Animal models and cell lines of pancreatic neuronimal models and cell lines of pancreatic neuroendocrine tumors

Pancreas

Volumn 42, Issue 6, 2013, Pages 912-923

  Babu, Varsha ^a   Paul, Navin ^a   Yu, Run ^a  

^a CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

animal models; cell lines; pancreatic neuroendocrine tumors

Indexed keywords

GLUCAGON RECEPTOR; INSULIN; MEN1 PROTEIN; PREPROGLUCAGON; PROTEIN; UNCLASSIFIED DRUG; VON HIPPEL LINDAU PROTEIN;

ANIMAL MODEL; CELL LINE; GASTRINOMA; GENE DELETION; GENE EXPRESSION; GENE INACTIVATION; GLUCAGONOMA; HUMAN; INSULINOMA; MIXED TUMOR; NONHUMAN; ONCOGENE; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET BETA CELL; PANCREATIC NEUROENDOCRINE TUMOR; PATHOGENESIS; PRIORITY JOURNAL; PROMOTER REGION; REVIEW; STEM CELL;

ANIMALS; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MICE, KNOCKOUT; MICE, TRANSGENIC; MOLECULAR TARGETED THERAPY; NEUROENDOCRINE TUMORS; PANCREATIC NEOPLASMS;

EID: 84880653183     PISSN: 08853177     EISSN: 15364828     Source Type: Journal    
DOI: 10.1097/MPA.0b013e31827ae993     Document Type: Review

References (119)

1. Asa SL. Pancreatic endocrine tumors. Mod Pathol. 2011;24:S66-S77.
2. Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005;19:753-781.
3. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35, 825 cases in the United States. J Clin Oncol. 2008;26:3063-3072.
4. Lawrence B, Gustaffson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:1-18.
5. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469-1492.
6. Jensen RT, Berna MJ, Bingham DB, et al. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113:1807-1843.
7. Vinik AI, Gonzalez MR. New and emerging syndromes due to neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:19-63.
8. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005;12:1083-1092.
9. Kvols LK, Revisiting CG. Moertel's land of small tumors. J Clin Oncol. 2008;26:5005-5007.
10. Yu R. Radiotherapy: radioactive somatostatin analog therapy against carcinoids. Nat Rev Endocrinol. 2010;6:428-430.
11. Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology. 2009;9:583-600.
12. Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29:2372-2327.
13. Vinik E, Silva MP, Vinik AI. Measuring the relationship of quality of life and health status, including tumor burden, symptoms, and biochemical measures in patients with neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:97-109.
14. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985;315:115-122.
15. Adams TE, Alpert S, Hanahan D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature. 1987;325:223-228.
16. Onrust SV, Hartl PM, Rosen SD, et al. Modulation of L-selectin ligand expression during an immune response accompanying tumorigenesis in transgenic mice. J Clin Invest. 1996;97:54-64.
17. Power RF, Holm R, Bishop AE, et al. Transgenic mouse model: a new approach for the investigation of endocrine pancreatic B-cell growth. Gut. 1987;28:121-129.
18. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-CYmediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001;20:672-682.
19. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220-231.
20. Alliouachene S, Tuttle RL, Boumard S, et al. Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. J Clin Invest. 2008;118:3629-3638.
21. Yao JC, Shah MH, Ito T, et al. RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523.
22. Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell. 2002;109:321-334.
23. Efrat S, Teitelamn G, Anwar M, et al. Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic alpha cells. Neuron. 1988;1:605-613.
24. Rindi G, Efrat S, Ghatei MA, et al. Glucagonomas of transgenic mice express a wide range of general neuroendocrine markers and bioactive peptides. Virchows Arch A Pathol Anat Histopathol. 1991;419:115-129.
25. Lee YC, Asa SL. Drucker DJ. Glucagon gene 5'-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice. J Biol Chem. 1992;267:10705-10708.
26. Asa SL, Lee YC, Drucker DJ. Development of colonic and pancreatic endocrine tumours in mice expressing a glucagon-SV40 T antigen transgene. Virchows Arch. 1996;427:595-606.
27. Marx SJ, Agarwal SK, Kester MB, et al. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog Horm Res. 1999;54:397-438.
28. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab. 2010;24:355-370.
29. Agarwal SK, Kennedy PA, Scacheri PC, et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm Metab Res. 2005;37:369-374.
30. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29:22-32.
31. Stewart C, Parente F, Piehl F, et al. Characterization of the mouse Men1 gene and its expression during development. Oncogene. 1998;17:2485-2493.
32. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA. 2001;98:1118-1123.
33. Bertolino P, Radovanovic I, Casse H, et al. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mech Dev. 2003;120:549-560.
34. Bertolino P, Tong WM, Galendo D, et al. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol. 2003;17:1880-1892.
35. Crabtree JS, Scacheri PC, Ward JM, et al. Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol. 2003;23:6075-6085.
36. Bertolino P, Tong WM, Herrera PL, et al. Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res. 2003;63:4836-4841.
37. Biondi CA, Gartside MG, Waring P, et al. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol Cell Biol. 2004;24:3125-3131.
38. Lu J, Herrera PL, Carreira C, et al. Alpha cellYspecific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development. Gastroenterology. 2010;138:1954-1965.
39. Shen HC, Ylaya K, Pechhold K, et al. Multiple endocrine neoplasia type 1 deletion in pancreatic alpha-cells leads to development of insulinomas in mice. Endocrinology. 2010;151:4024-4030.
40. Shen HC, He M, Powell A, et al. Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of Men1. Cancer Res. 2009;69:1858-1866.
41. Scacheri PC, Crabtree JS, Kennedy AL, et al. Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1. Mamm Genome. 2004;15:872-877.
42. Parker JC, Andrews KM, Allen MR, et al. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun. 2002;290:839-843.
43. Yu R, Nissen NN, Dhall D, et al. Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas. Pancreas. 2008;36:428-431.
44. Zhou C, Dhall D, Nissen NN, et al. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas. 2009;38: 941-946.
45. Yu R, Wawrowsky K, Zhou C. A natural inactivating mutant of human glucagon receptor exhibits multiple abnormalities in processing and signaling. Endocrinol Nutr. 2011;58:258-266.
46. Ouyang D, Dhall D, Yu R. Pathologic pancreatic endocrine cell hyperplasia. World J Gastroenterol. 2011;17:137-143.
47. Yu R, Dhall D, Nissen NN, et al. Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice. PLoS One. 2011;6:23397.
48. Yu R, Ren S-G, Miroha J. Glucagon receptor is required for long-term survival: a natural history study of the Mahvash disease in a murine model. Endocrinol Nutr. 2012;59:523-530.
49. Yu R, Chen CR, Liu X, et al. Rescue of a pathogenic mutant human glucagon receptor by pharmacological chaperones. J Mol Endocrinol. 2012;49:69-78.
50. Chen M, Gavrilova O, Zhao WQ, et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency. J Clin Invest. 2005;115: 3217-3227.
51. Hayashi Y, Yamamoto M, Mizoguchi H, et al. Mice deficient for glucagon geneYderived peptides display normoglycemia and hyperplasia of islet alpha cells but not of intestinal L-cells. Mol Endocrinol. 2009;23:1990-1999.
52. Furuta M, Yano H, Zhou A, et al. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci USA. 1997;94:6646-6651.
53. Gnarra JR, Ward JM, Porter FD, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci USA. 1997;94:9102-9107.
54. Shen HC, Adem A, Ylaya K, et al. Deciphering von Hippel-Lindau (VHL/Vhl)Yassociated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. PLoS One. 2009;4:e4897.
55. Montag AG, Oka T, Baek KH, et al. Tumors in hepatobiliary tract and pancreatic islet tissues of transgenic mice harboring gastrin simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci USA. 1993;90:6696-6700.
56. Bell RH Jr, Memoli VA, Longnecker DS. Hyperplasia and tumors of the islets of Langerhans in mice bearing an elastase I-SV40 T-antigen fusion gene. Carcinogenesis. 1990;11:1393-1398.
57. Dyer KR, Messing A. Metal-inducible pathology in the liver, pancreas, and kidney of transgenic mice expressing SV40 early region genes. Am J Pathol. 1989;135:401-410.
58. Theuring F, Götz W, Balling R, et al. Tumorigenesis and eye abnormalities in transgenic mice expressing MSV-SV40 large T-antigen. Oncogene. 1990;5:225-232.
59. Haas MJ, Dragan YP, Hikita H, et al. Transgene expression and repression in transgenic rats bearing the phosphoenolpyruvate carboxykinase-simian virus 40 T antigen or the phosphoenolpyruvate carboxykinase-transforming growth factor-alpha constructs. Am J Pathol. 1999;155:183-192.
60. Haas MJ, Sattler CA, Dragan YP, et al. Multiple polypeptide hormone expression in pancreatic islet cell carcinomas derived from phosphoenolpyruvatecarboxykinase-SV40 T antigen transgenic rats. Pancreas. 2000;20:206-214.
61. Hully JR, Su Y, Lohse JK, et al. Transgenic hepatocarcinogenesis in the rat. Am J Pathol. 1994;145:384-397.
62. Masiello P, Wollheim CB, Gori Z, et al. Streptozotocin-induced functioning islet cell tumor in the rat: high frequency of induction and biological properties of the tumor cells. Toxicol Pathol. 1984;12:274-280.
63. Masiello P, Wollheim CB, Janjic D, et al. Stimulation of insulin release by glucose in a transplantable rat islet cell tumor. Endocrinology. 1982;111:2091-2096.
64. Kloppel G. Anlauf M. Perren A. Endocrine precursor lesions of gastroenteropancreatic neuroendocrine tumors. Endocr Pathol. 2007;18:150-155.
65. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Dig Dis Sci. 1991;36:933-942.
66. Weinstein LS. Role of the Gnas Gene in Metabolic Regulation. Available at: nidb.nih.gov/search/searchreport.taf?projectbib=Y&ipid=65265&rpid=. Accessed August 19, 2012.
67. Folkman J, Watson K, Ingber D, et al. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339:58-61.
68. Bergers G, Hanahan D, Coussens LM. Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int J Dev Biol. 1998;42:995-1002.
69. Joyce JA, Laakkonen P, Bernasconi M, et al. Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell. 2003;4:393-403.
70. Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299-309.
71. Gocheva V, Chen X, Peters C, et al. Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer. Biol Chem. 2010;391: 937-945
72. Åkerblom B, Zang G, Zhuang ZW, et al. Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice: implications for tumor angiogenesis. Mol Oncol. 2012;6:333-346.
73. Wicki A, Rochlitz C, Orleth A, et al. Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth. Clin Cancer Res. 2012;18:454-464.
74. Mould AW, Duncan R, Serewko-Auret M, et al. Global expression profiling of murine MEN1-associated tumors reveals a regulatory role for menin in transcription, cell cycle and chromatin remodelling. Int J Cancer. 2007;121:776-783.
75. Fontanière S, Tost J, Wierinckx A, et al. Gene expression profiling in insulinomas of Men1 beta-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic beta-cell tumorigenesis. Endocr Relat Cancer. 2006;13:1223-1236.
76. Serewko-Auret MM, Mould AW, Loffler KA, et al. Alterations in gene expression in MEN1-associated insulinoma development. Pancreas. 2010;39:1140-1146.
77. Qian F, Hanahan D, Weissman IL. L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis. Proc Natl Acad Sci USA. 2001;98:3976-3981.
78. Scacheri PC, Kennedy AL, Chin K, et al. Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability. Cancer Res. 2004;64:7039-7044
79. Sennino B, Falcón BL, McCauley D, et al. Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res. 2007;67:7358-7367.
80. Zumsteg A, Caviezel C, Pisarsky L, et al. Repression of malignant tumor progression upon pharmacologic IGF1R blockade in a mouse model of insulinoma. Mol Cancer Res. 2012;10:800-809.
81. Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006;116:2610-2621.
82. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270-287.
83. Maione F, Capano S, Regano D, et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest. 2012;122:1832-1848.
84. Loffler KA, Biondi CA, Gartside M, et al. Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1. Int J Cancer. 2007;120:259-267.
85. Harding B, Lemos MC, Reed AA, et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer. 2009;16:1313-1327.
86. Seigne C, Fontanière S, Carreira C, et al. Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice. BMC Cancer. 2010;10:395.
87. Miyazaki J, Araki K, Yamato E, et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology. 1990;127:126-132.
88. Asfari M, Janjic D, Meda P, et al. Establishment of 2-mercaptoethanol- dependent differentiated insulin-secreting cell lines. Endocrinology. 1992;130:167-178.
89. Efrat S, Linde S, Kofod H, et al. Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. Proc Natl Acad Sci USA. 1988;85:9037-9041.
90. Powers AC, Efrat S, Mojsov S, et al. Proglucagon processing similar to normal islets in pancreatic alpha-like cell line derived from transgenic mouse tumor. Diabetes. 1990;39:406-414.
91. Gazdar AF, Chick WL, Oie HK, et al. Continuous, clonal, insulin-and somatostatin-secreting cell lines established from a transplantable rat islet cell tumor. Proc Natl Acad Sci USA. 1980;77:3519-3523.
92. Hamaguchi K, Gaskins HR, Leiter EH. NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. Diabetes. 1991;40:842-849.
93. Pettengill OS, Memoli VA, Brinck-Johnsen T, et al. Cell lines derived from pancreatic tumors of Tg(Ela-1-SV40E)Bri18 transgenic mice express somatostatin and T antigen. Carcinogenesis. 1994;15:61-65.
94. American Type Culture Collection. Available at: http://www.atcc.org/. Accessed Aug 19, 2012.
95. Skelin M, Rupnik M, Cencic A. Pancreatic beta cell lines and their applications in diabetes mellitus research. ALTEX. 2010;27:105-113.
96. Liu S-H, Rao DD, Nemunaitis J, et al. PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. PLoS ONE. 2012;7:e40452.
97. Lawrence JP, Ishizuka J, Haber B, et al. The effect of somatostatin on 5-hydroxytryptamine release from a carcinoid tumor. Surgery. 1990;108:1131-1134.
98. Evers BM, Ishizuka J, Townsend CM Jr, et al. The human carcinoid cell line, BON. A model system for the study of carcinoid tumors. Ann N Y Acad Sci. 1994;733:393-406.
99. Siddique ZL, Drozdov I, Floch J, et al. KRJ-I and BON cell lines: defining an appropriate enterochromaffin cell neuroendocrine tumor model. Neuroendocrinology. 2009;89:458-470.
100. Lopez JR, Claessen SM, Macville MV, et al. Spectral karyotypic and comparative genomic analysis of the endocrine pancreatic tumor cell line BON-1. Neuroendocrinology. 2010;91:131-141.
101. Kaku M, Nishiyama T, Yagawa K, et al. Establishment of a carcinoembryonic antigen-producing cell line from human pancreatic carcinoma. Gann. 1980;71:596-601.
102. Iguchi H, Hayashi I, Kono A. A somatostatin-secreting cell line established from a human pancreatic islet cell carcinoma (somatostatinoma): release experiment and immunohistochemical study. Cancer Res. 1990;50:3691-3693.
103. Doihara H, Nozawa K, Kojima R, et al. QGP-1 cells release 5-HT via TRPA1 activation; a model of human enterochromaffin cells. Mol Cell Biochem. 2009;331:239-245.
104. Gueli N, Toto A, Palmieri G, et al. In vitro growth of a cell line originated from a human insulinoma. J Exp Clin Cancer Res. 1987;6:281-285.
105. Jonnakuty C, Gragnoli C. Karyotype of the human insulinoma CM cell lineYbeta cell model in vitro? J Cell Physiol. 2007;213:661-662.
106. Gragnoli C. The CM cell line derived from liver metastasis of malignant human insulinoma is not a valid beta cell model for in vitro studies. J Cell Physiol. 2008;216:569-570.
107. Labriola L, Peters MG, Krogh K, et al. Generation and characterization of human insulin-releasing cell lines. BMC Cell Biol. 2009;10:49.
108. Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology. 2007;85:54-60.
109. Moreno A, Akcakanat A, Munsell MF, et al. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer. 2008;15:257-266.
110. Scholz A, Wagner K, Welzel M, et al. The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model. Gut. 2009;58:261-270.
111. Georgieva I, Koychev D, Wang Y, et al. ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio-and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines. Neuroendocrinology. 2010;91:121-130.
112. Zitzmann K, de Toni E, von Rüden J, et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer. 2011;18:277-285.
113. Meric-Bernstam F, Akcakanat A, Chen H, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18:1777-1789.
114. Gloesenkamp C, Nitzsche B, Lim AR, et al. Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors. Int J Oncol. 2012;40:1659-1667.
115. Jackson LN, Li J, Chen LA, et al. Overexpression of wild-type PKD2 leads to increased proliferation and invasion of BON endocrine cells. Biochem Biophys Res Commun. 2006;348:945-949.
116. Detjen KM, Rieke S, Deters A, et al. Angiopoietin-2 promotes disease progression of neuroendocrine tumors. Clin Cancer Res. 2010;16:420-429.
117. Silva SR, Bowen KA, Rychahou PG, et al. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer. 2011;128:1045-1056.
118. Ning L, Chen H, Kunnimalaiyaan M. Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells. Mol Cancer Res. 2010;8:775-782.
119. Zarebczan B, Pinchot SN, Kunnimalaiyaan M, et al. Hesperetin, a potential therapy for carcinoid cancer. Am J Surg. 2011;201:329-332.