Publikationsserver der Universitätsbibliothek Marburg
Titel:Prädiktive und prognostische Marker in pankreatischen neuroendokrinen Neoplasien in vitro und in vivo
Autor:Boch, Michael
Weitere Beteiligte: Michl, Patrick (Prof. Dr. med. )
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0737
URN: urn:nbn:de:hebis:04-z2017-07371
DOI: https://doi.org/10.17192/z2017.0737
DDC: Medizin
Publikationsdatum:2017-12-07
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Prädiktive Marker, Bon-1, CUX1, 5-Fluorouracil (5-FU), Pankreatische neuroendokrine Neoplasien, CUX1, Bon-1, miRNA, Prognostische Marker, Pankreatische neuroendokrine Neoplasien, Xenograft, Dacarbazin (DTIC), O6-Methylguanin-DNA-Methyltransferas

Zusammenfassung:
Bei pankreatischen neuroendokrinen Neoplasien (PNEN) handelt es sich um seltene Tumoren, die von den endokrinen Zellen des Pankreas ausgehen. Biomarker, welche eine effektive Selektion geeigneter Patienten für bestimmte systemische Chemotherapien ermöglichen, sowie Marker von prognostischer Relevanz fü den Therapieverlauf sind jedoch nur unzureichend beschrieben. Daher war das Ziel dieser Arbeit, sowohl in vitro, im Xenograft-Mausmodell als auch in humanen Geweben mögliche prognostische und prädiktive Biomarker zu identifizieren und zu evaluieren. Im Fokus stand hierbei der Transkriptionsfaktor CUX1, dessen Genprodukt in malignen Zellen Gene reguliert, die für proproliferative, antiapoptotische und motilitätsfördernde Prozesse von Bedeutung sind. Vorarbeiten unserer Arbeitsgruppe belegten eine signifikant gesteigerte CUX1-Expression in invasiven humanen Insulinomen. In stabil CUX1-überexprimierenden Bon1-Zelllinien konnten in vitro proproliferative, antiapoptotische und proangiogene Eigenschaften von CUX1 gezeigt werden. In der vorliegenden Arbeit wurden im Xenograft-Modell der Maus die tumorfördernden Eigenschaften von CUX1 bestätigt. CUX1-üerexprimierende Tumoren zeigten immunhistochemisch eine signifikant gesteigerte Proliferationsrate. Basierend auf diesen in vitro und in vivo Befunden im Mausmodell war es ein weiteres Ziel der Arbeit, die prognostische Relevanz des Transkriptionsfaktors CUX1 bei Patienten mit PNEN zu evaluieren, welche als systemische Chemotherapie eine Behandlung mit 5-Fluoruracil (5-FU)- bzw. Dacarbacin (DTIC) erhalten hatten. Eine hohe CUX1-Expression war bei Patienten mit 5-FU-basierter Therapie mit einem signifikant kürzeren progressionsfreien Überleben (PFS) vergesellschaftet. Jedoch war in dieser Kohorte weder zwischen dem Proliferationsindex Ki-67 noch dem Gesamtüberleben eine Korrelation mit der CUX1-Expression zu beobachten. Hieraus ergab sich als weitere Fragestellung, inwieweit CUX1, unabhängig von den Effekten auf die Proliferationsrate, Resistenzmechanismen gegen zytotoxische Chemotherapien induziert. Hierzu wurden potenziell CUX1-abhängige miRNAs und Enzyme, die in den Metabolismus der Chemotherapeutika eingreifen können, untersucht. Es konnten jedoch keine miRNAs identifiziert werden, die klar durch CUX1 reguliert werden. Ebenso wenig zeigten die Enzyme Thymidylatsynthase (TS), Dihydropyrimidin-Dehydrogenase (DPD) und O6-Methylguanin-DNA-Methyltransferase (MGMT) eine CUX1-abhängige Regulation. Aufgrund von Literaturdaten, dass die letztgenannten Enzyme für andere Tumorentitäten prognostische und prädiktive Aussagekraft besitzen, wurde deren Expression und Relevanz auch an Gewebeproben einer PNEN-Kohorte evaluiert. Die erhöhte DPD-Expression war signifikant mit einer erhöhten objektiven Ansprechrate (ORR) korreliert, zeigte allerdings keine Verlängerung des mittleren progressionsfreien Überlebens (mPFS), während die TS neben einem signifikant gesteigerten mPFS auch einen Trend zu einer besseren Krankheitskontrolle aufwies. Die MGMT hingegen war bei Patienten, die eine DTIC-basierte Therapie erhalten hatten, ohne prognostischen oder prädiktiven Wert. Die potentiellen Biomarker, welche in dieser Arbeit beschrieben wurden, sollten in prospektiven Studien weiter evaluiert werden.

Bibliographie / References

  1. Kubota T (2003). 5-fluorouracil and dihydropyrimidine dehydrogenase. Int. J. Clin. Oncol. 8:127-131.
  2. Matuo R, Sousa FG, Escargueil AE, Grivicich I, Garcia-Santos D, Chies JAB et al. (2009). 5- Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line. J Appl Toxicol 29:308-316.
  3. Bajetta E, Rimassa L, Carnaghi C, Seregni E, Ferrari L, Di Bartolomeo M et al. (1998). 5- fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer 83:372-378.
  4. Longley DB, Harkin DP, Johnston PG (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3:330-338.
  5. House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD et al. (2003). Aberrant Hypermethylation of Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms. Trans- actions of the … Meeting of the American Surgical Association 121:117-126.
  6. Goulet B, Baruch A, Moon N, Poirier M, Sansregret LL, Erickson A et al. (2004). A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Mol. Cell 14:207-219.
  7. Bennett RA, Pegg AE (1981). Alkylation of DNA in rat tissues following administration of strep- tozotocin. Cancer Res. 41:2786-2790.
  8. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A et al. (2007). A mammalian mi- croRNA expression atlas based on small RNA library sequencing. Cell 129:1401-1414.
  9. Lee HS, Chen M, Kim JH, Kim WH, Ahn S, Maeng K et al. (2014). Analysis of 320 gastroen- teropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival. Int. J. Cancer:n/a.
  10. Nagasaki T, Tsuchiya T, Tagawa T, Honda S, Yamasaki N, Miyazaki T et al. (2010). Analysis of 5-fluorouracil-related enzymes in pulmonary neuroendocrine carcinoma: differences in bio- logical properties compared to epithelial carcinoma. Clin Lung Cancer 11:412-422.
  11. Arnold CN, Sosnowski A, Schmitt-Gräff A, Arnold R, Blum HE (2007). Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int. J. Cancer 120:2157-2164.
  12. Livak KJ, Schmittgen TD (2001). Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods 25:402-408.
  13. El Hallani S, Boisselier B, Peglion F, Rousseau A, Colin C, Idbaih A et al. (2010). A new alterna- tive mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain 133:973-982.
  14. Turner HE, Harris AL, Melmed S, Wass JAH (2003). Angiogenesis in endocrine tumors. Endocr. Rev. 24:600-632.
  15. Bergers G, Benjamin LE (2003). Angiogenesis: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401-410.
  16. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. (2008). An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321:1807-1812.
  17. Goulet B, Truscott M, Nepveu A (2006). A novel proteolytically processed CDP/Cux isoform of 90 kDa is generated by cathepsin L. Biol. Chem. 387:1285-1293.
  18. Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248-254.
  19. Luzi E, Brandi ML (2011). Are microRNAs involved in the endocrine-specific pattern of tumor- igenesis in multiple endocrine neoplasia type 1? Endocr Pract 17 Suppl 3:58-63.
  20. Freudenberg N, Riede U, Werner M (2009). Basiswissen Allgemeine und Spezielle Pathologie. Heidelberg: Springer-Medizin-Verl.
  21. Schilsky RL (1998). Biochemical and clinical pharmacology of 5-fluorouracil. Oncology (Williston Park, N.Y.) 12:13-18.
  22. Meunier J, Lemoine F, Soumillon M, Liechti A, Weier M, Guschanski K et al. (2013). Birth and expression evolution of mammalian microRNA genes. Genome Res. 23:34-45.
  23. Holohan C, van Schaeybroeck S, Longley DB, Johnston PG (2013). Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714-726.
  24. Holland JF, editor (2000). Cancer medicine. Tumor Angiogenesis. 5th ed. Hamilton, Ontario, New York: B.C. Decker.
  25. Jakobovitz O, Nass D, DeMarco L, Barbosa AJ, Simoni FB, Rechavi G et al. (1996). Carcinoid tumors frequently display genetic abnormalities involving chromosome 11. J. Clin. Endo- crinol. Metab. 81:3164-3167.
  26. Oberg K (2002). Carcinoid tumors: molecular genetics, tumor biology, and update of diagnosis and treatment. Curr Opin Oncol 14:38-45.
  27. Santi DV, Hardy LW (1987). Catalytic mechanism and inhibition of tRNA (uracil-5- )methyltransferase: evidence for covalent catalysis. Biochemistry 26:8599-8606.
  28. Skalnik DG, Strauss EC, Orkin SH (1991). CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter. J. Biol. Chem. 266:16736-16744.
  29. Ai W, Toussaint E, Roman A (1999). CCAAT displacement protein binds to and negatively regu- lates human papillomavirus type 6 E6, E7, and E1 promoters. J. Virol. 73:4220-4229.
  30. Nishio H, Walsh MJ (2004). CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription. Proceedings of the National Academy of Sciences 101:11257-11262.
  31. Duff SE, Li C, Garland JM, Kumar S (2003). CD105 is important for angiogenesis: evidence and potential applications. FASEB J. 17:984-992.
  32. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984). Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki- 67. J. Immunol. 133:1710-1715.
  33. Parekh D, Ishizuka J, Townsend CM, Haber B, Beauchamp RD, Karp G et al. (1994). Charac- terization of a human pancreatic carcinoid in vitro: morphology, amine and peptide storage, and secretion. Pancreas 9:83-90.
  34. McLeod HL, Sludden J, Murray GI, Keenan RA, Davidson AI, Park K et al. (1998). Characteriza- tion of dihydropyrimidine dehydrogenase in human colorectal tumours. British journal of cancer 77:461-465.
  35. Turner NC, Strauss SJ, Sarker D, Gillmore R, Kirkwood A, Hackshaw A et al. (2010). Chemo- therapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J Can- cer 102:1106-1112.
  36. Lee AJX, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA et al. (2011). Chromo- somal Instability Confers Intrinsic Multidrug Resistance. Cancer Res. 71:1858-1870.
  37. Wang K, Zhang S, Marzolf B, Troisch P, Brightman A, Hu Z et al. (2009). Circulating mi- croRNAs, potential biomarkers for drug-induced liver injury. Proceedings of the National Academy of Sciences 106:4402-4407.
  38. Laemmli UK (1970). Cleavage of structural proteins during the assembly of the head of bacteri- ophage T4. Nature 227:680-685.
  39. Vicentini C, Fassan M, D'Angelo E, Corbo V, Silvestris N, Nuovo GJ et al. (2014). Clinical Appli- cation of MicroRNA Testing in Neuroendocrine Tumors of the Gastrointestinal Tract. Mole- cules 19:2458-2468.
  40. Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K (2011). Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after pro- gression on first-line chemotherapy. Cancer 117:4617-4622.
  41. Omura K (2003). Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5- FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines. Int. J. Clin. Oncol. 8:132-138.
  42. Diasio RB (1999). Clinical implications of dihydropyrimidine dehydrogenase inhibition. Oncology (Williston Park, N.Y.) 13:17-21.
  43. Diasio RB, Harris BE (1989a). Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215-237.
  44. Diasio RB, Harris BE (1989b). Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215-237.
  45. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydro- pyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin. Can- cer Res. 6:1322-1327.
  46. Zhao C, Bachu R, Popovic M, Devany M, Brenowitz M, Schlatterer JC et al. (2013). Conforma- tional heterogeneity of the protein-free human spliceosomal U2-U6 snRNA complex. RNA 19:561-573.
  47. Harada R, Dufort D, Denis-Larose C, Nepveu A (1994). Conserved cut repeats in the human cut homeodomain protein function as DNA binding domains. J. Biol. Chem. 269:2062-2067.
  48. Rickes S, Mönkemüller K, Malfertheiner P (2006). Contrast-enhanced ultrasound in the diagno- sis of pancreatic tumors. JOP 7:584-592.
  49. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. (2008). Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses. Science 321:1801-1806.
  50. Chinot OL, Barrié M, Fuentes S, Eudes N, Lancelot S, Metellus P et al. (2007). Correlation be- tween O6-methylguanine-DNA methyltransferase and survival in inoperable newly diag- nosed glioblastoma patients treated with neoadjuvant temozolomide. J. Clin. Oncol. 25:1470-1475.
  51. Chan AO, Kim SG, Bedeir A, Issa J, Hamilton SR, Rashid A (2003). CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene 22:924-934.
  52. Oberg K, Castellano D (2011). Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 30 Suppl 1:3-7.
  53. Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R et al. (2005). CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness. Cancer Cell 7:521-532.
  54. Krug S, Kuehnemuth B, Griesmann H, Neesse A, Muehlberg L, Boch M et al. (2014). CUX1 -a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. Endocr. Relat. Cancer.
  55. Ripka S, Neesse A, Riedel J, Bug E, Aigner A, Poulsom R et al. (2010). CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut 59:1101-1110.
  56. Stumpp P, Fleiter C, Purz S, Kahn T (2013). Diagnostischer Mehrwert der simultanen Ga68- DOTATOC-PET/MRT bei Patienten mit neuroendokrinem Tumor im Vergleich zur PET/CT. Fortschr Röntgenstr 185.
  57. Monica V, Scagliotti GV, Ceppi P, Righi L, Cambieri A, Lo Iacono M et al. (2009). Differential Thymidylate Synthase Expression in Different Variants of Large-Cell Carcinoma of the Lung. Clin. Cancer Res. 15:7547-7552.
  58. Jiang W, Lu Z, He Y, Diasio RB (1997). Dihydropyrimidine dehydrogenase activity in hepatocel- lular carcinoma: implication in 5-fluorouracil-based chemotherapy. Clin. Cancer Res. 3:395- 399.
  59. Ishikawa Y, Kubota T, Otani Y, Watanabe M, Teramoto T, Kumai K et al. (2000). Dihydropyrimi- dine Dehydrogenase and Messenger RNA Levels in Gastric Cancer. Possible Predictor for Sensitivity to 5-Fluorouracil. Japanese Journal of Cancer Research 91:105-112.
  60. van Kuilenburg ABP (2004). Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur. J. Cancer 40:939-950.
  61. Diasio RB, Johnson MR (1999). Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin. Cancer Res. 5:2672-2673.
  62. Altimari AF, Badrinath K, Reisel HJ, Prinz RA (1987). DTIC therapy in patients with malignant intra-abdominal neuroendocrine tumors. Surgery 102:1009-1017.
  63. Parker JB, Stivers JT (2011). Dynamics of uracil and 5-fluorouracil in DNA. Biochemistry 50:612-617.
  64. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC et al. (2009). Ef- fects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459-466.
  65. Falconi M, Bartsch DK, Eriksson B, Klöppel G, Lopes JM, O'Connor JM et al. (2012). ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neo- plasms of the Digestive System: Well-Differentiated Pancreatic Non-Functioning Tumors. Neuroendocrinology 95:120-134.
  66. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K, Steinmüller T et al. (2012). ENETS Consensus Guidelines for the management of patients with liver and other distant metasta- ses from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 95:157-176.
  67. Quarles KA, Sahu D, Havens MA, Forsyth ER, Wostenberg C, Hastings ML et al. (2013). En- semble analysis of primary microRNA structure reveals an extensive capacity to deform near the Drosha cleavage site. Biochemistry 52:795-807.
  68. Taal BG, Visser O (2004). Epidemiology of neuroendocrine tumours. Neuroendocrinology 80 Suppl 1:3-7.
  69. Yim K (2012). Everolimus and mTOR inhibition in pancreatic neuroendocrine tumors. CMAR:207.
  70. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, van Cutsem E et al. (2011). Everolimus for ad- vanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364:514-523.
  71. Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F (2013). Everolimus in advanced pancreat- ic neuroendocrine tumors: the clinical experience. Cancer Res. 73:1449-1453.
  72. Exon/intron structure and alternative transcripts of the CUTL1 gene. Gene 241:75-85.
  73. Moon NS, Rong Zeng W, Premdas P, Santaguida M, Bérubé G, Nepveu A (2002). Expression of N-terminally truncated isoforms of CDP/CUX is increased in human uterine leiomyomas. Int. J. Cancer 100:429-432.
  74. Auböck L, Höfler H (1983). Extraepithelial intraneural endocrine cells as starting-points for gas- trointestinal carcinoids. Virchows Arch A Pathol Anat Histopathol 401:17-33.
  75. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R et al. (2004). Fluorouracil, doxo- rubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J. Clin. Oncol. 22:4762-4771.
  76. Modlin IM, Oberg K, Chung DC, Jensen RT, Herder WW de, Thakker RV et al. (2008). Gastro- enteropancreatic neuroendocrine tumours. Lancet Oncol. 9:61-72.
  77. Herman JG, Baylin SB (2003). Gene silencing in cancer in association with promoter hyper- methylation. N. Engl. J. Med. 349:2042-2054.
  78. Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV (2003). Genetics of neuroendocrine and carcinoid tumours. Endocr. Relat. Cancer 10:437-450.
  79. Harada R, Vadnais C, Sansregret L, Leduy L, Bérubé G, Robert F et al. (2008). Genome-wide location analysis and expression studies reveal a role for p110 CUX1 in the activation of DNA replication genes. Nucleic Acids Res. 36:189-202.
  80. Li S, Essaghir A, Martijn C, Lloyd RV, Demoulin J, Öberg K et al. (2013b). Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol 26:685- 696.
  81. Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, Herder WW de et al. (2004). Guide- lines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consen- sus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuro- endocrinology 80:394-424.
  82. Hanahan D (1985). Heritable formation of pancreatic beta-cell tumours in transgenic mice ex- pressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115-122.
  83. Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004). High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39:167-169.
  84. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. (2004). Human mi- croRNA genes are frequently located at fragile sites and genomic regions involved in can- cers. Proc. Natl. Acad. Sci. U.S.A. 101:2999-3004.
  85. Tan EH, Tan CH (2011). Imaging of gastroenteropancreatic neuroendocrine tumors. World J Clin Oncol 2:28-43.
  86. Edler D, Blomgren H, Allegra CJ, Johnston PG, Lagerstedt U, Magnusson I et al. (1997). Im- munohistochemical determination of thymidylate synthase in colorectal cancer-- methodological studies. Eur. J. Cancer 33:2278-2281.
  87. Oi K, Makino M, Ozaki M, Takemoto H, Yamane N, Nakamura S et al. (2004). Immunohisto- chemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for pa- tients with Dukes' C colorectal cancer. Anticancer Res. 24:273-279.
  88. Pusztaszeri MP (2006). Immunohistochemical Expression of Endothelial Markers CD31, CD34, von Willebrand Factor, and Fli-1 in Normal Human Tissues. Journal of Histochemistry and Cytochemistry 54:385-395.
  89. Edler D, Kressner U, Ragnhammar P, Johnston PG, Magnusson I, Glimelius B et al. (2000). Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival. Clin. Cancer Res. 6:488-492.
  90. Johnston PG, Drake JC, Trepel J, Allegra CJ (1992). Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res. 52:4306-4312.
  91. Diasio RB (1998a). Improving 5-FU with a novel dihydropyrimidine dehydrogenase inactivator. Oncology (Williston Park, N.Y.) 12:51-56.
  92. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V et al. (2000). Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343:1350-1354.
  93. Häussler B, Albrecht M (2007). Innovationen gestalten den demographischen Wandel. Mit 6 Tabellen. Stuttgart [u.a.]: Schattauer.
  94. Klöppel G. Insulinome -Vortrag bei der SeAP-IAP.
  95. Huang CL, Yokomise H, Kobayashi S, Fukushima M, Hitomi S, Wada H (2000). Intratumoral expression of thymidylate synthase and dihydropyrimidine dehydrogenase in non-small cell lung cancer patients treated with 5-FU-based chemotherapy. Int. J. Oncol. 17:47-54.
  96. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. (2012). Intra- tumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N Engl J Med 366:883-892.
  97. Adams ER, Leffert JJ, Craig DJ, Spector T, Pizzorno G (1999). In vivo effect of 5-ethynyluracil on 5-fluorouracil metabolism determined by 19F nuclear magnetic resonance spectroscopy. Cancer Res. 59:122-127.
  98. Souliotis VL, Boussiotis VA, Pangalis GA, Kyrtopoulos SA (1991). In vivo formation and repair of O6 in human leukocyte DNA after intravenous exposure to dacarbazine. Carcinogenesis 12:285-288.
  99. Perren A, Schmitt A, Komminoth P, Pavel M (2009). Klassifikation gastroenteropankreatischer neuroendokriner Tumoren. Radiologe 49:198-205.
  100. Lauc G, Huffman JE, Pučić M, Zgaga L, Adamczyk B, Mužinić A et al. (2013). Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseas- es and haematological cancers. PLoS Genet. 9:e1003225.
  101. Bijnsdorp IV, Comijn EM, Padron JM, Gmeiner WH, Peters GJ (2007). Mechanisms of action of FdUMP[10]: metabolite activation and thymidylate synthase inhibition. Oncol. Rep. 18:287- 291.
  102. Eriksson B, Skogseid B, Lundqvist G, Wide L, Wilander E, Oberg K (1990a). Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tu- mors. Cancer 65:1883-1890.
  103. Eriksson B, Skogseid B, Lundqvist G, Wide L, Wilander E, Oberg K (1990b). Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tu- mors. Cancer 65:1883-1890.
  104. Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C et al. (2007). Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur. J. Cancer 43:935-946.
  105. Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G et al. (2011). Meta- static and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associ- ated With Disease Progression. Journal of Clinical Oncology 29:2372-2377.
  106. Hegi ME, Diserens A, Gorlia T, Hamou M, Tribolet N de, Weller M et al. (2005). MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352:997-1003.
  107. Zhang J, Wang J, Zhao F, Liu Q, Jiang K, Yang G (2010). MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin. Chim. Acta 411:846-852.
  108. Li A, Yu J, Kim H, Wolfgang CL, Canto MI, Hruban RH et al. (2013a). MicroRNA Array Analysis Finds Elevated Serum miR-1290 Accurately Distinguishes Patients with Low-Stage Pancre- atic Cancer from Healthy and Disease Controls. Clinical Cancer Research 19:3600-3610.
  109. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S et al. (2006). MicroRNA ex- pression abnormalities in pancreatic endocrine and acinar tumors are associated with dis- tinctive pathologic features and clinical behavior. J. Clin. Oncol. 24:4677-4684.
  110. Ruebel K, Leontovich AA, Stilling GA, Zhang S, Righi A, Jin L et al. (2010). MicroRNA expres- sion in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod. Pathol. 23:367-375.
  111. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expres- sion profiles classify human cancers. Nature 435:834-838.
  112. Pillai RS (2005). MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11:1753-1761.
  113. Lee Y, Kim M, Han J, Yeom K, Lee S, Baek SH et al. (2004). MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23:4051-4060.
  114. Bartel DP (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281- 297.
  115. He L, Hannon GJ (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5:522-531.
  116. Mourelatos Z, Dostie J, Paushkin S, Sharma A, Charroux B, Abel L et al. (2002). miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16:720- 728.
  117. Gerson SL (1989). Modulation of human lymphocyte O6-alkylguanine-DNA alkyltransferase by streptozotocin in vivo. Cancer Res. 49:3134-3138.
  118. Faivre S, Demetri G, Sargent W, Raymond E (2007). Molecular basis for sunitinib efficacy and future clinical development. Nature reviews. Drug discovery 6:734-745.
  119. Perren A, KOMMINOTH P, Heitz PU (2004). Molecular Genetics of Gastroenteropancreatic Endocrine Tumors. Ann. N. Y. Acad. Sci. 1014:199-208.
  120. Starker LF, Carling T (2009). Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Curr Opin Oncol 21:29-33.
  121. O'Toole D, Couvelard A, Rebours V, Zappa M, Hentic O, Hammel P et al. (2010a). Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendo- crine tumors. Endocrine Related Cancer 17:847-856.
  122. O'Toole D, Couvelard A, Rebours V, Zappa M, Hentic O, Hammel P et al. (2010b). Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendo- crine tumors. Endocr. Relat. Cancer 17:847-856.
  123. Gilbert JA, Adhikari LJ, Lloyd RV, Halfdanarson TR, Muders MH, Ames MM (2013). Molecular Markers for Novel Therapeutic Strategies in Pancreatic Endocrine Tumors. Pancreas 42:411-421.
  124. Borazan E, Aytekin A, Yilmaz L, Elci M, Karaca MS, Kervancioglu S et al. (2015). Multifocal Insulinoma in Pancreas and Effect of Intraoperative Ultrasonography. Case reports in sur- gery 2015:375124.
  125. Holzapfel K, Gärtner F, Rummeny E (2011). Multimodale Bildgebung bei neuroendokrinen Tu- moren des Pankreas. Radiologie up2date 11:355-367.
  126. Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-Nordhorn J et al. (2011). Neuroendo- crine tumors of midgut and hindgut origin: Tumor-node-metastasis classification determines clinical outcome. Cancer 117:3332-3341.
  127. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Euro- pean journal of cancer (Oxford, England : 1990) 45:228-247.
  128. Newell D, Gescher A, Harland S, Ross D, Rutty C (1987). N-methyl antitumour agents. A dis- tinct class of anticancer drugs? Cancer Chemother. Pharmacol. 19:91-102.
  129. Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U (2004). Nuclear export of microRNA pre- cursors. Science 303:95-98.
  130. Dostie J, Mourelatos Z, Yang M, Sharma A, Dreyfuss G (2003). Numerous microRNPs in neu- ronal cells containing novel microRNAs. RNA 9:180-186.
  131. Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC et al. (2009). O6- methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin. Cancer Res. 15:338-345.
  132. Middleton MR, Lunn JM, Morris C, Rustin G, Wedge SR, Brampton MH et al. (1998). O6- methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of re- sponse to temozolomide in melanoma. Br J Cancer 78:1199-1202.
  133. Jakob J, Hille M, Sauer C, Ströbel P, Wenz F, Hohenberger P (2012). O6-methylguanine-DNA methyltransferase (MGMT) Promoter methylation is a rare event in soft tissue sarcoma. Ra- diat Oncol 7:180.
  134. Esquela-Kerscher A, Slack FJ (2006). Oncomirs -microRNAs with a role in cancer. Nat Rev Cancer 6:259-269.
  135. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al. (2008). One Hundred Years After "Carcinoid": Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology 26:3063-3072.
  136. Kedinger V, Sansregret L, Harada R, Vadnais C, Cadieux C, Fathers K et al. (2009). p110 CUX1 homeodomain protein stimulates cell migration and invasion in part through a regula- tory cascade culminating in the repression of E-cadherin and occludin. J. Biol. Chem. 284:27701-27711.
  137. Lenz HJ, Hayashi K, Salonga D, Danenberg KD, Danenberg PV, Metzger R et al. (1998). p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival. Clin. Cancer Res. 4:1243-1250.
  138. Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R et al. (2010). Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 23:824-833.
  139. Jensen RT (1999). Pancreatic endocrine tumors: recent advances. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 10 Suppl 4:170-176.
  140. Ormanns S (2014). Pathologie und Molekularpathologie des Pankreaskarzinoms. Trillium Kreb- smedizin 23.
  141. Sun W (2005). Phase II/III Study of Doxorubicin With Fluorouracil Compared With Streptozocin With Fluorouracil or Dacarbazine in the Treatment of Advanced Carcinoid Tumors: Eastern Cooperative Oncology Group Study E1281. Journal of Clinical Oncology 23:4897-4904.
  142. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG (2001). Phase II trial of dacarba- zine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann. Oncol. 12:1139-1143.
  143. Bukowski RM, Tangen CM, Peterson RF, Taylor SA, Rinehart JJ, Eyre HJ et al. (1994). Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid. A Southwest Oncology Group study. Cancer 73:1505-1508.
  144. Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann R et al. (2006). Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J. Clin. Oncol. 24:4412-4417.
  145. Drucker E, Krapfenbauer K (2013). Pitfalls and limitations in translation from biomarker discov- ery to clinical utility in predictive and personalised medicine. The EPMA journal 4:7.
  146. Kim EC, Lau JS, Rawlings S, Lee AS (1997). Positive and negative regulation of the human thymidine kinase promoter mediated by CCAAT binding transcription factors NF-Y/CBF, dbpA, and CDP/cut. Cell Growth Differ. 8:1329-1338.
  147. Wilson PM, Ladner RD, Lenz H (2007). Predictive and prognostic markers in colorectal cancer. Gastrointest Cancer Res 1:237-246.
  148. Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM et al. (2006a). Predic- tive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phos- phorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncolo- gy 70:366-377.
  149. Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM et al. (2006b). Predic- tive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phos- phorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncolo- gy 70:366-377.
  150. Neufeld G, Kessler O (2006). Pro-angiogenic cytokines and their role in tumor angiogenesis. Cancer Metastasis Rev. 25:373-385.
  151. Gerdes J, Schwab U, Lemke H, Stein H (1983). Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int. J. Cancer 31:13-20.
  152. Wang M, Peng J, Yang W, Chen W, Mo S, Cai S (2011). Prognostic analysis for carcinoid tu- mours of the rectum: a single institutional analysis of 106 patients. Colorectal Disease 13:150-153.
  153. Pestalozzi BC, Peterson HF, Gelber RD, Goldhirsch A, Gusterson BA, Trihia H et al. (1997). Prognostic importance of thymidylate synthase expression in early breast cancer. J. Clin. Oncol. 15:1923-1931.
  154. Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK (2011). Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroen- docrine tumors. J. Clin. Oncol. 29:3044-3049.
  155. Sommer H, Santi DV (1974). Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2'-deoxyuridylate and methyl- enetetrahydrofolate. Biochem. Biophys. Res. Commun. 57:689-695.
  156. Lu ZH, Zhang R, Diasio RB (1992). Purification and characterization of dihydropyrimidine dehy- drogenase from human liver. J. Biol. Chem. 267:17102-17109.
  157. Nolan T, Hands RE, Bustin SA (2006). Quantification of mRNA using real-time RT-PCR. Nature protocols 1:1559-1582.
  158. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB et al. (2005). Radio- therapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352:987-996.
  159. Houghton JA, Tillman DM, Harwood FG (1995). Ratio of 2'-deoxyadenosine-5'- triphosphate/thymidine-5'-triphosphate influences the commitment of human colon carcino- ma cells to thymineless death. Clin. Cancer Res. 1:723-730.
  160. Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT et al. (2005). Real-time quantifi- cation of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e179.
  161. Heid CA, Stevens J, Livak KJ, Williams PM (1996). Real time quantitative PCR. Genome Res. 6:986-994.
  162. Huggett J, Dheda K, Bustin S, Zumla A (2005). Real-time RT-PCR normalisation; strategies and considerations. Genes and immunity 6:279-284.
  163. Michael MZ, O' Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003). Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol. Cancer Res. 1:882-891.
  164. Johnston SJ, Ridge SA, Cassidy J, McLeod HL (1999). Regulation of dihydropyrimidine dehy- drogenase in colorectal cancer. Clin. Cancer Res. 5:2566-2570.
  165. Modlin IM, Shapiro MD, Kidd M, Eick G (2007). Siegfried oberndorfer and the evolution of car- cinoid disease. Arch Surg 142:187-197.
  166. Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W (2004). Single processing center models for human Dicer and bacterial RNase III. Cell 118:57-68.
  167. Kloppel G, Rindi G, Anlauf M, Perren A, KOMMINOTH P (2007). Site-specific biology and pa- thology of gastroenteropancreatic neuroendocrine tumors. Virchows Archiv : an international journal of pathology 451 Suppl 1:S9-27.
  168. Randerath K, Tseng WC, Harris JS, Lu LJ (1983). Specific effects of 5-fluoropyrimidines and 5- azapyrimidines on modification of the 5 position of pyrimidines, in particular the synthesis of 5-methyluracil and 5-methylcytosine in nucleic acids. Recent Results Cancer Res. 84:283- 297.
  169. Ghoshal K, Jacob ST (1994). Specific inhibition of pre-ribosomal RNA processing in extracts from the lymphosarcoma cells treated with 5-fluorouracil. Cancer Res. 54:632-636.
  170. Moertel CG, Hanley JA, Johnson LA (1980). Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 303:1189-1194.
  171. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D (1992). Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 326:519-523.
  172. Raymond E, Dahan L, Raoul J, Bang Y, Borbath I, Lombard-Bohas C et al. (2011). Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med 364:501- 513.
  173. Amirmostofian M, Pourahmad Jaktaji J, Soleimani Z, Tabib K, Tanbakosazan F, Omrani M et al. (2013). Synthesis and Molecular-cellular Mechanistic Study of Pyridine Derivative of Dacarbazine. Iran J Pharm Res 12:255-265.
  174. Liu L, Gerson SL (2006). Targeted modulation of MGMT: clinical implications. Clin. Cancer Res. 12:328-331.
  175. Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H et al. (2007). Te- mozolomide as Monotherapy Is Effective in Treatment of Advanced Malignant Neuroendo- crine Tumors. Clinical Cancer Research 13:2986-2991.
  176. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE et al. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901-906.
  177. Williams ED, Sandler M (1963). The classification of carcinoid tum ours. Lancet 1:238-239.
  178. Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA, Sjoblom T et al. (2006). The colorectal microRNAome. Proc. Natl. Acad. Sci. U.S.A. 103:3687-3692.
  179. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. (2006). The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science 314:268-274.
  180. Xu P, Vernooy SY, Guo M, Hay BA (2003). The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol. 13:790-795.
  181. Rindi G (2010). The ENETS guidelines: the new TNM classification system. Tumori 96:806- 809.
  182. Chen K, Rajewsky N (2007). The evolution of gene regulation by transcription factors and mi- croRNAs. Nat Rev Genet 8:93-103.
  183. Klöppel G, Perren A, Heitz PU (2004). The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann. N. Y. Acad. Sci. 1014:13-27.
  184. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell 100:57-70.
  185. Fidler I (1994). The implications of angiogenesis for the biology and therapy of cancer metasta- sis. Cell 79:185-188.
  186. Kanamaru R, Kakuta H, Sato T, Ishioka C, Wakui A (1986). The inhibitory effects of 5- fluorouracil on the metabolism of preribosomal and ribosomal RNA in L-1210 cells in vitro. Cancer Chemother. Pharmacol. 17:43-46.
  187. Scholzen T, Gerdes J (2000). The Ki-67 protein: from the known and the unknown. J. Cell. Physiol. 182:311-322.
  188. Höfler H, Kasper M, Heitz PU (1983). The neuroendocrine system of normal human appendix, ileum and colon, and in neurogenic appendicopathy. Virchows Arch A Pathol Anat Histo- pathol 399:127-140.
  189. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J et al. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415-419.
  190. Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA et al. (2010). The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109-1113.
  191. Zhang K, Wang X, Zhou B, Zhang L (2013). The prognostic value of MGMT promoter methyla- tion in Glioblastoma multiforme: a meta-analysis. Fam. Cancer 12:449-458.
  192. Diasio RB (1998b). The role of dihydropyrimidine dehydrogenase (DPD) modulation in 5-FU pharmacology. Oncology (Williston Park, N.Y.) 12:23-27.
  193. Johnston PG, Fisher ER, Rockette HE, Fisher B, Wolmark N, Drake JC et al. (1994). The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in pa- tients with rectal cancer. J. Clin. Oncol. 12:2640-2647.
  194. Johnston PG, Mick R, Recant W, Behan KA, Dolan ME, Ratain MJ et al. (1997). Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer. J. Natl. Cancer Inst. 89:308-313.
  195. Edler D, Glimelius B, Hallström M, Jakobsen A, Johnston PG, Magnusson I et al. (2002). Thy- midylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J. Clin. Oncol. 20:1721-1728.
  196. Ceppi P, Volante M, Ferrero A, Righi L, Rapa I, Rosas R et al. (2008). Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. Clin. Cancer Res. 14:1059-1064.
  197. Hu YC, Komorowski RA, Graewin S, Hostetter G, Kallioniemi O, Pitt HA et al. (2003). Thymi- dylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer. Clin. Cancer Res. 9:4165-4171.
  198. Thymidylate synthase gene and protein expression correlate and are associated with re- sponse to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55:1407- 1412.
  199. Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW et al. (2012). TNM Stag- ing of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study. JNCI Journal of the National Cancer Institute 104:764-777.
  200. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. (1982). Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 5:649-655.
  201. Li S, Moy L, Pittman N, Shue G, Aufiero B, Neufeld EJ et al. (1999). Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT dis- placement protein/cut homolog, is associated with histone deacetylation. J. Biol. Chem. 274:7803-7815.
  202. Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H et al. (2011). Transdif- ferentiation of glioblastoma cells into vascular endothelial cells. Proceedings of the National Academy of Sciences 108:4274-4280.
  203. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, Vecchis L de (2007). Triazene com- pounds: mechanism of action and related DNA repair systems. Pharmacol. Res. 56:275- 287.
  204. Folkman J (1971). Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285:1182- 1186.
  205. Tsutsumi S, Taketani T, Nishimura K, Ge X, Taki T, Sugita K et al. (2003). Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements. Cancer Res. 63:4882-4887.
  206. Remmele W, Stegner HE (1987). Vorschlag zur einheitlichen Definition eines Immunreaktiven Score (IRS) für den immunhistochemischen Ostrogenrezeptor-Nachweis (ER-ICA) im Mammakarzinomgewebe. Pathologe 8:138-140.
  207. Ripka S, König A, Buchholz M, Wagner M, Sipos B, Klöppel G et al. (2007). WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Car- cinogenesis 28:1178-1187.

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