Development and Characteristics of Preclinical Experimental Models for the Research of Rare Neuroendocrine Bladder Cancer

No AccessJournal of UrologyInvestigative Urology1 Dec 2013Development and Characteristics of Preclinical Experimental Models for the Research of Rare Neuroendocrine Bladder Cancer Thomas Hofner, Stephan Macher-Goeppinger, Corinna Klein, Teresa Rigo-Watermeier, Christian Eisen, Sascha Pahernik, Markus Hohenfellner, Andreas Trumpp, and Martin R. Sprick Thomas HofnerThomas Hofner Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany Department of Urology, University Hospital Heidelberg, Heidelberg, Germany , Stephan Macher-GoeppingerStephan Macher-Goeppinger Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany , Corinna KleinCorinna Klein Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany , Teresa Rigo-WatermeierTeresa Rigo-Watermeier Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany , Christian EisenChristian Eisen Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany , Sascha PahernikSascha Pahernik Department of Urology, University Hospital Heidelberg, Heidelberg, Germany , Markus HohenfellnerMarkus Hohenfellner Department of Urology, University Hospital Heidelberg, Heidelberg, Germany , Andreas TrumppAndreas Trumpp Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany , and Martin R. SprickMartin R. Sprick Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany View All Author Informationhttps://doi.org/10.1016/j.juro.2013.06.053AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: For rare cancers such as neuroendocrine bladder cancer treatment options are limited due partly to the lack of preclinical models. Techniques to amplify rare primary neuroendocrine bladder cancer cells could provide novel tools for the discovery of drug and diagnostic targets. We developed preclinical experimental models for neuroendocrine bladder cancer. Materials and Methods: Fresh tumor tissue from 2 patients with neuroendocrine bladder cancer was used to establish in vitro and in vivo models. We analyzed additional archived tissues in the National Center of Tumor Diseases tissue bank from patients with neuroendocrine bladder cancer. Primary tumor samples were collected during radical cystectomy. PHA-665752 was used to inhibit MET in animal models and cell cultures. The expression of markers and drug targets in neuroendocrine bladder cancer was determined by flow cytometry. The growth of neuroendocrine bladder cancer in vitro was determined by counting live cells. Tumor growth in mice was assessed by measuring tumor volume. Groups were compared using the nonparametric Kruskal-Wallis test. Results: Xenograft models and serum-free cultures of neuroendocrine bladder cancer cells allowed screening for cell surface markers and drug targets. We found expression of the HGF receptor MET in neuroendocrine bladder cancer cultures, xenograft models and primary patient sections. The growth of neuroendocrine bladder cancer spheroids in vitro depended critically on HGF. Treatment of neuroendocrine bladder cancer bearing mice with a MET inhibitor significantly decreased tumor growth compared to that in control treated mice. Conclusions: Neuroendocrine bladder cancer xenografts and serum-free cultures provided suitable models in which to identify diagnostic markers and therapeutic targets. Using the models, we noted HGF dependent growth of human neuroendocrine bladder cancer and identified MET as a new treatment target for neuroendocrine bladder cancer. References 1 : Multidisciplinary approach in the treatment of patients with small cell bladder carcinoma. Eur J Surg Oncol2011; 37: 558. Google Scholar 2 : Small cell neuroendocrine carcinoma of the urinary bladder. A clinicopathologic study with emphasis on cytologic features. Cancer1997; 79: 356. Google Scholar 3 : Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network. BJU Int2009; 103: 747. Google Scholar 4 : Radical cystectomy for primary neuroendocrine tumors of the bladder: the University of Southern California experience. J Urol2005; 174: 93. Link, Google Scholar 5 : Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol2013; 64: 307. Google Scholar 6 : Large cell and small cell neuroendocrine bladder carcinoma: immunohistochemical and outcome study in a single institution. Am J Clin Pathol2007; 128: 733. Google Scholar 7 : Stem cells, cancer, and cancer stem cells. Nature2001; 414: 105. Google Scholar 8 : Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol2006; 24: 185. Google Scholar 9 : Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A2008; 105: 13427. Google Scholar 10 : Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A2009; 106: 14016. Google Scholar 11 : Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell2010; 17: 77. Google Scholar 12 : The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell2004; 6: 75. Google Scholar 13 : Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia. Blood1995; 85: 873. Google Scholar 14 : Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A2003; 100: 3983. Google Scholar 15 : The cancer stem cell: premises, promises and challenges. Nat Med2011; 17: 313. Google Scholar 16 : The increasing complexity of the cancer stem cell paradigm. Science2009; 324: 1670. Google Scholar 17 : Cancer stem cells: cell culture, markers, and targets for new therapies. J Cell Biochem2009; 108: 1031. Google Scholar 18 : Cancer stem cells in nervous system tumors. Oncogene2004; 23: 7267. Google Scholar 19 : EMMPRIN regulates the canonical Wnt/beta-catenin signaling pathway, a potential role in accelerating lung tumorigenesis. Oncogene2010; 29: 4145. Google Scholar 20 : CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer. Med Oncol2011; 28: 1363. Google Scholar 21 : Expression and clinical significance of CD147 in genitourinary carcinomas. J Surg Res2010; 160: 260. Google Scholar 22 : CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell2009; 138: 271. Google Scholar 23 : CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene2010; 29: 2672. Google Scholar 24 : Identification of pancreatic cancer stem cells. Cancer Res2007; 67: 1030. Google Scholar 25 : Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol2004; 35: 255. Google Scholar 26 : Standard and variant CD44 isoforms are commonly expressed in lung cancer of the non-small cell type but not of the small cell type. J Pathol1995; 177: 363. Google Scholar 27 : Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer1989; 64: 1347. Google Scholar 28 : PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription. Lab Invest2009; 89: 301. Google Scholar 29 : Expression patterns of PAX5, c-Met, and paxillin in neuroendocrine tumors of the lung. Arch Pathol Lab Med2010; 134: 1702. Google Scholar 30 : Novel molecular targets for the therapy of castration-resistant prostate cancer. Eur Urol2012; 61: 950. Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAndersson K (2018) This Month in Investigative UrologyJournal of Urology, VOL. 190, NO. 6, (1968-1969), Online publication date: 1-Dec-2013. Volume 190Issue 6December 2013Page: 2263-2270 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.KeywordsHGF proteinurinary bladderhumandisease modelscarcinomaproto-oncogene proteins c-metneuroendocrineanimalMetricsAuthor Information Thomas Hofner Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany Department of Urology, University Hospital Heidelberg, Heidelberg, Germany More articles by this author Stephan Macher-Goeppinger Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany More articles by this author Corinna Klein Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany More articles by this author Teresa Rigo-Watermeier Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany More articles by this author Christian Eisen Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany More articles by this author Sascha Pahernik Department of Urology, University Hospital Heidelberg, Heidelberg, Germany More articles by this author Markus Hohenfellner Department of Urology, University Hospital Heidelberg, Heidelberg, Germany More articles by this author Andreas Trumpp Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany Equal study contribution. Financial interest and/or other relationship with HI-STEM gGmbH. More articles by this author Martin R. Sprick Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center, Heidelberg, Germany Equal study contribution. More articles by this author Expand All Advertisement PDF downloadLoading ...