Top

Published in:

01-12-2014 | Original Article

Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer

Authors: Simone Bertz, Christine Abeé, Stephan Schwarz-Furlan, Joachim Alfer, Ferdinand Hofstädter, Robert Stoehr, Arndt Hartmann, Andreas KA Gaumann

Published in: Virchows Archiv | Issue 6/2014

Abstract

Compared to other members of the fibroblast growth factor receptor (FGFR) family, only few studies investigate FGFR3 in tumour angiogenesis. We investigated the connection between angiogenesis and FGF/FGFR expression including FGFR3 mutation status in urothelial carcinomas. Immunohistochemistry was performed in invasive and non-invasive urothelial cancers of 61 patients. Protein expression of CD31, factor VIII (FVIII), FGF-1/2, FGFR1, FGFR3 and FGFR4 and FGFR3 mutation status were evaluated. Morphometric assessment of angiogenesis including microvessel count (MVC) and vascular surface area (VSA) was analysed. Correlation and survival analyses (overall survival (OS) and disease-free survival (DFS)) with univariate and multivariate analyses were performed. CD31 values (MVC and VSA) significantly correlated with OS and DFS. OS and DFS were significantly better in patients with FGFR3 overexpression. Multivariate analysis revealed FGFR3 protein expression and tumour grading (WHO classification 2004) as independent prognostic factors of OS and VSA of CD31 and FGFR3 protein expression of DFS. FGFR3 mutation status was correlated with VSA measured by FVIII. FGFR3 may be able to induce a pro-angiogenic phenotype in urothelial carcinomas and significantly influence prognosis. Consequently, FGFR3 is a potential therapeutic target also from the angiogenesis perspective.

Antoine M, Wirz W, Tag CG, Mavituna M, Emans N, Korff T, Stoldt V, Gressner AM, Kiefer P (2005) Expression pattern of fibroblast growth factors (FGFs), their receptors and antagonists in primary endothelial cells and vascular smooth muscle cells. Growth Factors 23:87–95PubMedCrossRef

Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410. doi:10.1038/nrc1093 PubMedCrossRef

Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Diez G, de Medina S, Van Rhijn B, Bralet MP, Lefrere-Belda MA, Lahaye JB, Abbou CC, Bonaventure J, Zafrani ES, van der Kwast T, Thiery JP, Radvanyi F (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158:1955–1959PubMedCentralPubMedCrossRef

Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG, Nichols PW (1995) Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 87:1603–1612PubMedCrossRef

Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 23:18–20PubMed

Claffey KP, Abrams K, Shih SC, Brown LF, Mullen A, Keough M (2001) Fibroblast growth factor 2 activation of stromal cell vascular endothelial growth factor expression and angiogenesis. Lab Invest J Tech Meth Pathol 81:61–75CrossRef

Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22:201–207PubMedCrossRef

Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GN, Harris AL (1994) Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762–766PubMedCrossRef

Dietmaier W, Hartmann A, Wallinger S, Heinmoller E, Kerner T, Endl E, Jauch KW, Hofstadter F, Ruschoff J (1999) Multiple mutation analyses in single tumor cells with improved whole genome amplification. Am J Pathol 154:83–95. doi:10.1016/S0002-9440(10)65254-6 PubMedCentralPubMedCrossRef

10.

Folkman J (1996) Fighting cancer by attacking its blood supply. Sci Am 275:150–154PubMedCrossRef

11.

Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235:442–447PubMedCrossRef

12.

Forough R, Xi Z, MacPhee M, Friedman S, Engleka KA, Sayers T, Wiltrout RH, Maciag T (1993) Differential transforming abilities of non-secreted and secreted forms of human fibroblast growth factor-1. J Biol Chem 268:2960–2968PubMed

13.

Giri D, Ropiquet F, Ittmann M (1999) Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Canc Res Offic J Am Assoc Canc Res 5:1063–1071

14.

Gomez-Roman JJ, Saenz P, Molina M, Cuevas Gonzalez J, Escuredo K, Santa Cruz S, Junquera C, Simon L, Martinez A, Gutierrez Banos JL, Lopez-Brea M, Esparza C, Val-Bernal JF (2005) Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Canc Res Offic J Am Assoc Canc Res 11:459–465

15.

Hafner C, van Oers JM, Vogt T, Landthaler M, Stoehr R, Blaszyk H, Hofstaedter F, Zwarthoff EC, Hartmann A (2006) Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J Clin Invest 116:2201–2207PubMedCentralPubMedCrossRef

16.

Hartmann A, Schlake G, Zaak D, Hungerhuber E, Hofstetter A, Hofstaedter F, Knuechel R (2002) Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 62:809–818PubMed

17.

Hernandez S, Lopez-Knowles E, Lloreta J, Kogevinas M, Amoros A, Tardon A, Carrato A, Serra C, Malats N, Real FX (2006) Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol Offic J Am Soc Clin Oncol 24:3664–3671CrossRef

18.

Katoh M, Nakagama H (2014) FGF receptors: cancer biology and therapeutics. Med Res Rev 34:280–300. doi:10.1002/med.21288 PubMedCrossRef

19.

Knowles MA (2007) Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World J Urol 25:581–593PubMedCrossRef

20.

Knowles MA (2008) Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol 4:71–83. doi:10.2217/14796694.4.1.71 PubMedCrossRef

21.

Konerding MA, Fait E, Gaumann A (2001) 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. Br J Cancer 84:1354–1362PubMedCentralPubMedCrossRef

22.

Lamy A, Gobet F, Laurent M, Blanchard F, Varin C, Moulin C, Andreou A, Frebourg T, Pfister C (2006) Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J Urol 176:2686–2689PubMedCrossRef

23.

Lindgren D, Liedberg F, Andersson A, Chebil G, Gudjonsson S, Borg A, Mansson W, Fioretos T, Hoglund M (2006) Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene 25:2685–2696PubMedCrossRef

24.

Lopez-Knowles E, Hernandez S, Kogevinas M, Lloreta J, Amoros A, Tardon A, Carrato A, Kishore S, Serra C, Malats N, Real FX, Investigators ES (2006) The p53 pathway and outcome among patients with T1G3 bladder tumors. Clin Canc Res Offic J Am Assoc Canc Res 12:6029–6036CrossRef

25.

Matsumoto M, Ohtsuki Y, Ochii K, Seike Y, Iseda N, Sasaki T, Okada Y, Kurabayashi A, Furihata M (2004) Fibroblast growth factor receptor 3 protein expression in urothelial carcinoma of the urinary bladder, exhibiting no association with low-grade and/or non-invasive lesions. Oncol Rep 12:967–971PubMed

26.

Mhawech-Fauceglia P, Cheney RT, Fischer G, Beck A, Herrmann FR (2006) FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Eur J Surg Oncol 32:231–237PubMedCrossRef

27.

Nesbit M, Nesbit HK, Bennett J, Andl T, Hsu MY, Dejesus E, McBrian M, Gupta AR, Eck SL, Herlyn M (1999) Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 18:6469–6476. doi:10.1038/sj.onc.1203066 PubMedCrossRef

28.

Neuzillet Y, Paoletti X, Ouerhani S, Mongiat-Artus P, Soliman H, de The H, Sibony M, Denoux Y, Molinie V, Herault A, Lepage ML, Maille P, Renou A, Vordos D, Abbou CC, Bakkar A, Asselain B, Kourda N, El Gaaied A, Leroy K, Laplanche A, Benhamou S, Lebret T, Allory Y, Radvanyi F (2012) A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer. PLoS One 7:e48993PubMedCentralPubMedCrossRef

29.

Nourse MB, Rolle MW, Pabon LM, Murry CE (2007) Selective control of endothelial cell proliferation with a synthetic dimerizer of FGF receptor-1. Lab Invest J Tech Meth Pathol 87:828–835. doi:10.1038/labinvest.3700597 CrossRef

30.

Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178. doi:10.1016/j.cytogfr.2005.01.004 PubMedCrossRef

31.

Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140PubMed

32.

Ren T, Qing Y, Dai N, Li M, Qian C, Yang Y, Cheng Y, Li Z, Zhang S, Zhong Z, Wang D (2014) Apurinic/apyrimidinic endonuclease 1 induced upregulation of fibroblast growth factor 2 and its receptor 3 induces angiogenesis in human osteosarcoma cells. Cancer Sci 105:186–194PubMedCrossRef

33.

Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, He J, Palmer G, Yelensky R, Lipson D, Ali S, Balasubramanian S, Curran JA, Garcia L, Mahoney K, Downing SR, Hawryluk M, Miller VA, Stephens PJ (2014) Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol Offic J US Canad Acad Pathol Inc 27:271–280. doi:10.1038/modpathol.2013.135

34.

Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM, Lamszus K (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Canc 84:10–18CrossRef

35.

Soslow RA, Nabeya Y, Ying L, Blundell M, Altorki NK (1999) Acidic fibroblast growth factor is progressively increased in the development of oesophageal glandular dysplasia and adenocarcinoma. Histopathology 35:31–37PubMedCrossRef

36.

Stoehr R, Wissmann C, Suzuki H, Knuechel R, Krieg RC, Klopocki E, Dahl E, Wild P, Blaszyk H, Sauter G, Simon R, Schmitt R, Zaak D, Hofstaedter F, Rosenthal A, Baylin SB, Pilarsky C, Hartmann A (2004) Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest J Tech Meth Pathol 84:465–478. doi:10.1038/labinvest.3700068 CrossRef

37.

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

38.

Tomlinson DC, Lamont FR, Shnyder SD, Knowles MA (2009) Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer. Cancer Res 69:4613–4620PubMedCentralPubMedCrossRef

39.

Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129. doi:10.1038/nrc2780 PubMedCrossRef

40.

van Oers JM, Lurkin I, van Exsel AJ, Nijsen Y, van Rhijn BW, van der Aa MN, Zwarthoff EC (2005) A simple and fast method for the simultaneous detection of nine fibroblast growth factor receptor 3 mutations in bladder cancer and voided urine. Clin Canc Res Offic J Am Assoc Canc Res 11:7743–7748. doi:10.1158/1078-0432.CCR-05-1045 CrossRef

41.

van Oers JM, Wild PJ, Burger M, Denzinger S, Stoehr R, Rosskopf E, Hofstaedter F, Steyerberg EW, Klinkhammer-Schalke M, Zwarthoff EC, van der Kwast TH, Hartmann A (2007) FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumors. Eur Urol 52:760–768. doi:10.1016/j.eururo.2007.01.009 PubMedCrossRef

42.

van Rhijn BW, Lurkin I, Radvanyi F, Kirkels WJ, van der Kwast TH, Zwarthoff EC (2001) The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res 61:1265–1268PubMed

43.

van Rhijn BW, van der Kwast TH, Liu L, Fleshner NE, Bostrom PJ, Vis AN, Alkhateeb SS, Bangma CH, Jewett MA, Zwarthoff EC, Zlotta AR, Bapat B (2012) The FGFR3 mutation is related to favorable pT1 bladder cancer. J Urol 187:310–314. doi:10.1016/j.juro.2011.09.008 PubMed

44.

Vermeulen PB, Fox SB, Dirix LY, Colpaert C, Van Marck EA (2002) Heterogeneity of vascularisation in invasive breast carcinoma. Eur J Cancer 38:1951–1952PubMedCrossRef

45.

Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezzella F, Viale G, Weidner N, Harris AL, Dirix LY (1996) Quantification of angiogenesis in solid human tumors: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32A:2474–2484PubMedCrossRef

46.

Vermeulen PB, Verhoeven D, Fierens H, Hubens G, Goovaerts G, Van Marck E, De Bruijn EA, Van Oosterom AT, Dirix LY (1995) Microvessel quantification in primary colorectal carcinoma: an immunohistochemical study. Br J Cancer 71:340–343PubMedCentralPubMedCrossRef

47.

Weidner N (1999) Tumor vascularity and proliferation: clear evidence of a close relationship. J Pathol 189:297–299. doi:10.1002/(SICI)1096-9896(199911)189:3<297::AID-PATH434>3.0.CO;2-O PubMedCrossRef

48.

Williams SV, Hurst CD, Knowles MA (2013) Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 22:795–803. doi:10.1093/hmg/dds486 PubMedCentralPubMedCrossRef

49.

Zieger K, Dyrskjot L, Wiuf C, Jensen JL, Andersen CL, Jensen KM, Orntoft TF (2005) Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Canc Res Offic J Am Assoc Canc Res 11:7709–7719. doi:10.1158/1078-0432.CCR-05-1130 CrossRef

Title: Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer
Authors: Simone Bertz
Christine Abeé
Stephan Schwarz-Furlan
Joachim Alfer
Ferdinand Hofstädter
Robert Stoehr
Arndt Hartmann
Andreas KA Gaumann
Publication date: 01-12-2014
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 6/2014
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-014-1672-9

At a glance: The STEP trials

Springer Medicine

Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2014

Frequency of TERT promoter mutations in primary tumors of the liver

Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist

JMY protein, a regulator of P53 and cytoplasmic actin filaments, is expressed in normal and neoplastic tissues

Reproducibility of histological subtyping of malignant pleural mesothelioma

Total burden of intraplaque hemorrhage in coronary arteries relates to the use of coumarin-type anticoagulants but not platelet aggregation inhibitors

SATB1 is an independent prognostic factor in radically resected upper gastrointestinal tract adenocarcinoma