7DHH-9G97

    Article  CAS  PubMed  Google Scholar 

  15. Rausch S, Kruck S, Stenzl A, Bedke J (2014) IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy. Futur Oncol 10(6):937–948. doi:10.2217/fon.14.61

    Article  CAS  Google Scholar 

  16. Hisatsune A, Nakayama H, Kawasaki M, Horie I, Miyata T, Isohama Y, Kim KC, Katsuki H (2011) Anti-MUC1 antibody inhibits EGF receptor signaling in cancer cells. Biochem Biophys Res Commun 405(3):377–381. doi:10.1016/j.bbrc.2011.01.029

    Article  CAS  PubMed  Google Scholar 

  17. Oei AL, Moreno M, Verheijen RH, Sweep FC, Thomas CM, Massuger LF, von Mensdorff-Pouilly S (2008) Induction of IgG antibodies to MUC1 and survival in patients with epithelial ovarian cancer. Int J Cancer J Int Du Cancer 123(8):1848–1853. doi:10.1002/ijc.23725

    Article  CAS  Google Scholar 

  18. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847

    Article  CAS  PubMed  Google Scholar 

  19. Gnemmi V, Bouillez A, Gaudelot K, Hemon B, Ringot B, Pottier N, Glowacki F, Villers A, Vindrieux D, Cauffiez C, Van Seuningen I, Bernard D, Leroy X, Aubert S, Perrais M (2014) MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/beta-catenin pathway and interaction with SNAIL promoter. Cancer Lett 346(2):225–236. doi:10.1016/j.canlet.2013.12.029

    Article  CAS  PubMed  Google Scholar 

  20. Mohr AM, Bailey JM, Lewallen ME, Liu X, Radhakrishnan P, Yu F, Tapprich W, Hollingsworth MA (2013) MUC1 regulates expression of multiple microRNAs involved in pancreatic tumor progression, including the miR-200c/141 cluster. Plos One 8(10):e73306. doi:10.1371/journal.pone.0073306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Leroy X, Zini L, Leteurtre E, Zerimech F, Porchet N, Aubert JP, Gosselin B, Copin MC (2002) Morphologic subtyping of papillary renal cell carcinoma: correlation with prognosis and differential expression of MUC1 between the two subtypes. Modern Pathology 15(11):1126–1130. doi:10.1097/01.MP.0000036346.88874.25

    Article  PubMed  Google Scholar 

  22. Leroy X, Aubert S, Ballereau C, Birembaut P, Porchet N, Gosselin B, Copin MC (2005) Diffuse expression of MUC 1 in metastases of renal clear cell carcinoma as a possible therapeutic target for renal cancer. Histopathology 47(4):435–436. doi:10.1111/j.1365-2559.2005.02144.x

    Article  CAS  PubMed  Google Scholar 

  23. Perret AG, Clemencon A, Li G, Tostain J, Peoc’h M (2008) Differential expression of prognostic markers in histological subtypes of papillary renal cell carcinoma. BJU Int 102(2):183–187. doi:10.1111/j.1464-410X.2008.07605.x

    Article  PubMed  Google Scholar 

  24. Eichelberg C, Junker K, Ljungberg B, Moch H (2009) Diagnostic and prognostic molecular markers for renal cell carcinoma: a critical appraisal of the current state of research and clinical applicability. Eur Urol 55(4):851–863. doi:10.1016/j.eururo.2009.01.003

    Article  CAS  PubMed  Google Scholar 

  25. Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, Pietersz GA, Apostolopoulos V, Vaughan H, Karanikas V, Kyriakou P, McKenzie IF, Mitchell PL (2006) Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res 12(3 Pt 1):869–877. doi:10.1158/1078-0432.CCR-05-1574

    Article  CAS  PubMed  Google Scholar 

  26. Wierecky J, Mueller M, Brossart P (2006) Dendritic cell-based cancer immunotherapy targeting MUC-1. Cancer Immunol Immunother 55(1):63–67. doi:10.1007/s00262-005-0673-6

    Article  CAS  PubMed  Google Scholar 

  27. Akaza H, Tsukamoto T, Fujioka T, Tomita Y, Kitamura T, Ozono S, Miki T, Naito S, Zembutsu H, Nakamura Y (2011) Combined immunotherapy with low-dose IL-2 plus IFN-alpha for metastatic renal cell carcinoma: survival benefit for selected patients with lung metastasis and serum sodium level. Jpn J Clin Oncol 41(8):1023–1030. doi:10.1093/jjco/hyr067

    Article  PubMed  Google Scholar 

  28. Staehler M (2011) The role of metastasectomy in metastatic renal cell carcinoma. Nature Rev Urol 8(4):180–181. doi:10.1038/nrurol.2011.30

    Article  Google Scholar 

  29. Davis SD, Koizumi JH, Pitts WR (1989) Spontaneous regression of pulmonary metastases from renal cell carcinoma. Urology 33(2):141–144

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Claudia Hermann, Department of Pathology, University of Tübingen for technical assistance with the immunohistochemical analysis. SR is supported by a Fernidand-Eisenberger-Grant of the German Society of Urology (RaS1/FE-14).

Authors’ contributions

Steffen Rausch, Stephan Kruck, and Jens Bedke contributed to conception and design, data collection, data analysis, and manuscript writing/editing. Jörg Hennenlotter was involved in conception and design, collection of samples, data analysis. Daniel Schollenberger, Johanna Beermann, and Marcus Scharpf collected and analyzed the data. Arnulf Stenzl and Falko Fend supervised the study.

Author information

Authors and Affiliations

  1. Department of Urology, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Str.3, 72076, Tübingen, Germany

    Steffen Rausch, Johanna Beermann, Jörg Hennenlotter, Arnulf Stenzl, Daniel Schollenberger, Jens Bedke & Stephan Kruck

  2. Department of Pathology, Eberhard-Karls-University Tübingen, Liebermeisterstraße 8, 72076, Tübingen, Germany

    Marcus Scharpf & Falko Fend

Authors
  1. Steffen Rausch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johanna Beermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcus Scharpf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jörg Hennenlotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Falko Fend
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arnulf Stenzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel Schollenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jens Bedke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephan Kruck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens Bedke.

Ethics declarations

Conflict of interest

Steffen Rausch, Johanna Beermann, Marcus Scharpf, Jörg Hennenlotter, Falko Fend, Arnulf Stenzl, Daniel Schollenberger, Jens Bedke, and Stephan Kruck declare that no competing financial interests exist.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 23 kb)

Supplementary material 2 (DOCX 17 kb)

Supplementary Figure 1

A. Cytoplasmic expression patterns and immunoreactivity scores (0.0-3.0) of MUC1(200x magnification) B. Membranous expression patterns and immunoreactivity scores (0.0-3.0) of MUC1 (200x magnification) (DOCX 4941 kb)

Supplementary Figure 2

Kaplan-Meier survival curves in dependence of cytoplasmic, membranous, and overall MUC1 expression in primary RCC (A-C) and RCC metastasis (D-F) cohorts (DOCX 325 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rausch, S., Beermann, J., Scharpf, M. et al. Differential expression and clinical relevance of MUC1 in renal cell carcinoma metastasis. World J Urol 34, 1635–1641 (2016). https://doi.org/10.1007/s00345-016-1804-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-016-1804-8

Keywords

Search

Navigation