Neuroendocrine Tumors of the Pancreas: Molecular Pathogenesis and Perspectives on Targeted Therapies
DOI:
https://doi.org/10.6000/1929-2279.2014.03.03.4Keywords:
Neuroendocrine tumor, multiple endocrine neoplasia type I, von Hippel–Lindau disease, neurofibromatosis type I, tuberous sclerosis, targeted therapy, everolimus, sunitinib.Abstract
Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of neoplasms that are the second most common among pancreatic neoplasms. Treatment of PNETs appears to be quite difficult because diagnosis in many patients occurs only at the latest stage when distant metastases are recognized. Therefore, treatment with drugs targeting PNET oncogenesis is a promising strategy in such patients. In this work, we review the present knowledge on the molecular nature of PNETs, and the genetic basis of PNET-associated hereditary syndromes, including multiple endocrine neoplasia type I, von Hippel-Lindau disease, neurofibromatosis type I, and tuberous sclerosis. In addition, the results of phase III, randomized, placebo-controlled trials of the efficacy of everolimus and sunitinib for treatment of extensive non-resectable PNETs are reviewed.
References
Miglani A, Kar P. Neuroendocrine tumors of the pancreas. Trop Gastroenterol 2006; 27: 4-10.
Jensen RT, Norton JA. Endocrine tumors of the pancreas and gastrointestinal tract. In: Feldman M, Friedman LS, Brandt LJ, ed. Sleisinger and Fordtrans's gastrointestinal and liver disease, 9th ed. Philadelphia: WB Saunders 2010; 491-522.
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. http://dx.doi.org/10.1200/JCO.2007.15.4377
Walter T, Brixi-Benmansour H, Lombard-Bohas C, Cadiot G. New treatment strategies in advanced neuroendocrine tumours. Dig Liver Dis 2012; 44: 95-105. http://dx.doi.org/10.1016/j.dld.2011.08.022
Naraev BG, Strosberg JR, Halfdanarson TR. Current status and perspectives of targeted therapy in well-differentiated neuroendocrine tumors. Oncology 2012; 83: 117-127. http://dx.doi.org/10.1159/000339539
Verbeke CS. Endocrine tumours of the pancreas. Histopathology 2010; 56: 669-682. http://dx.doi.org/10.1111/j.1365-2559.2010.03490.x
Capurso G, Festa S, Valente R, et al. Molecular pathology and genetics of pancreatic endocrine tumours. J Mol Endocrinol 2012; 49: R37-50. http://dx.doi.org/10.1530/JME-12-0069
Rindi G, Bordi C. Endocrine tumours of the gastrointestinal tract: aetiology, molecular pathogenesis and genetics. Best Pract Res Clin Gastroenterol 2005; 19: 519-34. http://dx.doi.org/10.1016/j.bpg.2005.03.005
Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008; 135: 1469-92. http://dx.doi.org/10.1053/j.gastro.2008.05.047
Oberg K. Neuroendocrine tumours in 2012: Insights into signalling pathways could individualize therapy. Nat Rev Endocrinol 2013; 9: 70-2. http://dx.doi.org/10.1038/nrendo.2012.250
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331: 1199-203. http://dx.doi.org/10.1126/science.1200609
Corleto VD, Delle Fave G, Jensen RT. Molecular insights into gastrointestinal neuroendocrine tumors: Importance and recent advances. Dig Liver Dis 2002; 34: 668-80. http://dx.doi.org/10.1016/S1590-8658(02)80212-2
Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008; 9: 61-72. http://dx.doi.org/10.1016/S1470-2045(07)70410-2
Li AF, Li AC, Tsay SH, Li WY, Liang WY, Chen JY. Alterations in the p16INK4a/cyclin D1/RB pathway in gastrointestinal tract endocrine tumors. Am J Clin Pathol 2008; 130: 535-42. http://dx.doi.org/10.1309/TLLVXK9HVA89CHPE
Simon B, Lubomierski N. Implication of the INK4a/ARF locus in gastroenteropancreatic neuroendocrine tumorigenesis. Ann N Y Acad Sci 2004; 1014: 284-99. http://dx.doi.org/10.1196/annals.1294.033
Arnold CN, Sosnowski A, Schmitt-Gräff A, Arnold R, Blum HE. Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer 2007; 120: 2157-64. http://dx.doi.org/10.1002/ijc.22569
Romagosa C, Simonetti S, López-Vicente L, et al. p16 (Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene 2011; 30: 2087-97. http://dx.doi.org/10.1038/onc.2010.614
Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 1999; 18: 2367-2371. http://dx.doi.org/10.1038/sj.onc.1202585
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-? family signalling. Nature (London) 2003; 425: 577-584. http://dx.doi.org/10.1038/nature02006
ten Dijke P, Hill CS. New insights into TGF-?–Smad signalling. Trends Biochem Sci 2004; 29: 265-273. http://dx.doi.org/10.1016/j.tibs.2004.03.008
Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci 2008; 65: 1566-1584. http://dx.doi.org/10.1007/s00018-008-7440-8
Ménard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E. Role of HER2/neu in tumor progression and therapy. Cell Mol Life Sci 2004; 61: 2965-2978. http://dx.doi.org/10.1007/s00018-004-4277-7
Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 2009; 21: 177-184. http://dx.doi.org/10.1016/j.ceb.2008.12.010
Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg 1994; 219(6): 596-601. http://dx.doi.org/10.1097/00000658-199406000-00002
Goebel SU, Iwamoto M, Raffeld M, et al. Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. Cancer Res 2002; 62: 3702-3710.
Corbo V, Beghelli S, Bersani S, et al. Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. Ann Oncol 2012; 23: 127-134. http://dx.doi.org/10.1093/annonc/mdr048
Fjällskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET. Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 2003; 9: 1469-1473.
Furukawa M, Raffeld M, Mateo C, et al. Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases. Clin Cancer Res 2005; 11: 3233-3242. http://dx.doi.org/10.1158/1078-0432.CCR-04-1915
Peghini PL, Iwamoto M, Raffeld M, et al. Overexpression of epidermal growth factor and hepatocyte growth factor receptors in a proportion of gastrinomas correlates with aggressive growth and lower curability. Clin Cancer Res 2002; 8: 2273-2285.
Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 2012; 92: 1619-1649. http://dx.doi.org/10.1152/physrev.00046.2011
Koch CA, Gimm O, Vortmeyer AO, et al. Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? Ann N Y Acad Sci 2006; 1073: 517-526. http://dx.doi.org/10.1196/annals.1353.055
Zhang L, Smyrk TC, Oliveira AM, et al. KIT is an independent prognostic marker for pancreatic endocrine tumors: a finding derived from analysis of islet cell differentiation markers. Am J Surg Pathol 2009; 33: 1562-1569. http://dx.doi.org/10.1097/PAS.0b013e3181ac675b
Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 2008; 113: 1807-1843. http://dx.doi.org/10.1002/cncr.23648
Gaztambide S, Vazquez F, Castaño L. Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1). Minerva Endocrinol 2013; 38: 17-28.
Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332: 85-87. http://dx.doi.org/10.1038/332085a0
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. http://dx.doi.org/10.1002/humu.20605
Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820-823. http://dx.doi.org/10.1073/pnas.68.4.820
Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997; 57: 4682-4686.
Agarwal SK, Lee Burns A, Sukhodolets KE, et al. Molecular pathology of the MEN1 gene. Ann N Y Acad Sci 2004; 1014: 189-198. http://dx.doi.org/10.1196/annals.1294.020
Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 2005; 5: 367-375. http://dx.doi.org/10.1038/nrc1610
Poisson A, Zablewska B, Gaudray P. Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1. Cancer Lett 2003; 189: 1-10. http://dx.doi.org/10.1016/S0304-3835(02)00509-8
Yang Y, Hua X. In search of tumor suppressing functions of menin. Mol Cell Endocrinol 2007; 265-266: 34-41. http://dx.doi.org/10.1016/j.mce.2006.12.032
Milne TA, Hughes CM, Lloyd R, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 2005; 102: 749-754. http://dx.doi.org/10.1073/pnas.0408836102
Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 2005; 102: 14659-14664. http://dx.doi.org/10.1073/pnas.0503484102
Sato N, Sato M, Nakayama M, Saitoh R, Arai K, Masai H. Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex. Gene Cell 2003; 8: 451-463. http://dx.doi.org/10.1046/j.1365-2443.2003.00647.x
Schnepp RW, Hou Z, Wang H, et al. Functional interaction between tumor suppressor menin and activator of S-phase kinase. Cancer Res 2004; 64: 6791-6796. http://dx.doi.org/10.1158/0008-5472.CAN-04-0724
Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999; 96: 143-152. http://dx.doi.org/10.1016/S0092-8674(00)80967-8
Kim H, Lee JE, Cho EJ, Liu JO, Youn HD. Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. Cancer Res 2003; 63: 6135-6139.
Agarwal SK, Novotny EA, Crabtree JS, et al. Transcriptional factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc Natl Acad Sci USA 2003; 100: 10770-10775. http://dx.doi.org/10.1073/pnas.1834524100
Heppner C, Bilimoria KY, Agarwal SK, et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene 2001; 20: 4917-4925. http://dx.doi.org/10.1038/sj.onc.1204529
Lin SY, Elledge SJ. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 2003; 113: 881-889. http://dx.doi.org/10.1016/S0092-8674(03)00430-6
Hashimoto M, Kyo S, Hua X, et al. Role of menin in the regulation of telomerase activity in normal and cancer cells. Int J Oncol 2008; 33: 333-340.
Jin S, Mao H, Schnepp RW, et al. Menin associates with FANCD2, a protein involved in repair of DNA damage. Cancer Res 2003; 63: 4204-4210.
Sukhodolets KE, Hickman AB, Agarwal SK, et al. The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene. Mol Cell Biol 2003; 23: 493-509. http://dx.doi.org/10.1128/MCB.23.2.493-509.2003
Averous J, Proud CG. When translation meets transfor-mation: the mTOR story. Oncogene 2006; 25: 6423-6435. http://dx.doi.org/10.1038/sj.onc.1209887
Shida T, Kishimoto T, Furuya M, et al. Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors. Cancer Chemother Pharmacol 2010; 65: 889-893. http://dx.doi.org/10.1007/s00280-009-1094-6
Chen M, Van Ness M, Guo Y, Gregg J. Molecular pathology of pancreatic neuroendocrine tumors. J Gastrointest Oncol 2012; 3: 182-188.
Kasajima A, Pavel M, Darb-Esfahani S, et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011; 18: 181-192. http://dx.doi.org/10.1677/ERC-10-0126
Di Florio A, Adesso L, Pedrotti S, et al. Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells. Endocr Relat Cancer 2011; 18: 541-554. http://dx.doi.org/10.1530/ERC-10-0153
Wang Y, Ozawa A, Zaman S, et al. The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res 2011; 71: 371-382. http://dx.doi.org/10.1158/0008-5472.CAN-10-3221
Corcos O, Couvelard A, Giraud S, et al. Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features. Pancreas 2008; 37: 85-93. http://dx.doi.org/10.1097/MPA.0b013e31815f394a
Chou A, Toon C, Pickett J, Gill AJ. Von hippel-lindau syndrome. Front Horm Res 2013; 41: 30-49. http://dx.doi.org/10.1159/000345668
Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol 2006; 36: 337-343. http://dx.doi.org/10.1093/jjco/hyl052
Schmitt AM, Schmid S, Rudolph T, et al. VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer 2009; 16: 1219-1227. http://dx.doi.org/10.1677/ERC-08-0297
Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007; 6: 340-351. http://dx.doi.org/10.1016/S1474-4422(07)70075-3
McClatchey AI. Neurofibromatosis. Annu Rev Pathol 2007; 2: 191-216. http://dx.doi.org/10.1146/annurev.pathol.2.010506.091940
Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschläger M. The mTOR pathway and its role in human genetic diseases. Mutat Res 2008; 659: 284-292. http://dx.doi.org/10.1016/j.mrrev.2008.06.001
Schwartz RA, Fernández G, Kotulska K, Jó?wiak S. Tuber-ous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol 2007; 57: 189-202. http://dx.doi.org/10.1016/j.jaad.2007.05.004
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657-668. http://dx.doi.org/10.1016/S0140-6736(08)61279-9
Rosner M, Hanneder M, Siegel N, Valli A, Hengstschläger M. The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutat Res 2008; 658: 234-246. http://dx.doi.org/10.1016/j.mrrev.2008.01.001
Briest F, Grabowski P. PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms. Theranostics 2014; 4: 336-365. http://dx.doi.org/10.7150/thno.7851
Stevenson R, Libutti SK, Saif MW. Novel agents in gastroenteropancreatic neuroendocrine tumors. JOP 2013; 14: 152-154.
Oberstein PE, Remotti H, Saif MW, Libutti SK. Pancreatic neuroendocrine tumors: entering a new era. JOP 2012; 13: 169-173.
McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 2004; 27: 485-488. http://dx.doi.org/10.1097/01.coc.0000135343.06038.eb
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. http://dx.doi.org/10.1056/NEJMoa1009290
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501-513. http://dx.doi.org/10.1056/NEJMoa1003825
Wolin EM. PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors. Cancer Lett 2013; 335: 1-8. http://dx.doi.org/10.1016/j.canlet.2013.02.016
Downloads
Published
How to Cite
Issue
Section
