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Management of Neuroendocrine Tumors of the Pancreas and Digestive Tract pp 29–41Cite as

Relevance of Angiogenesis in Neuroendocrine Tumors

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Abstract

While traditional cytotoxic drugs have shown limited efficacy in neuroendocrine tumors (NETs), their biological features have been characterized and can be exploited therapeutically. Their most prominent trait is an extraordinary vascularization in low-grade NETs and a hypoxia-dependent angiogenesis in high-grade NETs, which is associated with a significant expression of many pro-angiogenic molecules. Therefore, several antiangiogenic compounds have been tested in these malignancies, and among these, sunitinib has demonstrated activity in pancreatic NET patients by dually targeting the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) pathways. In spite of these efficacious clinical results, apparent resistance to antiangiogenic therapies has been described in NET animal models and in clinical trials. Therefore, overcoming antiangiogenic resistance is a crucial step in the subsequent development of antiangiogenic therapies. Several strategies have been postulated to fight resistance, but preclinical studies and clinical trials will investigate and address these therapeutic approaches in the coming years in order to overcome resistance of antiangiogenic therapies in NETs.

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References

  1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072

    Article  PubMed  Google Scholar 

  2. Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, Belghiti J, Fléjou J, Degott C (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133–138

    Article  CAS  PubMed  Google Scholar 

  3. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  CAS  PubMed  Google Scholar 

  4. Couvelard A, O’Toole D, Turley H, Leek R, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F (2005) Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer 92(1):94–101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Marion-Audibert AM, Barel C, Gouysse G, Dumortier J, Pilleul F, Pourreyron C, Hervieu V, Poncet G, Lombard-Bohas C, Chayvialle JA, Partensky C, Scoazec JY (2003) Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors. Gastroenterology 125:1094–1104

    Article  PubMed  Google Scholar 

  6. Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, Ruszniewski P, Bedossa P (2008) Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res 14:6634–6639

    Article  CAS  PubMed  Google Scholar 

  7. Konstantinova I, Lammert E (2004) Microvascular development: learning from pancreatic islets. BioEssays 26:1069–1075

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122

    Article  CAS  PubMed  Google Scholar 

  9. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812

    Article  CAS  PubMed  Google Scholar 

  10. Parangi S, Dietrich W, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D et al (1995) Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. Cancer Res 55:6071–6076

    CAS  PubMed  Google Scholar 

  11. Varker KA, Campbell J, Shah MH (2008) Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors. Cancer Chemother Pharmacol 61:661–668

    Article  CAS  PubMed  Google Scholar 

  12. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24(3):401–406

    Article  CAS  PubMed  Google Scholar 

  13. Kulke MH, Bergsland EK, Ryan DP, Enzinger PC, Lynch TJ, Zhu AX, Meyerhardt JA, Heymach JV, Fogler WE, Sidor C, Michelini A, Kinsella K, Venook AP, Fuchs CS (2006) Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 24(22):3555–3561

    Article  CAS  PubMed  Google Scholar 

  14. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    Article  CAS  PubMed  Google Scholar 

  15. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2(3):270–287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, Evans DB, Vauthey JN, Xie K, Yao JC (2007) Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 109(8):1478–1486

    Article  CAS  PubMed  Google Scholar 

  17. Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA (2008) Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 26:1316–1323

    Article  CAS  PubMed  Google Scholar 

  18. Kulke MH, Stuart K, Earle CC, Bhargava P, Clark JW, Enzinger PC, Meyerhardt JA, Attawia M, Lawrence C, Fuchs CS (2006) A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol 24(18S):4044 (June 20 Supplement)

    Google Scholar 

  19. Kunz PL, Kuo T, Zahn JM, Kaiser HL, Norton JA, Visser BC, Longacre TA, Ford JM, Balise RR, Fisher GA (2010) A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol 28(15) (suppl; abstr 4104)

    Google Scholar 

  20. Venook AP, Ko AH, Tempero MA, Uy J, Weber T, Korn M, Bergsland EK (2008) Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol 26:abstr

    Google Scholar 

  21. Mitry E, Walter T, Baudin E, Kurtz JE, Ruszniewski P, Dominguez S, Bengrine-Lefevre L, Cadiot G, Kraemer S, Ducreux M (2012) Efficacy and safety of bevacizumab combined with capecitabine in progressive, metastatic well-differentiated digestive endocrine tumors (BETTER study). J Clin Oncol 30 (suppl; abstr 4071)

    Google Scholar 

  22. Ducreux M, Seitz JF, Smith D, O’Toole D, Lepère C, Bitoun L, Mitry E (2012) Efficacy and safety of bevacizumab combined with chemotherapy in the treatment of patients with metastatic well-differentiated duodeno-pancreatic endocrine tumors (BETTER study). J Clin Oncol 30 (suppl; abstr 4036)

    Google Scholar 

  23. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Franco M, Roswall P, Cortez E, Hanahan D, Pietras K (2011) Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118(10):2906–2917

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Bergers G, Song S, Meyer-Morse N et al (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose ‘‘chemo-switch’’ regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952

    Article  CAS  PubMed  Google Scholar 

  27. Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116(3):642–651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Fjallskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET (2003) Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 9:1469–1473

    PubMed  Google Scholar 

  29. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513

    Article  CAS  PubMed  Google Scholar 

  30. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, Li JZ, Baum CM, Fuchs CS (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26(20):3403–3410

    Article  CAS  PubMed  Google Scholar 

  31. Hobday TJ, Rubin J, Holen K, et al (2007) MC044 h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study. J Clin Oncol 25:abstr

    Google Scholar 

  32. Pavel ME, Bartel C, Heuck F, Neumann F, Tiling N, Pape UF, Plöckinger U, Wiedenmann B (2008) Open-label, non-randomized, multicenter phase II study evaluating the angiogenesis inhibitor PTK787/ZK222584 (PTK/ZK) in patients with advanced neuroendocrine carcinomas (NEC). J Clin Oncol 26:abstr

    Google Scholar 

  33. Anthony L, Chester M, Michael S, O’Dorisio TM, O’Dorisio MS (2008) Phase II open-label clinical trial of vatalanib (PTK/ZK) in patients with progressive neuroendocrine cancer. J Clin Oncol (May 20 suppl; abstr 14624)

    Google Scholar 

  34. Grande E, Castellano D, Garcia-Carbonero R, Teule A, Duran I, Fuster J, Sevilla I, Escudero P, Sastre J, Capdevila J (2012) PAZONET: Results of a phase II trial of pazopanib as a sequencing treatment in progressive metastatic neuroendocrine tumors (NETs) patients (pts), on behalf of the Spanish taskforce for NETs (GETNE) — NCT01280201. J Clin Oncol 30 (suppl; abstr 4119)

    Google Scholar 

  35. Phan AT, Yao JC, Fogelman DR, Hess KR, Ng CS, Bullock SA, Malinowski P, Regan E, Kulke M (2010) A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol 28(7) (suppl; abstr 4001)

    Google Scholar 

  36. Boehm T, Folkman J, Browder T, O’Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407

    Article  CAS  PubMed  Google Scholar 

  37. Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116(10):2610–2621

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Hirota K, Semenza GL (2006) Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 59(1):15–26

    Article  PubMed  Google Scholar 

  40. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295(5559):1526–1528

    Article  CAS  PubMed  Google Scholar 

  41. Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12(3):74–80

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231

    Article  PubMed Central  PubMed  Google Scholar 

  43. Takeda T, Okuyama H, Nishizawa Y, Tomita S, Inoue M (2012) Hypoxia inducible factor-1α is necessary for invasive phenotype in Vegf-deleted islet cell tumors. Sci Rep 2:494

    Article  PubMed Central  PubMed  Google Scholar 

  44. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239

    Article  CAS  PubMed  Google Scholar 

  45. Glade Bender J, Cooney EM, Kandel JJ, Yamashiro DJ (2004) Vascular remodeling and clinical resistance to antiangiogenic cancer therapy. Drug Resist Updat 7, 289–300

    Google Scholar 

  46. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103(2):159–165

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Yao JC, Phan A (2011) Overcoming antiangiogenic resistance. Clin Cancer Res 17(16):5217–5219

    Article  CAS  PubMed  Google Scholar 

  48. Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP et al (2009) Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 8:1867–1877

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Jia Z, Zhang J, Wei D, Wang L, Yuan P, Le X et al (2007) Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin. Cancer Res 67:4878–4885

    Article  CAS  PubMed  Google Scholar 

  50. Allen E, Walters IB, Hanahan D (2011) Brivanib, a Dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res 17:5299–5310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Kulke MH, Chan JA, Meyerhardt JA, Zhu AX, Abrams TA, Blaszkowsky LS, Regan E, Sidor C, Fuchs CS (2011) A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol 68:293–300

    Article  CAS  PubMed  Google Scholar 

  52. Castellano DE, Capdevila J, Salazar R, Sastre J, Alonso V, Llanos M, Garcia-Carbonero R, Abad A, Sevilla I, Duran I (2011) Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumor: a phase II study of the Spanish Neuroendocrine Tumor Group (GETNE0801). J Clin Oncol 29 (suppl; abstr 4113)

    Google Scholar 

  53. Yao JC, Phan AT, Fogleman D, Ng CS, Jacobs CB, Dagohoy CD, Leary C, Hess KR (2010) Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker. J Clin Oncol 28(15) (suppl; abstr 4002)

    Google Scholar 

  54. Hobday TJ, Qin R, Reidy DL, Moore MJ, Strosberg JR, Kaubisch A, Shah M, Kindler HL, Lenz HJ, Chen HX, Erlichman C (2012) Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET). J Clin Oncol 30 (suppl 4; abstr 260)

    Google Scholar 

  55. Franco M, Pàez-Ribes M, Cortez E, Casanovas O, Pietras K (2011) Use of a mouse model of pancreatic neuroendocrine tumors to find pericyte biomarkers of resistance to anti-angiogenic therapy. Horm Metab Res 43(12):884–889 Epub 2011 Sep 29

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Ramon Salazar for critical reading of the manuscript and helpful suggestions. The authors’ work is supported by research grants from MICINN (SAF2012-36575) and AGAUR (SGR681) from Spain. The authors declare that no conflict of interest exists.

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Authors and Affiliations

  1. Hereditary Cancer Program, Catalan Institute of Oncology–IDIBELL, Av. Gran Via, 199-203, E-08908, L’Hospitalet de Llobregat, Barcelona, Spain

    Alexandre Teulé

  2. Tumor Angiogenesis Group, Catalan Institute of Oncology–IDIBELL, Av. Gran Via, 199-203, E-08908, L’Hospitalet de Llobregat, Barcelona, Spain

    Laura Martín & Oriol Casanovas

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  1. Alexandre Teulé
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  2. Laura Martín
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  3. Oriol Casanovas
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Correspondence to Oriol Casanovas .

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Editors and Affiliations

  1. Medical Oncology, Bichat-Beaujon University Hospitals, Clichy cedex, France

    Eric Raymond

  2. Bichat-Beaujon University Hospitals Medical Oncology, Clichy cedex, France

    Sandrine Faivre

  3. Pancreatology, Bichat-Beaujon University Hospitals Gastroenterology and, Clichy cedex, France

    Philippe Ruszniewski

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Teulé, A., Martín, L., Casanovas, O. (2014). Relevance of Angiogenesis in Neuroendocrine Tumors. In: Raymond, E., Faivre, S., Ruszniewski, P. (eds) Management of Neuroendocrine Tumors of the Pancreas and Digestive Tract. Springer, Paris. https://doi.org/10.1007/978-2-8178-0430-9_3

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  • DOI: https://doi.org/10.1007/978-2-8178-0430-9_3

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