Skip to main content

Advertisement

SpringerLink
Log in

Angiogenesis in pancreatic cancer: current research status and clinical implications

  • Review Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  3. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29. https://doi.org/10.3322/caac.21208

    Article  PubMed  Google Scholar 

  4. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921. https://doi.org/10.1158/0008-5472.can-14-0155

    Article  CAS  PubMed  Google Scholar 

  5. Bosman F, Cameiro F, Hmban R (2010) WHO classification of tumours of the digestive system. IARC Press, Lyon

    Google Scholar 

  6. Kamisawa T, Wood LD, Itoi T, Takaori K (2016) Pancreatic cancer. The Lancet 388(10039):73–85. https://doi.org/10.1016/s0140-6736(16)00141-0

    Article  CAS  Google Scholar 

  7. Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J, Sima C, Hostetter G, Shepard HM, Von Hoff DD, Han H (2015) Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res 21(15):3561–3568. https://doi.org/10.1158/1078-0432.CCR-14-1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429. https://doi.org/10.1016/j.ccr.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ehehalt F, Saeger HD, Schmidt CM, Grutzmann R (2009) Neuroendocrine tumors of the pancreas. Oncologist 14(5):456–467. https://doi.org/10.1634/theoncologist.2008-0259

    Article  CAS  PubMed  Google Scholar 

  10. Capozzi M, C VONA, C DED, Ottaiano A, Tatangelo F, Romano GM, Tafuto S (2016) Antiangiogenic therapy in pancreatic neuroendocrine tumors. Anticancer Res 36(10):5025–5030. https://doi.org/10.21873/anticanres.11071

    Article  CAS  PubMed  Google Scholar 

  11. 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(6):501–513. https://doi.org/10.1056/NEJMoa1003825

    Article  CAS  PubMed  Google Scholar 

  12. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1):4–6

    Article  CAS  PubMed  Google Scholar 

  13. Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin Cancer Biol 19(5):329–337. https://doi.org/10.1016/j.semcancer.2009.05.003

    Article  CAS  PubMed  Google Scholar 

  14. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591. https://doi.org/10.1038/nrc2403

    Article  CAS  PubMed  Google Scholar 

  15. Bry M, Kivela R, Leppanen VM, Alitalo K (2014) Vascular endothelial growth factor-B in physiology and disease. Physiol Rev 94(3):779–794. https://doi.org/10.1152/physrev.00028.2013

    Article  CAS  PubMed  Google Scholar 

  16. Hoff PM, Machado KK (2012) Role of angiogenesis in the pathogenesis of cancer. Cancer Treat Rev 38(7):825–833. https://doi.org/10.1016/j.ctrv.2012.04.006

    Article  CAS  PubMed  Google Scholar 

  17. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. https://doi.org/10.1056/NEJMoa032691

    Article  CAS  PubMed  Google Scholar 

  18. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28(20):3239–3247. https://doi.org/10.1200/jco.2008.21.6457

    Article  CAS  PubMed  Google Scholar 

  19. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V (2010) Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 28(13):2144–2150. https://doi.org/10.1200/jco.2009.26.7849

    Article  CAS  PubMed  Google Scholar 

  20. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887. https://doi.org/10.1016/j.cell.2011.08.039

    Article  CAS  PubMed  Google Scholar 

  21. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12(10):943–953. https://doi.org/10.1038/ncb2103

    Article  CAS  PubMed  Google Scholar 

  22. Galie PA, Nguyen DH, Choi CK, Cohen DM, Janmey PA, Chen CS (2014) Fluid shear stress threshold regulates angiogenic sprouting. Proc Natl Acad Sci USA 111(22):7968–7973. https://doi.org/10.1073/pnas.1310842111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mentzer SJ, Konerding MA (2014) Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 17(3):499–509. https://doi.org/10.1007/s10456-014-9428-3

    Article  PubMed  PubMed Central  Google Scholar 

  24. Paku S, Dezso K, Bugyik E, Tovari J, Timar J, Nagy P, Laszlo V, Klepetko W, Dome B (2011) A new mechanism for pillar formation during tumor-induced intussusceptive angiogenesis: inverse sprouting. Am J Pathol 179(3):1573–1585. https://doi.org/10.1016/j.ajpath.2011.05.033

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hlushchuk R, Makanya AN, Djonov V (2011) Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again? Int J Dev Biol 55(4–5):563–567. https://doi.org/10.1387/ijdb.103231rh

    Article  CAS  PubMed  Google Scholar 

  26. Hlushchuk R, Riesterer O, Baum O, Wood J, Gruber G, Pruschy M, Djonov V (2008) Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation. Am J Pathol 173(4):1173–1185. https://doi.org/10.2353/ajpath.2008.071131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Djonov VG, Kurz H, Burri PH (2002) Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev Dyn 224(4):391–402. https://doi.org/10.1002/dvdy.10119

    Article  PubMed  Google Scholar 

  28. Milkiewicz M, Brown MD, Egginton S, Hudlicka O (2001) Association between shear stress, angiogenesis, and VEGF in skeletal muscles in vivo. Microcirculation (New York, NY: 1994) 8(4):229–241. https://doi.org/10.1038/sj/mn/7800074

    Article  CAS  Google Scholar 

  29. Egginton S, Zhou AL, Brown MD, Hudlicka O (2001) Unorthodox angiogenesis in skeletal muscle. Cardiovasc Res 49(3):634–646

    Article  CAS  PubMed  Google Scholar 

  30. Gianni-Barrera R, Trani M, Fontanellaz C, Heberer M, Djonov V, Hlushchuk R, Banfi A (2013) VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting. Angiogenesis 16(1):123–136. https://doi.org/10.1007/s10456-012-9304-y

    Article  CAS  PubMed  Google Scholar 

  31. Dill MT, Rothweiler S, Djonov V, Hlushchuk R, Tornillo L, Terracciano L, Meili-Butz S, Radtke F, Heim MH, Semela D (2012) Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 142(4):967–977.e962. https://doi.org/10.1053/j.gastro.2011.12.052

    Article  CAS  PubMed  Google Scholar 

  32. Dimova I, Hlushchuk R, Makanya A, Styp-Rekowska B, Ceausu A, Flueckiger S, Lang S, Semela D, Le Noble F, Chatterjee S, Djonov V (2013) Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells. Angiogenesis 16(4):921–937. https://doi.org/10.1007/s10456-013-9366-5

    Article  CAS  PubMed  Google Scholar 

  33. Van den Eynden GG, Bird NC, Majeed AW, Van Laere S, Dirix LY, Vermeulen PB (2012) The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin Exp Metastasis 29(6):541–549. https://doi.org/10.1007/s10585-012-9469-1

    Article  CAS  PubMed  Google Scholar 

  34. Budde MD, Gold E, Jordan EK, Frank JA (2012) Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI. Clin Exp Metastasis 29(1):51–62. https://doi.org/10.1007/s10585-011-9428-2

    Article  PubMed  Google Scholar 

  35. Franco M, Paez-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. https://doi.org/10.1055/s-0031-1284381

    Article  CAS  PubMed  Google Scholar 

  36. Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan M, Wotherspoon A, Gao ZH, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, Van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22(11):1294–1302. https://doi.org/10.1038/nm.4197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, Hegedus B, Hoetzenecker K, Renyi-Vamos F, Kuczynski EA, Vasudev NS, Larkin J, Gore M, Dvorak HF, Paku S, Kerbel RS, Dome B, Reynolds AR (2017) Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol 241(3):362–374. https://doi.org/10.1002/path.4845

    Article  CAS  PubMed  Google Scholar 

  38. Folberg R, Hendrix MJ, Maniotis AJ (2000) Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156(2):361–381. https://doi.org/10.1016/s0002-9440(10)64739-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155(3):739–752. https://doi.org/10.1016/s0002-9440(10)65173-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu WB, Xu GL, Jia WD, Li JS, Ma JL, Chen K, Wang ZH, Ge YS, Ren WH, Yu JH, Wang W, Wang XJ (2011) Prognostic significance and mechanisms of patterned matrix vasculogenic mimicry in hepatocellular carcinoma. Medical Oncol (Northwood London England) 28(Suppl 1):S228–S238. https://doi.org/10.1007/s12032-010-9706-x

    Article  Google Scholar 

  41. Tan LY, Mintoff C, Johan MZ, Ebert BW, Fedele C, Zhang YF, Szeto P, Sheppard KE, McArthur GA, Foster-Smith E, Ruszkiewicz A, Brown MP, Bonder CS, Shackleton M, Ebert LM (2016) Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome. Oncotarget 7(29):46492–46508. https://doi.org/10.18632/oncotarget.10216

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yang J, Zhu DM, Zhou XG, Yin N, Zhang Y, Zhang ZX, Li DC, Zhou J (2017) HIF-2alpha promotes the formation of vasculogenic mimicry in pancreatic cancer by regulating the binding of Twist1 to the VE-cadherin promoter. Oncotarget 8(29):47801–47815. https://doi.org/10.18632/oncotarget.17999

    Article  PubMed  PubMed Central  Google Scholar 

  43. Paulis YW, Soetekouw PM, Verheul HM, Tjan-Heijnen VC, Griffioen AW (2010) Signalling pathways in vasculogenic mimicry. Biochim Biophys Acta 1806(1):18–28. https://doi.org/10.1016/j.bbcan.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  44. Guo JQ, Zheng QH, Chen H, Chen L, Xu JB, Chen MY, Lu D, Wang ZH, Tong HF, Lin S (2014) Ginsenoside Rg3 inhibition of vasculogenic mimicry in pancreatic cancer through downregulation of VEcadherin/EphA2/MMP9/MMP2 expression. Int J Oncol 45(3):1065–1072. https://doi.org/10.3892/ijo.2014.2500

    Article  CAS  PubMed  Google Scholar 

  45. Mourad-Zeidan AA, Melnikova VO, Wang H, Raz A, Bar-Eli M (2008) Expression profiling of Galectin-3-depleted melanoma cells reveals its major role in melanoma cell plasticity and vasculogenic mimicry. Am J Pathol 173(6):1839–1852. https://doi.org/10.2353/ajpath.2008.080380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cong R, Sun Q, Yang L, Gu H, Zeng Y, Wang B (2009) Effect of Genistein on vasculogenic mimicry formation by human uveal melanoma cells. J Exp Clin Cancer Res 28:124. https://doi.org/10.1186/1756-9966-28-124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Blogowski W, Bodnarczuk T, Starzynska T (2016) Concise review: pancreatic cancer and bone marrow-derived stem cells. Stem Cells Transl Med 5(7):938–945. https://doi.org/10.5966/sctm.2015-0291

    Article  PubMed  PubMed Central  Google Scholar 

  48. Vizio B, Novarino A, Giacobino A, Cristiano C, Prati A, Brondino G, Ciuffreda L, Bellone G (2010) Pilot study to relate clinical outcome in pancreatic carcinoma and angiogenic plasma factors/circulating mature/progenitor endothelial cells: preliminary results. Cancer Sci 101(11):2448–2454. https://doi.org/10.1111/j.1349-7006.2010.01692.x

    Article  CAS  PubMed  Google Scholar 

  49. Vizio B, Biasi F, Scirelli T, Novarino A, Prati A, Ciuffreda L, Montrucchio G, Poli G, Bellone G (2013) Pancreatic-carcinoma-cell-derived pro-angiogenic factors can induce endothelial-cell differentiation of a subset of circulating CD34+ progenitors. J Transl Med 11:314. https://doi.org/10.1186/1479-5876-11-314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kurtagic E, Rich CB, Buczek-Thomas JA, Nugent MA (2015) Neutrophil elastase-generated fragment of vascular endothelial growth factor-A stimulates macrophage and endothelial progenitor cell migration. PLoS ONE 10(12):e0145115. https://doi.org/10.1371/journal.pone.0145115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yamazaki M, Nakamura K, Mizukami Y, Ii M, Sasajima J, Sugiyama Y, Nishikawa T, Nakano Y, Yanagawa N, Sato K, Maemoto A, Tanno S, Okumura T, Karasaki H, Kono T, Fujiya M, Ashida T, Chung DC, Kohgo Y (2008) Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci 99(6):1131–1138. https://doi.org/10.1111/j.1349-7006.2008.00795.x

    Article  CAS  PubMed  Google Scholar 

  52. Nakamura K, Sasajima J, Mizukami Y, Sugiyama Y, Yamazaki M, Fujii R, Kawamoto T, Koizumi K, Sato K, Fujiya M, Sasaki K, Tanno S, Okumura T, Shimizu N, Kawabe J, Karasaki H, Kono T, Ii M, Bardeesy N, Chung DC, Kohgo Y (2010) Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PLoS ONE 5(1):e8824. https://doi.org/10.1371/journal.pone.0008824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li A, Cheng XJ, Moro A, Singh RK, Hines OJ, Eibl G (2011) CXCR2-dependent endothelial progenitor cell mobilization in pancreatic cancer growth. Transl Oncol 4(1):20–28

    Article  PubMed  PubMed Central  Google Scholar 

  54. Vermeulen PB, Gasparini G, Fox SB, Colpaert C, Marson LP, Gion M, Belien JA, de Waal RM, Van Marck E, Magnani E, Weidner N, Harris AL, Dirix LY (2002) Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer (Oxford, England: 1990) 38(12):1564–1579

    Article  CAS  Google Scholar 

  55. Hoem D, Straume O, Immervoll H, Akslen LA, Molven A (2013) Vascular proliferation is associated with survival in pancreatic ductal adenocarcinoma. APMIS 121(11):1037–1046. https://doi.org/10.1111/apm.12057

    Article  CAS  PubMed  Google Scholar 

  56. Nishida T, Yoshitomi H, Takano S, Kagawa S, Shimizu H, Ohtsuka M, Kato A, Furukawa K, Miyazaki M (2016) Low stromal area and high stromal microvessel density predict poor prognosis in pancreatic cancer. Pancreas 45(4):593–600. https://doi.org/10.1097/mpa.0000000000000499

    Article  CAS  PubMed  Google Scholar 

  57. Jureidini R, da Cunha JE, Takeda F, Namur GN, Ribeiro TC, Patzina R, Figueira ER, Ribeiro U Jr, Bacchella T, Cecconello I (2016) Evaluation of microvessel density and p53 expression in pancreatic adenocarcinoma. Clinics (Sao Paulo Brazil) 71(6):315–319. https://doi.org/10.6061/clinics/2016(06)05

    Article  Google Scholar 

  58. van der Zee JA, van Eijck CH, Hop WC, van Dekken H, Dicheva BM, Seynhaeve AL, Koning GA, Eggermont AM, ten Hagen TL (2011) Angiogenesis: a prognostic determinant in pancreatic cancer? Eur J Cancer (Oxford England 1990) 47(17):2576–2584. https://doi.org/10.1016/j.ejca.2011.08.016

    Article  CAS  Google Scholar 

  59. Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD, Ellis LM (1996) Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res 2(10):1679–1684

    CAS  PubMed  Google Scholar 

  60. Barau A, Ruiz-Sauri A, Valencia G, Gomez-Mateo Mdel C, Sabater L, Ferrandez A, Llombart-Bosch A (2013) High microvessel density in pancreatic ductal adenocarcinoma is associated with high grade. Virchows Archiv 462(5):541–546. https://doi.org/10.1007/s00428-013-1409-1

    Article  CAS  PubMed  Google Scholar 

  61. Di Maggio F, Arumugam P, Delvecchio FR, Batista S, Lechertier T, Hodivala-Dilke K, Kocher HM (2016) Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma. Pancreatology 16(6):995–1004. https://doi.org/10.1016/j.pan.2016.05.393

    Article  CAS  PubMed  Google Scholar 

  62. Komar G, Kauhanen S, Liukko K, Seppanen M, Kajander S, Ovaska J, Nuutila P, Minn H (2009) Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness. Clin Cancer Res 15(17):5511–5517. https://doi.org/10.1158/1078-0432.ccr-09-0414

    Article  CAS  PubMed  Google Scholar 

  63. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25(6):735–747. https://doi.org/10.1016/j.ccr.2014.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Ruckert F, Grutzmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461. https://doi.org/10.1126/science.1171362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hexige S, Ardito-Abraham CM, Wu Y, Wei Y, Fang Y, Han X, Li J, Zhou P, Yi Q, Maitra A, Liu JO, Tuveson DA, Lou W, Yu L (2015) Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma. J Pathol 236(2):142–154. https://doi.org/10.1002/path.4506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97(6):512–523. https://doi.org/10.1161/01.RES.0000182903.16652.d7

    Article  CAS  PubMed  Google Scholar 

  67. Caporali A, Martello A, Miscianinov V, Maselli D, Vono R, Spinetti G (2017) Contribution of pericyte paracrine regulation of the endothelium to angiogenesis. Pharmacol Ther 171:56–64. https://doi.org/10.1016/j.pharmthera.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  68. Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E (2009) Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119(11):3356–3372. https://doi.org/10.1172/jci36308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McCarty MF, Somcio RJ, Stoeltzing O, Wey J, Fan F, Liu W, Bucana C, Ellis LM (2007) Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J Clin Invest 117(8):2114–2122. https://doi.org/10.1172/jci31334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gilles ME, Maione F, Cossutta M, Carpentier G, Caruana L, Di Maria S, Houppe C, Destouches D, Shchors K, Prochasson C, Mongelard F, Lamba S, Bardelli A, Bouvet P, Couvelard A, Courty J, Giraudo E, Cascone I (2016) Nucleolin targeting impairs the progression of pancreatic cancer and promotes the normalization of tumor vasculature. Cancer Res 76(24):7181–7193. https://doi.org/10.1158/0008-5472.can-16-0300

    Article  CAS  PubMed  Google Scholar 

  71. Wang WQ, Liu L, Xu HX, Luo GP, Chen T, Wu CT, Xu YF, Xu J, Liu C, Zhang B, Long J, Tang ZY, Yu XJ (2013) Intratumoral alpha-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. PLoS ONE 8(8):e71189. https://doi.org/10.1371/journal.pone.0071189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xie K, Wei D, Huang S (2006) Transcriptional anti-angiogenesis therapy of human pancreatic cancer. Cytokine Growth Factor Rev 17(3):147–156. https://doi.org/10.1016/j.cytogfr.2006.01.002

    Article  CAS  PubMed  Google Scholar 

  73. DiDonato JA, Mercurio F, Karin M (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246(1):379–400. https://doi.org/10.1111/j.1600-065X.2012.01099.x

    Article  CAS  PubMed  Google Scholar 

  74. Carbone C, Melisi D (2012) NF-kappaB as a target for pancreatic cancer therapy. Expert Opin Ther Targets 16(Suppl 2):S1–S10. https://doi.org/10.1517/14728222.2011.645806

    Article  CAS  PubMed  Google Scholar 

  75. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T (2010) NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 295(2):214–228. https://doi.org/10.1016/j.canlet.2010.03.003

    Article  CAS  PubMed  Google Scholar 

  76. Saito K, Matsuo Y, Imafuji H, Okubo T, Maeda Y, Sato T, Shamoto T, Tsuboi K, Morimoto M, Takahashi H, Ishiguro H, Takiguchi S (2018) Xanthohumol inhibits angiogenesis by suppressing nuclear factor-kappaB activation in pancreatic cancer. Cancer Sci 109(1):132–140. https://doi.org/10.1111/cas.13441

    Article  CAS  PubMed  Google Scholar 

  77. Wang L, Zhou W, Zhong Y, Huo Y, Fan P, Zhan S, Xiao J, Jin X, Gou S, Yin T, Wu H, Liu T (2017) Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-kappaB signaling pathway. Mol Cancer 16(1):61. https://doi.org/10.1186/s12943-017-0627-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Kage M, Nishio K, Kohno K, Kuwano M, Ono M (2009) N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression. Cancer Res 69(12):4983–4991. https://doi.org/10.1158/0008-5472.can-08-4882

    Article  CAS  PubMed  Google Scholar 

  79. Cai X, Lu W, Yang Y, Yang J, Ye J, Gu Z, Hu C, Wang X, Cao P (2013) Digitoflavone inhibits IkappaBalpha kinase and enhances apoptosis induced by TNFalpha through downregulation of expression of nuclear factor kappaB-regulated gene products in human pancreatic cancer cells. PLoS ONE 8(10):e77126. https://doi.org/10.1371/journal.pone.0077126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Waters JA, Matos J, Yip-Schneider M, Aguilar-Saavedra JR, Crean CD, Beane JD, Dumas RP, Suvannasankha A, Schmidt CM (2015) Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts. Surgery 158(4):881–888. https://doi.org/10.1016/j.surg.2015.04.043 discussion 888–889.

    Article  PubMed  Google Scholar 

  81. Sankpal UT, Maliakal P, Bose D, Kayaleh O, Buchholz D, Basha R (2012) Expression of specificity protein transcription factors in pancreatic cancer and their association in prognosis and therapy. Curr Med Chem 19(22):3779–3786

    Article  CAS  PubMed  Google Scholar 

  82. Huang C, Xie K (2012) Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev 23(1–2):25–35. https://doi.org/10.1016/j.cytogfr.2012.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Abdelrahim M, Smith R 3rd, Burghardt R, Safe S (2004) Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res 64(18):6740–6749. https://doi.org/10.1158/0008-5472.can-04-0713

    Article  CAS  PubMed  Google Scholar 

  84. Abdelrahim M, Baker CH, Abbruzzese JL, Sheikh-Hamad D, Liu S, Cho SD, Yoon K, Safe S (2007) Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res 67(7):3286–3294. https://doi.org/10.1158/0008-5472.can-06-3831

    Article  CAS  PubMed  Google Scholar 

  85. Higgins KJ, Abdelrahim M, Liu S, Yoon K, Safe S (2006) Regulation of vascular endothelial growth factor receptor-2 expression in pancreatic cancer cells by Sp proteins. Biochem Biophys Res Commun 345(1):292–301. https://doi.org/10.1016/j.bbrc.2006.04.111

    Article  CAS  PubMed  Google Scholar 

  86. Hu H, Han T, Zhuo M, Wu LL, Yuan C, Wu L, Lei W, Jiao F, Wang LW (2017) Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent signalling in pancreatic cancer. Sci Rep 7(1):470. https://doi.org/10.1038/s41598-017-00288-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K (2004) Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64(6):2030–2038

    Article  CAS  PubMed  Google Scholar 

  88. Abdelrahim M, Baker CH, Abbruzzese JL, Safe S (2006) Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst 98(12):855–868. https://doi.org/10.1093/jnci/djj232

    Article  CAS  PubMed  Google Scholar 

  89. Yuan P, Wang L, Wei D, Zhang J, Jia Z, Li Q, Le X, Wang H, Yao J, Xie K (2007) Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer 110(12):2682–2690. https://doi.org/10.1002/cncr.23092

    Article  CAS  PubMed  Google Scholar 

  90. Zhong Z, Wen Z, Darnell JE, Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–98

    Article  CAS  PubMed  Google Scholar 

  91. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063. https://doi.org/10.1074/jbc.R700016200

    Article  CAS  PubMed  Google Scholar 

  92. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22(3):319–329. https://doi.org/10.1038/sj.onc.1206122

    Article  CAS  PubMed  Google Scholar 

  93. Boreddy SR, Sahu RP, Srivastava SK (2011) Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-alpha/VEGF/Rho-GTPases: pivotal role of STAT-3. PLoS ONE 6(10):e25799. https://doi.org/10.1371/journal.pone.0025799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Huang C, Huang R, Chang W, Jiang T, Huang K, Cao J, Sun X, Qiu Z (2012) The expression and clinical significance of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma. Neoplasma 59(1):52–61. https://doi.org/10.4149/neo_2012_007

    Article  CAS  PubMed  Google Scholar 

  95. Trevino JG, Gray MJ, Nawrocki ST, Summy JM, Lesslie DP, Evans DB, Sawyer TK, Shakespeare WC, Watowich SS, Chiao PJ, McConkey DJ, Gallick GE (2006) Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis 9(2):101–110. https://doi.org/10.1007/s10456-006-9038-9

    Article  CAS  PubMed  Google Scholar 

  96. Huang C, Jiang T, Zhu L, Liu J, Cao J, Huang KJ, Qiu ZJ (2011) STAT3-targeting RNA interference inhibits pancreatic cancer angiogenesis in vitro and in vivo. Int J Oncol 38(6):1637–1644. https://doi.org/10.3892/ijo.2011.1000

    Article  CAS  PubMed  Google Scholar 

  97. Lin L, Hutzen B, Zuo M, Ball S, Deangelis S, Foust E, Pandit B, Ihnat MA, Shenoy SS, Kulp S, Li PK, Li C, Fuchs J, Lin J (2010) Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res 70(6):2445–2454. https://doi.org/10.1158/0008-5472.can-09-2468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Li H, Huang C, Huang K, Wu W, Jiang T, Cao J, Feng Z, Qiu Z (2011) STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS ONE 6(10):e25941. https://doi.org/10.1371/journal.pone.0025941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Niu F, Li Y, Lai FF, Ni L, Ji M, Jin J, Yang HZ, Wang C, Zhang DM, Chen XG (2015) LB-1 exerts antitumor activity in pancreatic cancer by inhibiting HIF-1alpha and Stat3 signaling. J Cell Physiol 230(9):2212–2223. https://doi.org/10.1002/jcp.24949

    Article  CAS  PubMed  Google Scholar 

  100. Moser C, Ruemmele P, Gehmert S, Schenk H, Kreutz MP, Mycielska ME, Hackl C, Kroemer A, Schnitzbauer AA, Stoeltzing O, Schlitt HJ, Geissler EK, Lang SA (2012) STAT5b as molecular target in pancreatic cancer–inhibition of tumor growth, angiogenesis, and metastases. Neoplasia (New York NY) 14(10):915–925

    Article  CAS  Google Scholar 

  101. Sahraei M, Roy LD, Curry JM, Teresa TL, Nath S, Besmer D, Kidiyoor A, Dalia R, Gendler SJ, Mukherjee P (2012) MUC1 regulates PDGFA expression during pancreatic cancer progression. Oncogene 31(47):4935–4945. https://doi.org/10.1038/onc.2011.651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Polvani S, Tarocchi M, Tempesti S, Mello T, Ceni E, Buccoliero F, D’Amico M, Boddi V, Farsi M, Nesi S, Nesi G, Milani S, Galli A (2014) COUP-TFII in pancreatic adenocarcinoma: clinical implication for patient survival and tumor progression. Int J Cancer 134(7):1648–1658. https://doi.org/10.1002/ijc.28502

    Article  CAS  PubMed  Google Scholar 

  103. Ninomiya I, Yamazaki K, Oyama K, Hayashi H, Tajima H, Kitagawa H, Fushida S, Fujimura T, Ohta T (2014) Pioglitazone inhibits the proliferation and metastasis of human pancreatic cancer cells. Oncol Lett 8(6):2709–2714. https://doi.org/10.3892/ol.2014.2553

    Article  PubMed  PubMed Central  Google Scholar 

  104. Toole BP, Slomiany MG (2008) Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin Cancer Biol 18(4):244–250. https://doi.org/10.1016/j.semcancer.2008.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1):112–120. https://doi.org/10.1136/gutjnl-2012-302529

    Article  CAS  PubMed  Google Scholar 

  106. Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, Tjulandin SA, Gladkov OA, Holcombe RF, Korn R, Raghunand N, Dychter S, Jiang P, Shepard HM, Devoe CE (2016) Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res 22(12):2848–2854. https://doi.org/10.1158/1078-0432.ccr-15-2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Banerjee S, Modi S, McGinn O, Zhao X, Dudeja V, Ramakrishnan S, Saluja AK (2016) Impaired synthesis of stromal components in response to minnelide improves vascular function, drug delivery, and survival in pancreatic cancer. Clin Cancer Res 22(2):415–425. https://doi.org/10.1158/1078-0432.ccr-15-1155

    Article  CAS  PubMed  Google Scholar 

  108. Nagase H, Kudo D, Suto A, Yoshida E, Suto S, Negishi M, Kakizaki I, Hakamada K (2017) 4-Methylumbelliferone suppresses hyaluronan synthesis and tumor progression in SCID mice intra-abdominally inoculated with pancreatic cancer cells. Pancreas 46(2):190–197. https://doi.org/10.1097/mpa.0000000000000741

    Article  CAS  PubMed  Google Scholar 

  109. Nieskoski MD, Marra K, Gunn JR, Hoopes PJ, Doyley MM, Hasan T, Trembly BS, Pogue BW (2017) Collagen complexity spatially defines microregions of total tissue pressure in pancreatic cancer. Sci Rep 7(1):10093. https://doi.org/10.1038/s41598-017-10671-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Aguilera KY, Rivera LB, Hur H, Carbon JG, Toombs JE, Goldstein CD, Dellinger MT, Castrillon DH, Brekken RA (2014) Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res 74(4):1032–1044. https://doi.org/10.1158/0008-5472.can-13-2800

    Article  CAS  PubMed  Google Scholar 

  111. Berchtold S, Grunwald B, Kruger A, Reithmeier A, Hahl T, Cheng T, Feuchtinger A, Born D, Erkan M, Kleeff J, Esposito I (2015) Collagen type V promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Cancer Lett 356(2 Pt B):721–732. https://doi.org/10.1016/j.canlet.2014.10.020

    Article  CAS  PubMed  Google Scholar 

  112. Matsuo Y, Raimondo M, Woodward TA, Wallace MB, Gill KR, Tong Z, Burdick MD, Yang Z, Strieter RM, Hoffman RM, Guha S (2009) CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer. Int J Cancer 125(5):1027–1037. https://doi.org/10.1002/ijc.24383

    Article  CAS  PubMed  Google Scholar 

  113. Hill KS, Gaziova I, Harrigal L, Guerra YA, Qiu S, Sastry SK, Arumugam T, Logsdon CD, Elferink LA (2012) Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer. PLoS ONE 7(7):e40420. https://doi.org/10.1371/journal.pone.0040420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Matsuo Y, Ochi N, Sawai H, Yasuda A, Takahashi H, Funahashi H, Takeyama H, Tong Z, Guha S (2009) CXCL8/IL-8 and CXCL12/SDF-1alpha co-operatively promote invasiveness and angiogenesis in pancreatic cancer. Int J Cancer 124(4):853–861. https://doi.org/10.1002/ijc.24040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wente MN, Mayer C, Gaida MM, Michalski CW, Giese T, Bergmann F, Giese NA, Buchler MW, Friess H (2008) CXCL14 expression and potential function in pancreatic cancer. Cancer Lett 259(2):209–217. https://doi.org/10.1016/j.canlet.2007.10.021

    Article  CAS  PubMed  Google Scholar 

  116. Uzunoglu FG, Kolbe J, Wikman H, Gungor C, Bohn BA, Nentwich MF, Reeh M, Konig AM, Bockhorn M, Kutup A, Mann O, Izbicki JR, Vashist YK (2013) VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma. Ann Oncol 24(5):1282–1290. https://doi.org/10.1093/annonc/mds634

    Article  CAS  PubMed  Google Scholar 

  117. Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie B, Tada M, Mohri D, Miyabayashi K, Asaoka Y, Maeda S, Ikenoue T, Tateishi K, Wright CV, Koike K, Omata M, Moses HL (2011) Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. J Clin Invest 121(10):4106–4117. https://doi.org/10.1172/jci42754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Maeda S, Kuboki S, Nojima H, Shimizu H, Yoshitomi H, Furukawa K, Miyazaki M, Ohtsuka M (2017) Duffy antigen receptor for chemokines (DARC) expressing in cancer cells inhibits tumor progression by suppressing CXCR2 signaling in human pancreatic ductal adenocarcinoma. Cytokine 95:12–21. https://doi.org/10.1016/j.cyto.2017.02.007

    Article  CAS  PubMed  Google Scholar 

  119. Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL (2017) Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res 23(1):137–148. https://doi.org/10.1158/1078-0432.ccr-16-0870

    Article  CAS  PubMed  Google Scholar 

  120. Zhao B, Cui K, Wang CL, Wang AL, Zhang B, Zhou WY, Zhao WH, Li S (2011) The chemotactic interaction between CCL21 and its receptor, CCR7, facilitates the progression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis. J Hepatobiliary Pancreat Sci 18(6):821–828. https://doi.org/10.1007/s00534-011-0395-4

    Article  PubMed  Google Scholar 

  121. Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54. https://doi.org/10.1038/ng1060

    Article  CAS  PubMed  Google Scholar 

  122. Schaffner F, Ray AM, Dontenwill M (2013) Integrin alpha5beta1, the fibronectin receptor, as a pertinent therapeutic target in solid tumors. Cancers 5(1):27–47. https://doi.org/10.3390/cancers5010027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB, Ramakrishnan V (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61. https://doi.org/10.1186/1479-5876-5-61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, DuBridge RB, Ramakrishnan V (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs 26(1):7–12. https://doi.org/10.1007/s10637-007-9078-z

    Article  CAS  PubMed  Google Scholar 

  125. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071—22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1100–1108. https://doi.org/10.1016/s1470-2045(14)70379-1

    Article  CAS  PubMed  Google Scholar 

  126. Murphy PA, Begum S, Hynes RO (2015) Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors. PLoS ONE 10(3):e0120872. https://doi.org/10.1371/journal.pone.0120872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. St John AL, Chan CY, Staats HF, Leong KW, Abraham SN (2012) Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. Nat Mater 11(3):250–257. https://doi.org/10.1038/nmat3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR, Gouma DJ, van der Heide S, van den Wijngaard RM, de Jonge WJ, Boeckxstaens GE (2008) Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus. Gut 57(1):33–40. https://doi.org/10.1136/gut.2007.120238

    Article  CAS  PubMed  Google Scholar 

  129. Ma Y, Hwang RF, Logsdon CD, Ullrich SE (2013) Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res 73(13):3927–3937. https://doi.org/10.1158/0008-5472.can-12-4479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D (2004) Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57(6):630–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ammendola M, Sacco R, Sammarco G, Donato G, Zuccala V, Luposella M, Patruno R, Marech I, Montemurro S, Zizzo N, Gadaleta CD, Ranieri G (2014) Mast cells density positive to tryptase correlates with angiogenesis in pancreatic ductal adenocarcinoma patients having undergone surgery. Gastroenterol Res Pract 2014:951957. https://doi.org/10.1155/2014/951957

    Article  PubMed  PubMed Central  Google Scholar 

  132. Cai SW, Yang SZ, Gao J, Pan K, Chen JY, Wang YL, Wei LX, Dong JH (2011) Prognostic significance of mast cell count following curative resection for pancreatic ductal adenocarcinoma. Surgery 149(4):576–584. https://doi.org/10.1016/j.surg.2010.10.009

    Article  PubMed  Google Scholar 

  133. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13(10):1211–1218. https://doi.org/10.1038/nm1649

    Article  CAS  PubMed  Google Scholar 

  134. Guo X, Zhai L, Xue R, Shi J, Zeng Q, Gao C (2016) Mast cell tryptase contributes to pancreatic cancer growth through promoting angiogenesis via activation of angiopoietin-1. Int J Mol Sci. https://doi.org/10.3390/ijms17060834

    Article  PubMed  PubMed Central  Google Scholar 

  135. Marech I, Ammendola M, Sacco R, Capriuolo GS, Patruno R, Rubini R, Luposella M, Zuccala V, Savino E, Gadaleta CD, Ribatti D, Ranieri G (2014) Serum tryptase, mast cells positive to tryptase and microvascular density evaluation in early breast cancer patients: possible translational significance. BMC Cancer 14:534. https://doi.org/10.1186/1471-2407-14-534

    Article  PubMed  PubMed Central  Google Scholar 

  136. Ammendola M, Sacco R, Sammarco G, Donato G, Montemurro S, Ruggieri E, Patruno R, Marech I, Cariello M, Vacca A, Gadaleta CD, Ranieri G (2014) Correlation between serum tryptase, mast cells positive to tryptase and microvascular density in colo-rectal cancer patients: possible biological-clinical significance. PLoS ONE 9(6):e99512. https://doi.org/10.1371/journal.pone.0099512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zambirinis CP, Levie E, Nguy S, Avanzi A, Barilla R, Xu Y, Seifert L, Daley D, Greco SH, Deutsch M, Jonnadula S, Torres-Hernandez A, Tippens D, Pushalkar S, Eisenthal A, Saxena D, Ahn J, Hajdu C, Engle DD, Tuveson D, Miller G (2015) TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J Exp Med 212(12):2077–2094. https://doi.org/10.1084/jem.20142162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M (2017) Autophagy is required for activation of pancreatic stellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. Gastroenterology 152(6):1492–1506.e1424. https://doi.org/10.1053/j.gastro.2017.01.010

    Article  CAS  PubMed  Google Scholar 

  139. Qian D, Lu Z, Xu Q, Wu P, Tian L, Zhao L, Cai B, Yin J, Wu Y, Staveley-O’Carroll KF, Jiang K, Miao Y, Li G (2017) Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis. Cancer Lett 397:43–51. https://doi.org/10.1016/j.canlet.2017.03.024

    Article  CAS  PubMed  Google Scholar 

  140. Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, Riches JC, Marshall JF, Chin-Aleong J, Chelala C, Gribben JG, Ramsay AG, Kocher HM (2013) Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 145(5):1121–1132. https://doi.org/10.1053/j.gastro.2013.07.025

    Article  CAS  PubMed  Google Scholar 

  141. Mace TA, Bloomston M, Lesinski GB (2013) Pancreatic cancer-associated stellate cells: A viable target for reducing immunosuppression in the tumor microenvironment. Oncoimmunology 2(7):e24891. https://doi.org/10.4161/onci.24891

    Article  PubMed  PubMed Central  Google Scholar 

  142. Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress TM, Habisch HJ, Hwang RF, Jaster R, Kleeff J, Kloppel G, Kordes C, Logsdon CD, Masamune A, Michalski CW, Oh J, Phillips PA, Pinzani M, Reiser-Erkan C, Tsukamoto H, Wilson J (2012) StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61(2):172–178. https://doi.org/10.1136/gutjnl-2011-301220

    Article  CAS  PubMed  Google Scholar 

  143. Haqq J, Howells LM, Garcea G, Metcalfe MS, Steward WP, Dennison AR (2014) Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur J Cancer (Oxford England: 1990) 50(15):2570–2582. https://doi.org/10.1016/j.ejca.2014.06.021

    Article  Google Scholar 

  144. Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, Shimosegawa T (2008) Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 295(4):G709–G717. https://doi.org/10.1152/ajpgi.90356.2008

    Article  CAS  PubMed  Google Scholar 

  145. Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, Biankin AV, Goldstein D, Pirola RC, Wilson JS, Apte MV (2010) Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 177(5):2585–2596. https://doi.org/10.2353/ajpath.2010.090899

    Article  PubMed  PubMed Central  Google Scholar 

  146. Erkan M, Reiser-Erkan C, Michalski CW, Deucker S, Sauliunaite D, Streit S, Esposito I, Friess H, Kleeff J (2009) Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia (New York NY) 11(5):497–508

    Article  CAS  Google Scholar 

  147. Patel MB, Pothula SP, Xu Z, Lee AK, Goldstein D, Pirola RC, Apte MV, Wilson JS (2014) The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer. Carcinogenesis 35(8):1891–1900. https://doi.org/10.1093/carcin/bgu122

    Article  CAS  PubMed  Google Scholar 

  148. Pothula SP, Xu Z, Goldstein D, Biankin AV, Pirola RC, Wilson JS, Apte MV (2016) Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br J Cancer 114(3):269–280. https://doi.org/10.1038/bjc.2015.478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27(13):2231–2237. https://doi.org/10.1200/jco.2008.20.0238

    Article  PubMed  Google Scholar 

  150. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O’Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM (2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28(22):3617–3622. https://doi.org/10.1200/jco.2010.28.1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wen PY, Schiff D, Cloughesy TF, Raizer JJ, Laterra J, Smitt M, Wolf M, Oliner KS, Anderson A, Zhu M, Loh E, Reardon DA (2011) A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro-Oncology 13(4):437–446. https://doi.org/10.1093/neuonc/noq198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhu M, Tang R, Doshi S, Oliner KS, Dubey S, Jiang Y, Donehower RC, Iveson T, Loh EY, Zhang Y (2015) Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression. Br J Cancer 112(3):429–437. https://doi.org/10.1038/bjc.2014.649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604. https://doi.org/10.1016/j.immuni.2010.05.007

    Article  CAS  PubMed  Google Scholar 

  154. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167(2):e211–e219. https://doi.org/10.1016/j.jss.2009.05.026

    Article  PubMed  Google Scholar 

  155. Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, Kato Y, Aizawa M, Ochiai A (2012) Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci 103(11):2012–2020. https://doi.org/10.1111/j.1349-7006.2012.02411.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Dineen SP, Lynn KD, Holloway SE, Miller AF, Sullivan JP, Shames DS, Beck AW, Barnett CC, Fleming JB, Brekken RA (2008) Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res 68(11):4340–4346. https://doi.org/10.1158/0008-5472.can-07-6705

    Article  CAS  PubMed  Google Scholar 

  157. Penny HL, Sieow JL, Adriani G, Yeap WH, See Chi Ee P, San Luis B, Lee B, Lee T, Mak SY, Ho YS, Lam KP, Ong CK, Huang RY, Ginhoux F, Rotzschke O, Kamm RD, Wong SC (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5(8):e1191731. https://doi.org/10.1080/2162402x.2016.1191731

    Article  PubMed  PubMed Central  Google Scholar 

  158. Kurahara H, Takao S, Kuwahata T, Nagai T, Ding Q, Maeda K, Shinchi H, Mataki Y, Maemura K, Matsuyama T, Natsugoe S (2012) Clinical significance of folate receptor beta-expressing tumor-associated macrophages in pancreatic cancer. Ann Surg Oncol 19(7):2264–2271. https://doi.org/10.1245/s10434-012-2263-0

    Article  PubMed  Google Scholar 

  159. Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, Acevedo LM, Manglicmot JR, Song X, Wrasidlo W, Blair SL, Ginsberg MH, Cheresh DA, Hirsch E, Field SJ, Varner JA (2011) Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19(6):715–727. https://doi.org/10.1016/j.ccr.2011.04.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang SW, Kerbel RS, Varner JA (2011) Combined blockade of integrin-alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res 71(22):6965–6975. https://doi.org/10.1158/0008-5472.can-11-0588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Partecke LI, Gunther C, Hagemann S, Jacobi C, Merkel M, Sendler M, van Rooijen N, Kading A, Trung DN, Lorenz E, Diedrich S, Weiss FU, Heidecke CD, von Bernstorff W (2013) Induction of M2-macrophages by tumour cells and tumour growth promotion by M2-macrophages: a quid pro quo in pancreatic cancer. Pancreatology 13(5):508–516. https://doi.org/10.1016/j.pan.2013.06.010

    Article  CAS  PubMed  Google Scholar 

  162. Griesmann H, Drexel C, Milosevic N, Sipos B, Rosendahl J, Gress TM, Michl P (2017) Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. Gut 66(7):1278–1285. https://doi.org/10.1136/gutjnl-2015-310049

    Article  CAS  PubMed  Google Scholar 

  163. Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS (2017) The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2(Hi) macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol Cancer Ther 16(11):2486–2501. https://doi.org/10.1158/1535-7163.mct-17-0241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Li N, Li Y, Li Z, Huang C, Yang Y, Lang M, Cao J, Jiang W, Xu Y, Dong J, Ren H (2016) Hypoxia inducible factor 1 (HIF-1) recruits macrophage to activate pancreatic stellate cells in pancreatic ductal adenocarcinoma. Int J Mol Sci. https://doi.org/10.3390/ijms17060799

    Article  PubMed  PubMed Central  Google Scholar 

  165. Pyonteck SM, Gadea BB, Wang HW, Gocheva V, Hunter KE, Tang LH, Joyce JA (2012) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31(11):1459–1467. https://doi.org/10.1038/onc.2011.337

    Article  CAS  PubMed  Google Scholar 

  166. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24(6):695–709. https://doi.org/10.1016/j.ccr.2013.11.007

    Article  CAS  PubMed  Google Scholar 

  167. Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW (2009) A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4(8):e6562. https://doi.org/10.1371/journal.pone.0006562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bausch D, Pausch T, Krauss T, Hopt UT, Fernandez-del-Castillo C, Warshaw AL, Thayer SP, Keck T (2011) Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. Angiogenesis 14(3):235–243. https://doi.org/10.1007/s10456-011-9207-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, Ramachandran V, Sung B, Chakraborty A, Bresalier RS, Logsdon C, Aggarwal BB, Krishnan S, Guha S (2008) Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res 68(15):6100–6108. https://doi.org/10.1158/0008-5472.can-08-0540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Heath VL, Bicknell R (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6(7):395–404. https://doi.org/10.1038/nrclinonc.2009.52

    Article  CAS  PubMed  Google Scholar 

  171. Ivy SP, Wick JY, Kaufman BM (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6(10):569–579. https://doi.org/10.1038/nrclinonc.2009.130

    Article  CAS  PubMed  Google Scholar 

  172. Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 12(3):256–262. https://doi.org/10.1016/s1470-2045(11)70004-3

    Article  CAS  PubMed  Google Scholar 

  173. Goncalves A, Gilabert M, Francois E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL (2012) BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol 23(11):2799–2805. https://doi.org/10.1093/annonc/mds135

    Article  CAS  PubMed  Google Scholar 

  174. Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA (2013) Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer (Oxford England 1990) 49(12):2633–2642. https://doi.org/10.1016/j.ejca.2013.04.002

    Article  CAS  Google Scholar 

  175. Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A, Ishii H, Ohkawa S, Furukawa M, Maguchi H, Ikeda M, Togashi Y, Nishio K, Ohashi Y (2015) Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci 106(7):883–890. https://doi.org/10.1111/cas.12674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/nejm197111182852108

    Article  CAS  PubMed  Google Scholar 

  177. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544. https://doi.org/10.1200/jco.2006.09.6305

    Article  CAS  PubMed  Google Scholar 

  178. Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14(11):1131–1138. https://doi.org/10.1634/theoncologist.2009-0121

    Article  CAS  PubMed  Google Scholar 

  179. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. https://doi.org/10.1056/NEJMoa0708857

    Article  CAS  PubMed  Google Scholar 

  180. Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE (2010) Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 11(7):619–626. https://doi.org/10.1016/s1470-2045(10)70132-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals 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. https://doi.org/10.1016/j.ccr.2009.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 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. https://doi.org/10.1016/j.ccr.2009.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Ribatti D (2011) Antiangiogenic therapy accelerates tumor metastasis. Leuk Res 35(1):24–26. https://doi.org/10.1016/j.leukres.2010.07.038

    Article  PubMed  Google Scholar 

  184. Shao YY, Lu LC, Cheng AL, Hsu CH (2011) Increasing incidence of brain metastasis in patients with advanced hepatocellular carcinoma in the era of antiangiogenic targeted therapy. Oncologist 16(1):82–86. https://doi.org/10.1634/theoncologist.2010-0272

    Article  PubMed  PubMed Central  Google Scholar 

  185. Zhu XD, Sun HC, Xu HX, Kong LQ, Chai ZT, Lu L, Zhang JB, Gao DM, Wang WQ, Zhang W, Zhuang PY, Wu WZ, Wang L, Tang ZY (2013) Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models. Angiogenesis 16(4):809–820. https://doi.org/10.1007/s10456-013-9357-6

    Article  CAS  PubMed  Google Scholar 

  186. Yin T, He S, Ye T, Shen G, Wan Y, Wang Y (2014) Antiangiogenic therapy using sunitinib combined with rapamycin retards tumor growth but promotes metastasis. Transl Oncol 7(2):221–229. https://doi.org/10.1016/j.tranon.2014.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  187. Rofstad EK, Gaustad JV, Egeland TA, Mathiesen B, Galappathi K (2010) Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 127(7):1535–1546. https://doi.org/10.1002/ijc.25176

    Article  CAS  PubMed  Google Scholar 

  188. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 106(16):6742–6747. https://doi.org/10.1073/pnas.0902280106

    Article  PubMed  PubMed Central  Google Scholar 

  189. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9(4):239–252. https://doi.org/10.1038/nrc2618

    Article  CAS  PubMed  Google Scholar 

  190. Galluzzo M, Pennacchietti S, Rosano S, Comoglio PM, Michieli P (2009) Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis. J Clin Invest 119(4):865–875. https://doi.org/10.1172/jci36579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827. https://doi.org/10.1038/nature04186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. https://doi.org/10.1038/nrc2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP (2010) The autophagic tumor stroma model of cancer or “battery-operated tumor growth”: A simple solution to the autophagy paradox. Cell Cycle (Georgetown Tex) 9(21):4297–4306. https://doi.org/10.4161/cc.9.21.13817

    Article  CAS  Google Scholar 

  194. Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, Da Violante G, Gourlaouen M, Salih M, Jones MC, Jones DT, Saunders G, Kostourou V, Perron-Sierra F, Norman JC, Tucker GC, Hodivala-Dilke KM (2009) Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med 15(4):392–400. https://doi.org/10.1038/nm.1941

    Article  CAS  PubMed  Google Scholar 

  195. Elice F, Rodeghiero F, Falanga A, Rickles FR (2009) Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol 22(1):115–128. https://doi.org/10.1016/j.beha.2009.01.001

    Article  CAS  PubMed  Google Scholar 

  196. Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, Chen X, Walsh AJ, Skala MC, Moses HL, Merchant NB (2015) Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology 149(7):1932.e1939–1943.e1939. https://doi.org/10.1053/j.gastro.2015.07.058

    Article  CAS  Google Scholar 

  197. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453(7193):410–414. https://doi.org/10.1038/nature06868

    Article  CAS  PubMed  Google Scholar 

  198. Huang Y, Snuderl M, Jain RK (2011) Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. Cancer Cell 19(1):1–2. https://doi.org/10.1016/j.ccr.2011.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73(10):2943–2948. https://doi.org/10.1158/0008-5472.can-12-4354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wang WQ, Liu L, Sun HC, Fu YL, Xu HX, Chai ZT, Zhang QB, Kong LQ, Zhu XD, Lu L, Ren ZG, Tang ZY (2012) Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization. J Hematol Oncol 5:69. https://doi.org/10.1186/1756-8722-5-69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Zhang H, Ren Y, Tang X, Wang K, Liu Y, Zhang L, Li X, Liu P, Zhao C, He J (2015) Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis. Sci Rep 5:8888. https://doi.org/10.1038/srep08888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427. https://doi.org/10.1038/nrd3455

    Article  CAS  PubMed  Google Scholar 

  203. Astsaturov IA, Meropol NJ, Alpaugh RK, Burtness BA, Cheng JD, McLaughlin S, Rogatko A, Xu Z, Watson JC, Weiner LM, Cohen SJ (2011) Phase II and coagulation cascade biomarker study of bevacizumab with or without docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma. Am J Clin Oncol 34(1):70–75. https://doi.org/10.1097/COC.0b013e3181d2734a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, Burris H, Rosen P, Hidalgo M, Ritch P, Baker AF, Raghunand N, Crowley J, Von Hoff DD (2014) Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol 74(2):379–387. https://doi.org/10.1007/s00280-014-2499-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Lassau N, Coiffier B, Kind M, Vilgrain V, Lacroix J, Cuinet M, Taieb S, Aziza R, Sarran A, Labbe-Devilliers C, Gallix B, Lucidarme O, Ptak Y, Rocher L, Caquot LM, Chagnon S, Marion D, Luciani A, Feutray S, Uzan-Augui J, Benatsou B, Bonastre J, Koscielny S (2016) Selection of an early biomarker for vascular normalization using dynamic contrast-enhanced ultrasonography to predict outcomes of metastatic patients treated with bevacizumab. Ann Oncol 27(10):1922–1928. https://doi.org/10.1093/annonc/mdw280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Gore J, Craven KE, Wilson JL, Cote GA, Cheng M, Nguyen HV, Cramer HM, Sherman S, Korc M (2015) TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget 6(10):7504–7521. https://doi.org/10.18632/oncotarget.3233

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (81625016), the National Natural Science Foundation of China (81472670, 81402397, and 81402398), the National Natural Science Foundation of Shanghai (14ZR1407600), and the “Yang-Fan” Plan for Young Scientists of Shanghai (14YF1401100).

Author information

Author notes

  1. Shuo Li and Hua-Xiang Xu have contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China

    Shuo Li, Hua-Xiang Xu, Chun-Tao Wu, Wen-Quan Wang, Wei Jin, He-Li Gao, Hao Li, Shi-Rong Zhang, Jin-Zhi Xu, Zi-Hao Qi, Quan-Xing Ni, Xian-Jun Yu & Liang Liu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Shuo Li, Hua-Xiang Xu, Chun-Tao Wu, Wen-Quan Wang, Wei Jin, He-Li Gao, Hao Li, Shi-Rong Zhang, Jin-Zhi Xu, Zi-Hao Qi, Quan-Xing Ni, Xian-Jun Yu & Liang Liu

  3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

    Shuo Li, Hua-Xiang Xu, Chun-Tao Wu, Wen-Quan Wang, Wei Jin, He-Li Gao, Hao Li, Shi-Rong Zhang, Jin-Zhi Xu, Zi-Hao Qi, Quan-Xing Ni, Xian-Jun Yu & Liang Liu

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

    Shuo Li, Hua-Xiang Xu, Chun-Tao Wu, Wen-Quan Wang, Wei Jin, He-Li Gao, Hao Li, Shi-Rong Zhang, Jin-Zhi Xu, Zi-Hao Qi, Quan-Xing Ni, Xian-Jun Yu & Liang Liu

Authors
  1. Shuo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hua-Xiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chun-Tao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Quan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. He-Li Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shi-Rong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jin-Zhi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zi-Hao Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Quan-Xing Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xian-Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Liang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xian-Jun Yu or Liang Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Xu, HX., Wu, CT. et al. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis 22, 15–36 (2019). https://doi.org/10.1007/s10456-018-9645-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-018-9645-2

Keywords

Search

Navigation