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Signaltransduktion im Urothelkarzinom

Wie genau kennen wir die Ziele für eine zielgerichtete Therapie?

Signal transduction in urothelial cancer

How exactly do we know the targets for targeted therapy?

  • Urologische Forschung
  • Published:
Der Urologe Aims and scope Submit manuscript

Zusammenfassung

Mit zielgerichteter Tumortherapie konnte in den letzten Jahren die Lebensqualität vieler Krebspatienten verbessert und sogar ihr Überleben verlängert werden. Möglich wurde dies durch das wachsende Verständnis tumorspezifischer Signalwege. Auch beim Urothelkarzinom wurden spezifische Veränderungen von Tumorsignalwegen identifiziert. Dazu gehören Mutationen von FGFR3, HRAS und PIK3CA, die insbesondere in papillären Tumoren zu einer Überaktivierung des MAP-Kinase- und des Akt-Signalweges führen. Im Vergleich dazu sind Veränderungen des RB1- und des p53-Regulationssystems, welche einen unmittelbaren Einfluss auf die Zellzykluskontrolle haben, häufiger in invasiven Karzinomen anzutreffen. Dass eine zielgerichtete Tumortherapie beim Urothelkarzinom sich dennoch bisher als wenig erfolgreich erwiesen hat, mag wesentlich durch die noch unvollständige Erforschung von Signaltransduktionswegen bei dieser Tumorart bedingt sein. Zielgene tumorspezifischer Signalwege werden durch epigenetische Mechanismen kontrolliert und ihre Induzierbarkeit determiniert. Daher ist die Entschlüsselung dieser Kontrollmechanismen wichtig für die Entwicklung zielgerichteter Therapien beim Urothelkarzinom.

Abstract

Targeted therapies have helped to improve the quality of life and prolong the survival of many cancer patients. This progress is based on the growing understanding of cellular signal transduction pathways and regulatory systems in human cancers. In urothelial carcinoma, a number of specific alterations have been identified. These include mutations in FGFR3, HRAS, and PIK3CA leading to overactivity of MAPK and Akt signaling pathways especially in papillary tumors. In comparison, the RB1 and p53 regulatory systems that act more directly on cell cycle control are more commonly compromised in invasive carcinomas. Nevertheless, targeted therapies have shown little efficacy in the treatment of urothelial carcinoma so far, owing presumably to our incomplete knowledge of molecular changes affecting signal transduction pathways in this cancer type. Target genes of cancer pathways are regulated by epigenetic mechanisms, which determine their inducibility. Elucidating these control mechanisms could therefore prove important for developing targeted therapies for urothelial carcinoma.

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Literatur

  1. Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28:1254–1261

    Article  CAS  PubMed  Google Scholar 

  2. Bartkova J, Horejsi Z, Koed K et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–870

    Article  CAS  PubMed  Google Scholar 

  3. Billerey C, Chopin D, Aubriot-Lorton MH et al (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158:1955–1959

    CAS  PubMed  Google Scholar 

  4. Cappellen D, De Oliveira C, Ricol D et al (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 23:18–20

    CAS  PubMed  Google Scholar 

  5. Chatterjee SJ, Datar R, Youssefzadeh D et al (2004) Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol 22:1007–1013

    Article  CAS  PubMed  Google Scholar 

  6. Cohen DJ, Hochster HS (2007) Update on clinical data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic colorectal cancer. Clin Colorectal Cancer 7(Suppl 1):21–27

    Article  Google Scholar 

  7. Cunningham D, Atkin W, Lenz HJ et al (2010) Colorectal cancer. Lancet 375:1030–1047

    Article  PubMed  Google Scholar 

  8. Florl AR, Schulz WA (2008) Chromosomal instability in bladder cancer. Arch Toxicol 82:173–182

    Article  CAS  PubMed  Google Scholar 

  9. Frolov MV, Dyson NJ (2004) Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci 117:2173–2181

    Article  CAS  PubMed  Google Scholar 

  10. Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606

    Article  CAS  PubMed  Google Scholar 

  11. Hoshino R, Chatani Y, Yamori T et al (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822

    Article  CAS  PubMed  Google Scholar 

  12. Jebar AH, Hurst CD, Tomlinson DC et al (2005) FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24:5218–5225

    Article  CAS  PubMed  Google Scholar 

  13. Knowles MA (2008) Molecular pathogenesis of bladder cancer. Int J Clin Oncol 13:287–297

    Article  CAS  PubMed  Google Scholar 

  14. Lindgren D, Frigyesi A, Gudjonsson S et al (2010) Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 70:3463–3472

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Knowles E, Hernandez S, Malats N et al (2006) PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res 66:7401–7404

    Article  CAS  PubMed  Google Scholar 

  16. Merseburger AS, Waalkes S, Kuczyk MA (2009) Current state of systemic therapy of metastatic renal cell carcinoma. Urologe A 48:983–989

    Article  CAS  PubMed  Google Scholar 

  17. Qu W, Kang YD, Zhou MS et al (2009) Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells. Urol Oncol, doi:10.1016/j.urolonc.2008.11.018

  18. Ringhoffer M, Rinnab L, Kufer R et al (2009) Systemic therapy of metastatic renal cell carcinoma: from many options to the therapeutic strategy. Urologe A 48:1308–1317

    Article  CAS  PubMed  Google Scholar 

  19. Schulz W (2007) Molecular biology of human cancers. Springer, Dordrecht

  20. Schulz WA (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119:1513–1518

    Article  CAS  PubMed  Google Scholar 

  21. Shi TP, Xu H, Wei JF et al (2008) Association of low expression of notch-1 and jagged-1 in human papillary bladder cancer and shorter survival. J Urol 180:361–366

    Article  CAS  PubMed  Google Scholar 

  22. Siddiqui H, Solomon DA, Gunawardena RW et al (2003) Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition. Mol Cell Biol 23:7719–7731

    Article  CAS  PubMed  Google Scholar 

  23. Swiatkowski S, Seifert HH, Steinhoff C et al (2003) Activities of MAP-kinase pathways in normal uroepithelial cells and urothelial carcinoma cell lines. Exp Cell Res 282:48–57

    Article  CAS  PubMed  Google Scholar 

  24. Tomlinson DC, Baldo O, Harnden P et al (2007) FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 213:91–98

    Article  CAS  PubMed  Google Scholar 

  25. Van Rhijn BW, Lurkin I, Radvanyi F et al (2001) The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res 61:1265–1268

    Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Unsere aktuellen Arbeiten zur Signaltransduktion werden durch die Fa. Bayer Healthcare und die Jürgen-Manchot-Stiftung gefördert.

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Authors and Affiliations

  1. Urologische Klinik, Medizinische Fakultät, Heinrich-Heine-Universität, Moorenstraße 5, 40625, Düsseldorf, Deutschland

    G. Niegisch, A. Koch, J. Knievel, W.A. Schulz & P. Albers

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  1. G. Niegisch
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  2. A. Koch
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  3. J. Knievel
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  4. W.A. Schulz
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  5. P. Albers
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Correspondence to G. Niegisch.

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Niegisch, G., Koch, A., Knievel, J. et al. Signaltransduktion im Urothelkarzinom. Urologe 49, 1401–1405 (2010). https://doi.org/10.1007/s00120-010-2448-8

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  • DOI: https://doi.org/10.1007/s00120-010-2448-8

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