Skip to main content

Advertisement

Log in

Growth factors and receptors as prognostic markers in urothelial carcinoma

  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

Growth factors and their receptors are significant to the biology of transitional cell carcinoma of the bladder. In this context, characterization of gene expression, amplification, and mutation has established the relevance of receptors as potential targets of novel therapeutic agents. Because these characteristics vary across disease states, they may serve as prognostic indicators of recurrence, progression, response to therapy, and mortality. This review focuses on the prognostic value of the human epidermal growth factor receptor family, including epidermal growth factor receptor (EGFR), human EGFR-2 (HER2), HER3, HER4, vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor-3 (FGFR3). EGFR and HER2 seem to indicate a poor prognosis, and HER4 and FGFR3 appear to be favorable prognostic indicators. However, validation studies are required to answer many remaining questions.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2007. CA Cancer J Clin, 2007, 57:43–66.

    Article  PubMed  Google Scholar 

  2. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al.: Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 2000, 164:680–684.

    Article  PubMed  CAS  Google Scholar 

  3. Habuchi T, Marberger M, Droller MJ, et al.: Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. Urology 2005, 66:64–74.

    Article  PubMed  Google Scholar 

  4. Rotterud R, Fossa SD, Nesland JM: Protein networking in bladder cancer: immunoreactivity for FGFR3, EGFR, ERBB2, KAI1, PTEN, and RAS in normal and malignant urothelium. Histol Histopathol 2007, 22:349–363.

    PubMed  CAS  Google Scholar 

  5. Memon AA, Sorensen BS, Meldgaard P, et al.: The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Br J Cancer 2006, 94:1703–1709.

    PubMed  CAS  Google Scholar 

  6. Mellon K, Wright C, Kelly P, et al.: Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995, 153:919–925.

    Article  PubMed  CAS  Google Scholar 

  7. Kassouf W, Black PC, Tuziak T, et al.: Distinctive expression patterns of ErbB family receptors signify an aggressive variant of bladder cancer. J Urol 2007, In press.

  8. Chow NH, Liu HS, Lee EI, et al.: Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. Anticancer Res 1997, 17:1293–1296.

    PubMed  CAS  Google Scholar 

  9. Chow NH, Liu HS, Yang HB, et al.: Expression patterns of erbB receptor family in normal urothelium and transitional cell carcinoma. An immunohistochemical study. Virchows Arch 1997, 430:461–466.

    Article  PubMed  CAS  Google Scholar 

  10. Valentine A, Ritchie JL, Nevin GB, McKeown SR: Prognostic role of P27kip1 and epidermal growth factor receptor in transitional cell carcinoma of the bladder. Uro-Oncology 2002, 2:41–46.

    CAS  Google Scholar 

  11. Colquhoun AJ, Sundar S, Rajjayabun PH, et al.: Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer. Clin Oncol (R Coll Radiol), 2006, 8:702–709.

    Google Scholar 

  12. Chakravarti A, Winter K, Wu CL, et al.: Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2005, 62:309–317.

    PubMed  CAS  Google Scholar 

  13. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006, 24:5034–5042.

    Article  PubMed  CAS  Google Scholar 

  14. Blehm KN, Spiess PE, Bondaruk JE, et al.: Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clin Cancer Res 2006, 12:4671–4677.

    Article  PubMed  CAS  Google Scholar 

  15. Jacobs MA, Wotkowicz C, Baumgart ED, et al.: Epidermal growth factor receptor status and the response of bladder carcinoma cells to erlotinib. J Urol 2007, 178:1510–1514.

    Article  PubMed  CAS  Google Scholar 

  16. Sauter G, Haley J, Chew K, et al.: Epidermal-growth-factor-receptor expression is associated with rapid tumor proliferation in bladder cancer. Int J Cancer 1994, 57:508–514.

    Article  PubMed  CAS  Google Scholar 

  17. Gazzaniga P, Gradilone A, Silvestri I, et al.: High levels of transforming growth factor-alpha (TGF-alpha) mRNA may predict local relapses in early stage urinary bladder cancer. Eur J Cancer 1998, 34:934–936.

    Article  PubMed  CAS  Google Scholar 

  18. Ravery V, Grignon D, Angulo J, et al.: Evaluation of epidermal growth factor receptor, transforming growth factor alpha, epidermal growth factor and c-erbB2 in the progression of invasive bladder cancer. Urol Res 1997, 25:9–17.

    Article  PubMed  CAS  Google Scholar 

  19. Thogersen VB, Sorensen BS, Poulsen SS, et al.: A subclass of HER1 ligands are prognostic markers for survival in bladder cancer patients. Cancer Res 2001, 61:6227–6233.

    PubMed  CAS  Google Scholar 

  20. Adam RM, Danciu T, McLellan DL, et al.: A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Res 2003, 63:484–490.

    PubMed  CAS  Google Scholar 

  21. Kramer C, Klasmeyer K, Bojar H, et al.: Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome. Cancer 2007, 109:2016–2024.

    Article  PubMed  CAS  Google Scholar 

  22. Mellon JK, Lunec J, Wright C, et al.: C-erbB-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value. J Urol 1996, 155:321–326.

    Article  PubMed  CAS  Google Scholar 

  23. Chow NH, Chan SH, Tzai TS, et al.: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001, 7:1957–1962.

    PubMed  CAS  Google Scholar 

  24. Hussain MH, MacVicar GR, Petrylak DP, et al.: Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 2007, 25:2218–2224.

    Article  PubMed  CAS  Google Scholar 

  25. Junttila TT, Laato M, Vahlberg T, et al.: Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Clin Cancer Res 2003, 9:5346–5357.

    PubMed  CAS  Google Scholar 

  26. Krüger S, Weitsch G, Buttner H, et al.: Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome. Int J Oncol 2002, 21:981–987.

    PubMed  Google Scholar 

  27. Jimenez RE, Hussain M, Bianco FJ Jr., et al.: Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 2001, 7:2440–2447.

    PubMed  CAS  Google Scholar 

  28. Moch H, Sauter G, Moore D, et al.: p53 and erbB-2 protein overexpression are associated with early invasion and metastasis in bladder cancer. Virchows Arch A Pathol Anat Histopathol 1993, 423:329–334.

    Article  PubMed  CAS  Google Scholar 

  29. Kruger S, Lange I, Kausch I, Feller AC: Protein expression and gene copy number analysis of topoisomerase 2alpha, HER2 and P53 in minimally invasive urothelial carcinoma of the urinary bladder—a multitissue array study with prognostic implications. Anticancer Res 2005, 25:263–271.

    PubMed  Google Scholar 

  30. Gandour-Edwards R, Lara PN Jr., Folkins AK, et al.: Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? Cancer 2002, 95:1009–1015.

    Article  PubMed  CAS  Google Scholar 

  31. Memon AA, Sorensen BS, Melgard P, et al.: Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer 2004, 91:2034–2041.

    Article  PubMed  CAS  Google Scholar 

  32. Røtterud R, Nesland JM, Berner A, Fossa SD, et al.: Expression of the epidermal growth factor receptor family in normal and malignant urothelium. BJU Int 2005, 95:1344–1350.

    Article  PubMed  CAS  Google Scholar 

  33. Junttila TT, Sundvall M, Lundin M, et al.: Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res 2005, 65:1384–1393.

    Article  PubMed  CAS  Google Scholar 

  34. Bochner BH, Cote RJ, Weidner N, et al.: Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 1995, 87:1603–1612.

    Article  PubMed  CAS  Google Scholar 

  35. O’Brien T, Cranston D, Fuggle S, et al.: Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 1995, 55:510–513.

    PubMed  CAS  Google Scholar 

  36. Sato K, Sasaki R, Ogura Y, et al.: Expression of vascular endothelial growth factor gene and its receptor (flt-1) gene in urinary bladder cancer. Tohoku J Exp Med 1998, 185:173–184.

    Article  PubMed  CAS  Google Scholar 

  37. Crew JP, O’Brien T, Bradburn M, et al.: Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res 1997, 57:5281–5285.

    PubMed  CAS  Google Scholar 

  38. Inoue K, Slaton JW, Karashima T, et al.: The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Clin Cancer Res 2000, 6:4866–4873.

    PubMed  CAS  Google Scholar 

  39. Li N, Kanda K, Fukumori T, et al.: Expression of vascular endothelial growth factor isoforms and platelet-derived endothelial cell growth factor in bladder cancer. Urol Oncol 2000, 6:10–15.

    PubMed  Google Scholar 

  40. Suzuki K, Morita T, Tokue A: Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder. Int J Urol 2005, 12:152–158.

    Article  PubMed  CAS  Google Scholar 

  41. Zu X, Tang Z, Li Y, et al.: Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis. BJU Int 2006, 98:1090–1093.

    Article  PubMed  Google Scholar 

  42. Mylona E, Magkou C, Gorantonakis G, et al.: Evaluation of the vascular endothelial growth factor (VEGF)-C role in urothelial carcinomas of the bladder. Anticancer Res 2006, 26:3567–3571.

    PubMed  CAS  Google Scholar 

  43. Xia G, Kumar SR, Hawes D, et al.: Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer. J Urol 2006, 175:1245–1252.

    Article  PubMed  CAS  Google Scholar 

  44. Gakiopoulou-Givalou H, Nakopoulou L, Panayotopoulou EG, et al.: Non-endothelial KDR/flk-1 expression is associated with increased survival of patients with urothelial bladder carcinomas. Histopathology 2003, 43:272–279.

    Article  PubMed  CAS  Google Scholar 

  45. Hernandez S, Lopez-Knowles E, Lloreta J, et al.: Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 2006, 24:3664–3671.

    Article  PubMed  CAS  Google Scholar 

  46. Gomez-Roman JJ, Saenz P, Molina M, et al.: Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res 2005, 11:459–465.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  49. van Rhijn BW, Vis AN, van der Kwast TH, et al.: Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 2003, 21:1912–1921.

    Article  PubMed  CAS  Google Scholar 

  50. Mhawech-Fauceglia P, Cheney RT, Fischer G, et al.: FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Eur J Surg Oncol 2006, 32:231–237.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Colin P. N. Dinney.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Black, P.C., Dinney, C.P.N. Growth factors and receptors as prognostic markers in urothelial carcinoma. Curr Urol Rep 9, 55–61 (2008). https://doi.org/10.1007/s11934-008-0011-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11934-008-0011-6

Keywords

Navigation