Journal of Cancer Research and Clinical Oncology

, Volume 142, Issue 6, pp 1137–1161 | Cite as

Process of hepatic metastasis from pancreatic cancer: biology with clinical significance

  • Haojun Shi
  • Ji Li
  • Deliang Fu
Review – Cancer Research



Pancreatic cancer shows a remarkable preference for the liver to establish secondary tumors. Selective metastasis to the liver is attributed to the development of potential microenvironment for the survival of pancreatic cancer cells. This review aims to provide a full understanding of the hepatic metastatic process from circulating pancreatic cancer cells to their settlement in the liver, serving as a basic theory for efficient prediction and treatment of metastatic diseases.


A systematic search of relevant original articles and reviews was performed on PubMed, EMBASE and Cochrane Library for the purpose of this review.


Three interrelated phases are delineated as the contributions of the interaction between pancreatic cancer cells and the liver to hepatic metastasis process. Chemotaxis of disseminated pancreatic cancer cells and simultaneous defensive formation of platelets or neutrophils facilitate specific metastasis toward the liver. Remodeling of extracellular matrix and stromal cells in hepatic lobules and angiogenesis induced by proangiogenic factors support the survival and growth of clinical micrometastasis colonizing the liver. The bimodal role of the immune system or prevalence of cancer cells over the immune system makes metastatic progression successfully proceed from micrometastasis to macrometastasis.


Pancreatic cancer is an appropriate research object of cancer metastasis representing more than a straight cascade. If any of the successive or simultaneous phases, especially tumor-induced immunosuppression, is totally disrupted, hepatic metastasis will be temporarily under control or even cancelled forever. To shrink cancers on multiple fronts and prolong survival for patients, novel oral or intravenous anti-cancer agents covering one or different phases of metastatic pancreatic cancer are expected to be integrated into innovative strategies on the premise of safety and efficacious biostability.


Pancreatic cancer Hepatic metastasis Cell adhesion Remodeling of extracellular matrix Angiogenesis Tumor-induced immunosuppression 



The review was supported by the National Natural Science Foundation of China (Grant NO.81472221 and 81201896).

Compliance with ethical standards

Conflict of interest

We declare that we have no conflict of interest.

Ethical statement

This review does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

All authors have given their informed consent prior to their inclusion in the review and have agreed to submit the review in its present form.


  1. Abdelrahim M, Safe S (2005) Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol 68(2):317–329PubMedGoogle Scholar
  2. 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):6740–6749PubMedCrossRefGoogle Scholar
  3. 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):855–868PubMedCrossRefGoogle Scholar
  4. 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):3286–3294PubMedCrossRefGoogle Scholar
  5. Airoldi I, Cocco C, Morandi F, Prigione I, Pistoia V (2008) CXCR5 may be involved in the attraction of human metastatic neuroblastoma cells to the bone marrow. Cancer Immunol Immunother 57(4):541–548PubMedCrossRefGoogle Scholar
  6. Amedei A, Niccolai E, Benagiano M, Della Bella C, Cianchi F, Bechi P, Taddei A, Bencini L, Farsi M, Cappello P, Prisco D, Novelli F, D’Elios MM (2013) Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. Cancer Immunol Immunother 62(7):1249–1260PubMedCrossRefGoogle Scholar
  7. American Cancer Society (2014) Cancer facts and figures 2014. American Cancer Society, AtlantaGoogle Scholar
  8. Ando K, Takahashi F, Motojima S, Nakashima K, Kaneko N, Hoshi K, Takahashi K (2013) Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J Clin Oncol 31(6):e69–e72PubMedCrossRefGoogle Scholar
  9. Aosasa S, Ono S, Mochizuki H, Tsujimoto H, Osada S, Takayama E, Seki S, Hiraide H (2000) Activation of monocytes and endothelial cells depends on the severity of surgical stress. World J Surg 24(1):10–16PubMedCrossRefGoogle Scholar
  10. Aspinall AI, Curbishley SM, Lalor PF, Weston CJ, Blahova Miroslava, Liaskou E, Adams RM, Holt AP, Adams DH (2010) CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium. Hepatology 51(6):2030–2039PubMedPubMedCentralCrossRefGoogle Scholar
  11. Aviezer D, Cotton S, David M, Segev A, Khaselev N, Galili N, Gross Z, Yayon A (2000) Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis. Cancer Res 60(11):2973–2980PubMedGoogle Scholar
  12. Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, Horuk R, Sparre-Ulrich AH, Locati M, Luster AD, Mantovani A, Matsushima K, Murphy PM, Nibbs R, Nomiyama H, Power CA, Proudfoot AE, Rosenkilde MM, Rot A, Sozzani S, Thelen M, Yoshie O, Zlotnik A (2013) International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66(1):1–79PubMedCrossRefGoogle Scholar
  13. Banerjee T, Duhadaway JB, Gaspari P, Sutanto-Ward E, Munn DH, Mellor AL, Malachowski WP, Prendergast GC, Muller AJ (2008) A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene 27(20):2851–2857PubMedCrossRefGoogle Scholar
  14. Baribaud F, Edwards TG, Sharron M, Brelot A, Heveker N, Price K, Mortari F, Alizon M, Tsang M, Doms RW (2001) Antigenically distinct conformations of CXCR4. J Virol 75(19):8957–8967PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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):235–243PubMedPubMedCentralCrossRefGoogle Scholar
  16. Beauchamp RD, Lyons RM, Yang EY, Coffey RJ Jr, Moses HL (1990) Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines. Pancreas 5(4):369–380PubMedCrossRefGoogle Scholar
  17. Benson DD, Meng X, Fullerton DA, Moore EE, Lee JH, Ao L, Silliman CC, Barnett CC Jr (2012) Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma. Am J Physiol Regul Integr Comp Physiol 302(9):R1067–R1075PubMedPubMedCentralCrossRefGoogle Scholar
  18. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11(10):889–896PubMedCrossRefGoogle Scholar
  19. Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, Majdic O, Gajewski TF, Theobald M, Andreesen R, Mackensen A (2006) Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119(2):317–327PubMedCrossRefGoogle Scholar
  20. Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, Wilson D, Xu Q, Raz E (2008) Control of chemokine-guided cell migration by ligand sequestration. Cell 132(3):463–473PubMedCrossRefGoogle Scholar
  21. Bourd-Boittin K, Basset L, Bonnier D, L’helgoualc’h A, Samson M, Théret N (2009) CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver. J Cell Mol Med 13(8A):1526–1535PubMedPubMedCentralCrossRefGoogle Scholar
  22. Brennecke P, Arlt MJ, Campanile C, Husmann K, Gvozdenovic A, Apuzzo T, Thelen M, Born W, Fuchs B (2014) CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice. Clin Exp Metastasis 31(3):339–349PubMedPubMedCentralCrossRefGoogle Scholar
  23. Brodt P, Fallavollita L, Bresalier RS, Meterissian S, Norton CR, Wolitzky BA (1997) Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. Int J Cancer 71(4):612–619PubMedCrossRefGoogle Scholar
  24. Brown KM, Domin C, Aranha GV, Yong S, Shoup M (2005) Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am J Surg 189(3):278–282PubMedCrossRefGoogle Scholar
  25. Bürkle A, Niedermeier M, Schmitt-Gräff A, Wierda WG, Keating MJ, Burger JA (2007) Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood 110(9):3316–3325PubMedCrossRefGoogle Scholar
  26. Burns JM, Dairaghi DJ, Deitz M, Tsang M, Schall TJ (2002) Comprehensive mapping of poxvirus vCCI chemokine-binding protein. Expanded range of ligand interactions and unusual dissociation kinetics. J Biol Chem 277(4):2785–2789PubMedCrossRefGoogle Scholar
  27. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203(9):2201–2213PubMedPubMedCentralCrossRefGoogle Scholar
  28. Bursill CA, Cash JL, Channon KM, Greaves DR (2006) Membrane-bound CC chemokine inhibitor 35 K provides localized inhibition of CC chemokine activity in vitro and in vivo. J Immunol 177(8):5567–5573PubMedCrossRefGoogle Scholar
  29. Cady SG, Sono M (1991) 1-Methyl-dl-tryptophan, beta-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch Biochem Biophys 291(2):326–333PubMedCrossRefGoogle Scholar
  30. Cambien B, Richard-Fiardo P, Karimdjee BF, Martini V, Ferrua B, Pitard B, Schmid-Antomarchi H, Schmid-Alliana A (2011) CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRβ in colorectal carcinoma. PLoS ONE 6(12):e28842PubMedPubMedCentralCrossRefGoogle Scholar
  31. Cappello P, Tomaino B, Chiarle R, Ceruti P, Novarino A, Castagnoli C, Migliorini P, Perconti G, Giallongo A, Milella M, Monsurrò V, Barbi S, Scarpa A, Nisticò P, Giovarelli M, Novelli F (2009) An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer 125(3):639–648PubMedCrossRefGoogle Scholar
  32. Cardillo TM, Ying Z, Gold DV (2001) Therapeutic advantage of (90)yttrium- versus (131)iodine-labeled PAM4 antibody in experimental pancreatic cancer. Clin Cancer Res 7(10):3186–3192PubMedGoogle Scholar
  33. Celesti G, Di Caro G, Bianchi P, Grizzi F, Marchesi F, Basso G, Rahal D, Delconte G, Catalano M, Cappello P, Roncalli M, Zerbi A, Montorsi M, Novelli F, Mantovani A, Allavena P, Malesci A, Laghi L (2013) Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis. Br J Cancer 109(9):2424–2433PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chari A, Pri-Chen H, Jagannath S (2013) Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma. Clin Lymphoma Myeloma Leuk 13(3):333–337PubMedCrossRefGoogle Scholar
  35. Chase SD, Magnani JL, Simon SI (2012) E-selectin ligands as mechanosensitive receptors on neutrophils in health and disease. Ann Biomed Eng 40(4):849–859PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chen SH, Dallas MR, Balzer EM, Konstantopoulos K (2012) Mucin 16 is a functional selectin ligand on pancreatic cancer cells. FASEB J 26(3):1349–1359PubMedPubMedCentralCrossRefGoogle Scholar
  37. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67(19):9518–9527PubMedCrossRefGoogle Scholar
  38. Connolly MK, Mallen-St Clair J, Bedrosian AS, Malhotra A, Vera V, Ibrahim J, Henning J, Pachter HL, Bar-Sagi D, Frey AB, Miller G (2010) Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor. J Leukoc Biol 87(4):713–725PubMedPubMedCentralCrossRefGoogle Scholar
  39. Dambly-Chaudière C, Cubedo N, Ghysen A (2007) Control of cell migration in the development of the posterior lateral line: antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev Biol 7:23PubMedPubMedCentralCrossRefGoogle Scholar
  40. Dambrauskas Z, Svensson H, Joshi M, Hyltander A, Naredi P, Iresjö BM (2014) Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma. Int J Oncol 44(1):99–104PubMedGoogle Scholar
  41. Danielczyk A, Stahn R, Faulstich D, Löffler A, Märten A, Karsten U, Goletz S (2006) PankoMab: a potent new generation anti-tumour MUC1 antibody. Cancer Immunol Immunother 55(11):1337–1347PubMedCrossRefGoogle Scholar
  42. Décaillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P (2011) CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem 286(37):32188–32197PubMedPubMedCentralCrossRefGoogle Scholar
  43. Degen JL, Palumbo JS (2012) Hemostatic factors, innate immunity and malignancy. Thromb Res 129(Suppl 1):S1–S5PubMedCrossRefGoogle Scholar
  44. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS (2014) Jemal A (2014) Cancer treatment and survivorship statistics. CA Cancer J Clin 64(4):252–271PubMedCrossRefGoogle Scholar
  45. Deshane J, Garner CC, Sontheimer H (2003) Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem 278(6):4135–4144PubMedCrossRefGoogle Scholar
  46. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121(6):1845–1854PubMedGoogle Scholar
  47. Dong C, Slattery MJ, Rank BM, You J (2002) In vitro characterization and micromechanics of tumor cell chemotactic protrusion, locomotion, and extravasation. Ann Biomed Eng 30(3):344–355PubMedPubMedCentralCrossRefGoogle Scholar
  48. Dotor J, López-Vázquez AB, Lasarte JJ, Sarobe P, García-Granero M, Riezu-Boj JI, Martínez A, Feijoó E, López-Sagaseta J, Hermida J, Prieto J, Borrás-Cuesta F (2007) Identification of peptide inhibitors of transforming growth factor beta 1 using a phage-displayed peptide library. Cytokine 39(2):106–115PubMedCrossRefGoogle Scholar
  49. Dziadek S, Kunz H (2004) Synthesis of tumor-associated glycopeptide antigens for the development of tumor-selective vaccines. Chem Rec 3(6):308–321PubMedCrossRefGoogle Scholar
  50. Efsen E, Grappone C, DeFranco RM, Milani S, Romanelli RG, Bonacchi A, Caligiuri A, Failli P, Annunziato F, Pagliai G, Pinzani M, Laffi G, Gentilini P, Marra F (2002) Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans. J Hepatol 37(1):39–47PubMedCrossRefGoogle Scholar
  51. El Haibi CP, Sharma PK, Singh R, Johnson PR, Suttles J, Singh S, Lillard JW Jr (2010) PI3Kp110-, Src-, FAK-dependent and DOCK2-independent migration and invasion of CXCL13-stimulated prostate cancer cells. Mol Cancer 9:85PubMedPubMedCentralCrossRefGoogle Scholar
  52. El Kholy NM, Sallam MM, Ahmed MB, Sallam RM, Asfour IA, Hammouda JA, Habib HZ, Abu-Zahra F (2011) Expression of indoleamine 2,3-dioxygenase in acute myeloid leukemia and the effect of its inhibition on cultured leukemia blast cells. Med Oncol 28(1):270–278PubMedCrossRefGoogle Scholar
  53. El-Ghlban S, Kasai T, Shigehiro T, Yin HX, Sekhar S, Ida M, Sanchez A, Mizutani A, Kudoh T, Murakami H, Seno M (2014) Chlorotoxin-Fc fusion inhibits release of MMP-2 from pancreatic cancer cells. Biomed Res Int 2014:152659PubMedPubMedCentralCrossRefGoogle Scholar
  54. Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9(8):454–467PubMedCrossRefGoogle Scholar
  55. Erpenbeck L, Schön MP (2010) Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 115(17):3427–3436PubMedPubMedCentralCrossRefGoogle Scholar
  56. Ewing J (1928) Neoplastic diseases, 6th edn. W. B. Sanders, PhiladelphiaGoogle Scholar
  57. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761PubMedCrossRefGoogle Scholar
  58. Fannon M, Forsten-Williams K, Nugent MA, Gregory KJ, Chu CL, Goerges-Wildt AL, Panigrahy D, Kaipainen A, Barnes C, Lapp C, Shing Y (2008) Sucrose octasulfate regulates fibroblast growth factor-2 binding, transport, and activity: potential for regulation of tumor growth. J Cell Physiol 215(2):434–441PubMedPubMedCentralCrossRefGoogle Scholar
  59. Faouzi S, Lepreux S, Bedin C, Dubuisson L, Balabaud C, Bioulac-Sage P, Desmoulière A, Rosenbaum J (1999) Activation of cultured rat hepatic stellate cells by tumoral hepatocytes. Lab Invest 79(4):485–493PubMedGoogle Scholar
  60. Ferro V, Dredge K, Liu L, Hammond E, Bytheway I, Li C, Johnstone K, Karoli T, Davis K, Copeman E, Gautam A (2007) PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 33(5):557–568Google Scholar
  61. Fong AM, Premont RT, Richardson RM, Yu YR, Lefkowitz RJ, Patel DD (2002) Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci U S A 99(11):7478–7483PubMedPubMedCentralCrossRefGoogle Scholar
  62. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034PubMedPubMedCentralCrossRefGoogle Scholar
  63. Freitas C, Desnoyer A, Meuris F, Bachelerie F, Balabanian K, Machelon V (2014) The relevance of the chemokine receptor ACKR3/CXCR7 on CXCL12-mediated effects in cancers with a focus on virus-related cancers. Cytokine Growth Factor Rev 25(3):307–316PubMedCrossRefGoogle Scholar
  64. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16(3):183–194PubMedPubMedCentralCrossRefGoogle Scholar
  65. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H (2004) CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28(1):e26–e31PubMedCrossRefGoogle Scholar
  66. Galustian C, Childs RA, Stoll M, Ishida H, Kiso M, Feizi T (2002) Synergistic interactions of the two classes of ligand, sialyl-Lewis(a/x) fuco-oligosaccharides and short sulpho-motifs, with the P- and L-selectins: implications for therapeutic inhibitor designs. Immunology 105(3):350–359PubMedPubMedCentralCrossRefGoogle Scholar
  67. Gastpar H, Ambrus JL, Ambrus CM (1982) Platelet cancer cell interaction in metastasis formation. Platelet aggregation inhibitors: a possible approach to metastasis prevention. Prog Clin Biol Res 89:63–82PubMedGoogle Scholar
  68. Gebauer F, Wicklein D, Stübke K, Nehmann N, Schmidt A, Salamon J, Peldschus K, Nentwich MF, Adam G, Tolstonog G, Bockhorn M, Izbicki JR, Wagener C, Schumacher U (2013) Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp–/rag2– mice. Gut 62(5):741–750PubMedCrossRefGoogle Scholar
  69. Gil-Guerrero L, Dotor J, Huibregtse IL, Casares N, López-Vázquez AB, Rudilla F, Riezu-Boj JI, López-Sagaseta J, Hermida J, Van Deventer S, Bezunartea J, Llopiz D, Sarobe P, Prieto J, Borrás-Cuesta F, Lasarte JJ (2008) In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. J Immunol 181(1):126–135PubMedCrossRefGoogle Scholar
  70. Gold DV, Cardillo T, Goldenberg DM, Sharkey RM (2001) Localization of pancreatic cancer with radiolabeled monoclonal antibody PAM4. Crit Rev Oncol Hematol 39(1–2):147–154PubMedCrossRefGoogle Scholar
  71. Goydos JS, Elder E, Whiteside TL, Finn OJ, Lotze MT (1996) A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma. J Surg Res 63(1):298–304PubMedCrossRefGoogle Scholar
  72. Gravel S, Malouf C, Boulais PE, Berchiche YA, Oishi S, Fujii N, Leduc R, Sinnett D, Heveker N (2010) The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem 285(49):37939–37943PubMedPubMedCentralCrossRefGoogle Scholar
  73. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899PubMedPubMedCentralCrossRefGoogle Scholar
  74. Grymula K, Tarnowski M, Wysoczynski M, Drukala J, Barr FG, Ratajczak J, Kucia M, Ratajczak MZ (2010) Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas. Int J Cancer 127(11):2554–2568PubMedPubMedCentralCrossRefGoogle Scholar
  75. Gulec SA, Cohen SJ, Pennington KL, Zuckier LS, Hauke RJ, Horne H, Wegener WA, Teoh N, Gold DV, Sharkey RM, Goldenberg DM (2011) Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial. Clin Cancer Res 17(12):4091–4100PubMedPubMedCentralCrossRefGoogle Scholar
  76. Guleng B, Tateishi K, Ohta M, Kanai F, Jazag A, Ijichi H, Tanaka Y, Washida M, Morikane K, Fukushima Y, Yamori T, Tsuruo T, Kawabe T, Miyagishi M, Taira K, Sata M, Omata M (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 65(13):5864–5871PubMedCrossRefGoogle Scholar
  77. Hanaoka H, Mukai T, Tamamura H, Mori T, Ishino S, Ogawa K, Iida Y, Doi R, Fujii N, Saji H (2006) Development of a 111In-labeled peptide derivative targeting a chemokine receptor, CXCR4, for imaging tumors. Nucl Med Biol 33(4):489–494PubMedCrossRefGoogle Scholar
  78. Haq M, Shafii A, Zervos EE, Rosemurgy AS (2000) Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer. Cancer Res 60(12):3207–3211PubMedGoogle Scholar
  79. Hassan S, Buchanan M, Jahan K, Aguilar-Mahecha A, Gaboury L, Muller WJ, Alsawafi Y, Mourskaia AA, Siegel PM, Salvucci O, Basik M (2011) CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int J Cancer 129(1):225–232PubMedCrossRefGoogle Scholar
  80. Hattermann K, Mentlein R (2013) An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Ann Anat 195(2):103–110PubMedCrossRefGoogle Scholar
  81. Hattermann K, Held-Feindt J, Lucius R, Müerköster SS, Penfold ME, Schall TJ, Mentlein R (2010) The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 70(8):3299–3308PubMedCrossRefGoogle Scholar
  82. He Y, Song W, Lei J, Li Z, Cao J, Huang S, Meng J, Xu H, Jin Z, Xue H (2012) Anti-CXCR4 monoclonal antibody conjugated to ultrasmall superparamagnetic iron oxide nanoparticles in an application of MR molecular imaging of pancreatic cancer cell lines. Acta Radiol 53(9):1049–1058PubMedCrossRefGoogle Scholar
  83. Hendrix CW, Collier AC, Lederman MM, Schols D, Pollard RB, Brown S, Jackson JB, Coombs RW, Glesby MJ, Flexner CW, Bridger GJ, Badel K, MacFarland RT, Henson GW, Calandra G; AMD3100 HIV Study Group (2004) Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 37(2):1253–1262CrossRefGoogle Scholar
  84. Hernandez L, Magalhaes MA, Coniglio SJ, Condeelis JS, Segall JE (2011) Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis. Breast Cancer Res 13(6):R128PubMedPubMedCentralCrossRefGoogle Scholar
  85. Higashi K, Asano K, Yagi M, Yamada K, Arakawa T, Ehashi T, Mori T, Sumida K, Kushida M, Ando S, Kinoshita M, Kakehi K, Tachibana T, Saito K (2014) Expression of the clustered NeuAcα2-3Galβ O-glycan determines the cell differentiation state of the cells. J Biol Chem 289(37):25833–25843PubMedPubMedCentralCrossRefGoogle Scholar
  86. Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12(18):5423–5434PubMedCrossRefGoogle Scholar
  87. Ho M, Feng M, Fisher RJ, Rader C, Pastan I (2011) A novel high-affinity human monoclonal antibody to mesothelin. Int J Cancer 128(9):2020–2030PubMedPubMedCentralCrossRefGoogle Scholar
  88. Honn KV, Tang DG, Crissman JD (1992) Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 11(3–4):325–351PubMedCrossRefGoogle Scholar
  89. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801PubMedCrossRefGoogle Scholar
  90. Huang RB, Eniola-Adefeso O (2012) Shear stress modulation of IL-1β-induced E-selectin expression in human endothelial cells. PLoS ONE 7(2):e31874PubMedPubMedCentralCrossRefGoogle Scholar
  91. Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, Vilardell F, Wang Z, Keller JW, Banerjee P, Herman JM, Cameron JL, Yeo CJ, Halushka MK, Eshleman JR, Raben M, Klein AP, Hruban RH, Hidalgo M, Laheru D (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27(11):1806–1813PubMedPubMedCentralCrossRefGoogle Scholar
  92. Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, Maekawa Y, Yasutomo K, Shimada M (2006) Clinical roles of increased populations of Foxp3+ CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 33(4):386–390PubMedCrossRefGoogle Scholar
  93. Iki K, Tsutsumi M, Kido A, Sakitani H, Takahama M, Yoshimoto M, Motoyama M, Tatsumi K, Tsunoda T, Konishi Y (1999) Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine. Carcinogenesis 20(7):1323–1329PubMedCrossRefGoogle Scholar
  94. Imamura T, Iguchi H, Manabe T, Ohshio G, Yoshimura T, Wang ZH, Suwa H, Ishigami S, Imamura M (1995) Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis. Pancreas 11(4):357–364PubMedCrossRefGoogle Scholar
  95. Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N (2013) Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108(4):914–923PubMedPubMedCentralCrossRefGoogle Scholar
  96. Ischenko I, Guba M, Yezhelyev M, Papyan A, Schmid G, Green T, Fennell M, Jauch KW, Bruns CJ (2007) Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer. Angiogenesis 10(3):167–182PubMedCrossRefGoogle Scholar
  97. Iwamura T, Caffrey TC, Kitamura N, Yamanari H, Setoguchi T, Hollingsworth MA (1997) P-selectin expression in a metastatic pancreatic tumor cell line (SUIT-2). Cancer Res 57(6):1206–1212PubMedGoogle Scholar
  98. Jähnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY, Bosch L, De Vrieze S, Serruys B, Ulrichts H, Vandevelde W, Saunders M, De Haard HJ, Schols D, Leurs R, Vanlandschoot P, Verrips T, Smit MJ (2010) CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proc Natl Acad Sci U S A 107(47):20565–20570PubMedPubMedCentralCrossRefGoogle Scholar
  99. Ji SQ, Cao J, Zhang QY, Li YY, Yan YQ, Yu FX (2013) Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion. Braz J Med Biol Res 46(9):758–764PubMedPubMedCentralCrossRefGoogle Scholar
  100. Justinger C, Schlüter C, Oliviera-Frick V, Kopp B, Rubie C, Schilling MK (2008) Increased growth factor expression after hepatic and pancreatic resection. Oncol Rep 20(6):1527–1531PubMedGoogle Scholar
  101. Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N (2009) AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol 75(5):1240–1247PubMedCrossRefGoogle Scholar
  102. Kamisawa T, Isawa T, Koike M, Tsuruta K, Okamoto A (1995) Hematogenous metastases of pancreatic ductal carcinoma. Pancreas 11(4):345–349PubMedCrossRefGoogle Scholar
  103. Kang N, Gores GJ, Shah VH (2011) Hepatic stellate cells: partners in crime for liver metastases? Hepatology 54(2):707–713PubMedPubMedCentralCrossRefGoogle Scholar
  104. Kashima K, Watanabe M, Sato Y, Hata J, Ishii N, Aoki Y (2014) Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor-4. Cancer Sci 105(10):1343–1350PubMedPubMedCentralCrossRefGoogle Scholar
  105. Khatib AM, Auguste P, Fallavollita L, Wang N, Samani A, Kontogiannea M, Meterissian S, Brodt P (2005) Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol 167(3):749–759PubMedPubMedCentralCrossRefGoogle Scholar
  106. Kilian M, Gregor JI, Heukamp I, Hanel M, Ahlgrimm M, Schimke I, Kristiansen G, Ommer A, Walz MK, Jacobi CA, Wenger FA (2006) Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer. Prostaglandins Leukot Essent Fatty Acids 75(6):429–434PubMedCrossRefGoogle Scholar
  107. Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, Hong SH, Ren L, Wong D, Korz W, Merzouk A, Salari H, Zhang H, Hwang ST, Khanna C, Helman LJ (2008) Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis 25(3):201–211PubMedPubMedCentralCrossRefGoogle Scholar
  108. Kim J, Yip ML, Shen X, Li H, Hsin LY, Labarge S, Heinrich EL, Lee W, Lu J, Vaidehi N (2012) Identification of anti-malarial compounds as novel antagonists to chemokine receptor CXCR4 in pancreatic cancer cells. PLoS ONE 7(2):e31004PubMedPubMedCentralCrossRefGoogle Scholar
  109. Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174:21–34PubMedCrossRefGoogle Scholar
  110. Kobayashi N, Kubota K, Kato S, Watanabe S, Shimamura T, Kirikoshi H, Saito S, Ueda M, Endo I, Inayama Y, Maeda S, Nakajima A (2010) FOXP3+ regulatory T cells and tumoral indoleamine 2,3-dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 10(5):631–640PubMedCrossRefGoogle Scholar
  111. Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS (2010) Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther 9(2):489–498PubMedCrossRefGoogle Scholar
  112. Korc M (2007) Pancreatic cancer-associated stroma production. Am J Surg 194(4 Suppl):S84–S86PubMedPubMedCentralCrossRefGoogle Scholar
  113. Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res 6(9):3530–3535PubMedGoogle Scholar
  114. Kowarik MC, Cepok S, Sellner J, Grummel V, Weber MS, Korn T, Berthele A, Hemmer B (2012) CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation 9:93PubMedPubMedCentralCrossRefGoogle Scholar
  115. Krieg A, Riemer JC, Telan LA, Gabbert HE, Knoefel WT (2015) CXCR4-A Prognostic and clinicopathological biomarker for pancreatic ductal adenocarcinoma: a meta-analysis. PLoS One 10(6):e0130192PubMedPubMedCentralCrossRefGoogle Scholar
  116. Kuniyasu H, Abbruzzese JL, Cleary KR, Fidler IJ (2001) Induction of ductal and stromal hyperplasia by basic fibroblast growth factor produced by human pancreatic carcinoma. Int J Oncol 19(4):681–685PubMedGoogle Scholar
  117. 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–e219PubMedCrossRefGoogle Scholar
  118. Lasky LA (1992) Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science 258(5084):964–969PubMedCrossRefGoogle Scholar
  119. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268PubMedCrossRefGoogle Scholar
  120. Läubli H, Borsig L (2010) Selectins promote tumor metastasis. Semin Cancer Biol 20(3):169–177PubMedCrossRefGoogle Scholar
  121. Lee Y, Kim SJ, Park HD, Park EH, Huang SM, Jeon SB, Kim JM, Lim DS, Koh SS (2010) PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression. Oncogene 29(1):56–67PubMedCrossRefGoogle Scholar
  122. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 187(4):655–660PubMedPubMedCentralCrossRefGoogle Scholar
  123. Lekstan A, Lampe P, Lewin-Kowalik J, Olakowski M, Jablonska B, Labuzek K, Jedrzejowska-Szypulka H, Olakowska E, Gorka D, Filip I, Dranka-Bojarowska D (2012) Concentrations and activities of metalloproteinases 2 and 9 and their inhibitors (TIMPS) in chronic pancreatitis and pancreatic adenocarcinoma. J Physiol Pharmacol 63(6):589–599PubMedGoogle Scholar
  124. Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, Geller BA, Schmotzer A, Potter DP, Whiteside T, Finn OJ, Ramanathan RK (2008) A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther 6(B):955–964PubMedPubMedCentralGoogle Scholar
  125. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057PubMedCrossRefGoogle Scholar
  126. Li D, Wang H, Xiang JJ, Deng N, Wang PP, Kang YL, Tao J, Xu M (2010) Monoclonal antibodies targeting basic fibroblast growth factor inhibit the growth of B16 melanoma in vivo and in vitro. Oncol Rep 24(2):457–463PubMedGoogle Scholar
  127. Li Q, Gao S, Yu Y, Wang W, Chen X, Wang R, Li T, Wang C, Li X, Wu X (2012) A novel bFGF antagonist peptide inhibits breast cancer cell growth. Mol Med Rep 6(1):210–214PubMedGoogle Scholar
  128. Liang Z, Zhan W, Zhu A, Yoon Y, Lin S, Sasaki M, Klapproth JM, Yang H, Grossniklaus HE, Xu J, Rojas M, Voll RJ, Goodman MM, Arrendale RF, Liu J, Yun CC, Snyder JP, Liotta DC, Shim H (2012) Development of a unique small molecule modulator of CXCR4. PLoS ONE 7(4):e34038PubMedPubMedCentralCrossRefGoogle Scholar
  129. Lim JY, Lee SE, Park G, Choi EY, Min CK (2014) Inhibition of indoleamine 2,3-dioxygenase by stereoisomers of 1-methyl tryptophan in an experimental graft-versus-tumor model. Exp Hematol 42(10):862-866.e3CrossRefGoogle Scholar
  130. Lin N, Chen Z, Lu Y, Li Y, Hu K, Xu R (2014) Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma. Hepatol Res 45(3):326–336PubMedCrossRefGoogle Scholar
  131. Ling X, Spaeth E, Chen Y, Shi Y, Zhang W, Schober W, Hail N Jr, Konopleva M, Andreeff M (2013) The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo. PLoS ONE 8(3):e58426PubMedPubMedCentralCrossRefGoogle Scholar
  132. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA (2010) Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115(17):3520–3530PubMedCrossRefGoogle Scholar
  133. Liu C, Billadeau DD, Abdelhakim H, Leof E, Kaibuchi K, Bernabeu C, Bloom GS, Yang L, Boardman L, Shah VH, Kang N (2013) IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver. J Clin Invest 123(3):1138–1156PubMedPubMedCentralCrossRefGoogle Scholar
  134. Liyanage UK, Goedegebuure PS, Moore TT, Viehl CT, Moo-Young TA, Larson JW, Frey DM, Ehlers JP, Eberlein TJ, Linehan DC (2006) Increased prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother 29(4):416–424PubMedCrossRefGoogle Scholar
  135. Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, Laschinger M, Büchler MW, Friess H (2008) Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Let 268(1):98–109CrossRefGoogle Scholar
  136. Lui GY, Kovacevic Z, Menezes SV, Kalinowski DS, Merlot AM, Sahni S, Richardson DR (2015) Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion. Mol Pharmacol 87(3):543–560PubMedCrossRefGoogle Scholar
  137. Luker KE, Lewin SA, Mihalko LA, Schmidt BT, Winkler JS, Coggins NL, Thomas DG, Luker GD (2012) Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene 31(45):4750–4758PubMedPubMedCentralCrossRefGoogle Scholar
  138. Luo W, Yu Y, Wang R, He D, Wang C, Zeng X, Chen X, Tan X, Huang T, Wu X (2014) P7 peptides targeting bFGF sensitize colorectal cancer cells to CPT-11. Int J Mol Med 33(1):194–200PubMedGoogle Scholar
  139. Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A 98(5):2449–2454PubMedPubMedCentralCrossRefGoogle Scholar
  140. Lutz MP, Esser IB, Flossmann-Kast BB, Vogelmann R, Lührs H, Friess H, Büchler MW, Adler G (1998) Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem Biophys Res Commun 243(2):503–508PubMedCrossRefGoogle Scholar
  141. Ma WF, Du J, Fu LP, Fang R, Chen HY, Cai SH (2009) Phenotypic knockout of CXCR4 by a novel recombinant protein TAT/54R/KDEL inhibits tumors metastasis. Mol Cancer Res 7(10):1613–1621PubMedCrossRefGoogle Scholar
  142. MacDonald IC, Schmidt EE, Morris VL, Chambers AF, Groom AC (1992) Intravital videomicroscopy of the chorioallantoic microcirculation: a model system for studying metastasis. Microvasc Res 44(2):185–199PubMedCrossRefGoogle Scholar
  143. Macgregor-Das AM, Iacobuzio-Donahue CA (2013) Molecular pathways in pancreatic carcinogenesis. J Surg Oncol 107(1):8–14PubMedPubMedCentralCrossRefGoogle Scholar
  144. Maehara N, Matsumoto K, Kuba K, Mizumoto K, Tanaka M, Nakamura T (2001) NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells. Br J Cancer 84(6):864–873PubMedPubMedCentralCrossRefGoogle Scholar
  145. Maehara N, Nagai E, Mizumoto K, Sato N, Matsumoto K, Nakamura T, Narumi K, Nukiwa T, Tanaka M (2002) Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer. Clin Exp Metastasis 19(5):417–426PubMedCrossRefGoogle Scholar
  146. Maitra A, Hruban RH (2008) Pancreatic cancer. Annu Rev Pathol 3:157–188PubMedPubMedCentralCrossRefGoogle Scholar
  147. Majuri ML, Mattila P, Renkonen R (1992) Recombinant E-selectin-protein mediates tumor cell adhesion via sialyl-Le(a) and sialyl-Le(x). Biochem Biophys Res Commun 182(3):1376–1382PubMedCrossRefGoogle Scholar
  148. Makrilia N, Kollias A, Manolopoulos L, Syrigos K (2009) Cell adhesion molecules: role and clinical significance in cancer. Cancer Invest 27(10):1023–1037PubMedCrossRefGoogle Scholar
  149. Mamelak AN, Jacoby DB (2007) Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601). Expert Opin Drug Deliv 4(2):175–186PubMedCrossRefGoogle Scholar
  150. Mantovani A, Romero P, Palucka AK, Marincola FM (2008) Tumor immunity: effector response to tumor and role of the microenvironment. Lancet 371(9614):771–783PubMedCrossRefGoogle Scholar
  151. Mao C, Domenico DR, Kim K, Hanson DJ, Howard JM (1995) Observations on the developmental patterns and the consequences of pancreatic exocrine adenocarcinoma: findings of 154 autopsies. Arch Surg 130(2):125–134PubMedCrossRefGoogle Scholar
  152. Marchesi F, Monti P, Leone BE, Zerbi A, Vecchi A, Piemonti L, Mantovani A, Allavena P (2004) Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer Res 64(22):8420–8427PubMedCrossRefGoogle Scholar
  153. Marchesi F, Piemonti L, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A, Doni A, Bianchi P, Laghi L, Malesci A, Cervo L, Malosio M, Reni M, Zerbi A, Di Carlo V, Mantovani A, Allavena P (2008) The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res 68(21):9060–9069PubMedCrossRefGoogle Scholar
  154. Marcos-Ramiro B, García-Weber D, Millán J (2014) TNF-induced endothelial barrier disruption: beyond actin and Rho. Thromb Haemost 112(6):1088–1102PubMedCrossRefGoogle Scholar
  155. Matthaei H, Schulick RD, Hruban RH, Maitra A (2011) Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol 8(3):141–150PubMedPubMedCentralCrossRefGoogle Scholar
  156. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290(5496):1574–1577PubMedCrossRefGoogle Scholar
  157. Medina-Echeverz J, Fioravanti J, Díaz-Valdés N, Frank K, Aranda F, Gomar C, Ardaiz N, Dotor J, Umansky V, Prieto J, Berraondo P (2014) Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases. PLoS ONE 9(5):e96799PubMedPubMedCentralCrossRefGoogle Scholar
  158. Meijer J, Zeelenberg IS, Sipos B, Roos E (2006) The CXCR5 chemokine receptor is expressed by carcinoma cells and promotes growth of colon carcinoma in the liver. Cancer Res 66(19):9576–9582PubMedCrossRefGoogle Scholar
  159. Metz R, Duhadaway JB, Rust S, Munn DH, Muller AJ, Mautino M, Prendergast GC (2010) Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Mol Cancer Ther 9(6):1864–1871PubMedPubMedCentralCrossRefGoogle Scholar
  160. Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, Pasquali C, Calori G, Pessi F, Sperti C, Di Carlo V, Allavena P, Piemonti L (2003) The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 63(21):7451–7461PubMedGoogle Scholar
  161. Moo-Young TA, Larson JW, Belt BA, Tan MC, Hawkins WG, Eberlein TJ, Goedegebuure PS, Linehan DC (2009) Tumor-derived TGF-beta mediates conversion of CD4+ Foxp3+ regulatory T cells in a murine model of pancreas cancer. J Immunother 32(1):12–21PubMedCrossRefGoogle Scholar
  162. Moretti S, Menicali E, Voce P, Morelli S, Cantarelli S, Sponziello M, Colella R, Fallarino F, Orabona C, Alunno A, de Biase D, Bini V, Mameli MG, Filetti S, Gerli R, Macchiarulo A, Melillo RM, Tallini G, Santoro M, Puccetti P, Avenia N, Puxeddu E (2014) Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment. J Clin Endocrinol Metab 99(5):E832–E840PubMedCrossRefGoogle Scholar
  163. Mori T, Doi R, Koizumi M, Toyoda E, Ito D, Kami K, Masui T, Fujimoto K, Tamamura H, Hiramatsu K, Fujii N, Imamura M (2004a) CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther 3(1):29–37PubMedGoogle Scholar
  164. Mori T, Doi R, Koizumi M, Toyoda E, Ito D, Kami K, Masui T, Fujimoto K, Tamamura H, Hiramatsu K, Fujii N, Imamura M (2004b) CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther 3(1):29–37PubMedGoogle Scholar
  165. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11(3):312–319PubMedCrossRefGoogle Scholar
  166. Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R, Prendergast GC (2010) Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res 70(5):1845–1853PubMedPubMedCentralCrossRefGoogle Scholar
  167. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154PubMedPubMedCentralCrossRefGoogle Scholar
  168. Nagakawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y (2002) Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas 24(2):169–178PubMedCrossRefGoogle Scholar
  169. Nakahashi C, Oda T, Kinoshita T, Ueda T, Konishi M, Nakagohri T, Inoue K, Furuse J, Ochiai A, Ohkohchi N (2003) The impact of liver metastasis on mortality in patients initially diagnosed with locally advanced or resectable pancreatic cancer. Int J Gastrointest Cancer 33(2–3):155–164PubMedCrossRefGoogle Scholar
  170. Nakatani K, Kaneda K, Seki S, Nakajima Y (2004) Pit cells as liver-associated natural killer cells: morphology and function. Med Electron Microsc 37(1):29–36PubMedCrossRefGoogle Scholar
  171. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121–124PubMedCrossRefGoogle Scholar
  172. Nguyen DX, Massagué J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352PubMedCrossRefGoogle Scholar
  173. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 103(33):12493–12498PubMedPubMedCentralCrossRefGoogle Scholar
  174. Nummer D, Suri-Payer E, Schmitz-Winnenthal H, Bonertz A, Galindo L, Antolovich D, Koch M, Büchler M, Weitz J, Schirrmacher V, Beckhove P (2007) Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst 99(15):1188–1199PubMedCrossRefGoogle Scholar
  175. Oettle H et al (2012) Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. J Clin Oncol 30:4034Google Scholar
  176. Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, Ishii N, Yanaihara N, Yamada K, Takikawa O, Kawaguchi R, Isonishi S, Tanaka T, Urashima M (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11(16):6030–6039PubMedCrossRefGoogle Scholar
  177. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 98(24):13866–13871PubMedPubMedCentralCrossRefGoogle Scholar
  178. Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao S, Azuma M, Yagita H, Miura S (2009) Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol 35(4):741–749PubMedGoogle Scholar
  179. Olaso E, Salado C, Egilegor E, Gutierrez V, Santisteban A, Sancho-Bru P, Friedman SL, Vidal-Vanaclocha F (2003) Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 37(3):674–685PubMedCrossRefGoogle Scholar
  180. Opitz CA, Litzenburger UM, Opitz U, Sahm F, Ochs K, Lutz C, Wick W, Platten M (2011) The indoleamine-2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan upregulates IDO1 in human cancer cells. PLoS ONE 6(5):e19823PubMedPubMedCentralCrossRefGoogle Scholar
  181. Orr FW, Wang HH (2001) Tumor cell interactions with the microvasculature: a rate-limiting step in metastasis. Surg Oncol Clin N Am 10(2):357–381PubMedGoogle Scholar
  182. Paget S (1889) The distribution of secondary growth in cancer of the breast. Lancet 1:571–573CrossRefGoogle Scholar
  183. Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Jirousková M, Degen JL (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105(1):178–185PubMedCrossRefGoogle Scholar
  184. Paschos KA, Majeed AW, Bird NC (2014) Natural history of hepatic metastases from colorectal cancer–pathobiological pathways with clinical significance. World J Gastroenterol 20(14):3719–3737PubMedPubMedCentralCrossRefGoogle Scholar
  185. Peng YP, Zhu Y, Zhang JJ, Xu ZK, Qian ZY, Dai CC, Jiang KR, Wu JL, Gao WT, Li Q, Du Q, Miao Y (2013) Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J Transl Med 11:262PubMedPubMedCentralCrossRefGoogle Scholar
  186. Percherancier Y, Berchiche YA, Slight I, Volkmer-Engert R, Tamamura H, Fujii N, Bouvier M, Heveker N (2005) Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers. J Biol Chem 280(11):9895–9903PubMedCrossRefGoogle Scholar
  187. Pereira JP, Kelly LM, Cyster JG (2010) Finding the right niche: b-cell migration in the early phases of T-dependent antibody responses. Int Immunol 22(6):413–419PubMedPubMedCentralCrossRefGoogle Scholar
  188. Pertovaara L, Sistonen L, Bos TJ, Vogt PK, Keski-Oja J, Alitalo K (1989) Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation. Mol Cell Biol 9(3):1255–1262PubMedPubMedCentralCrossRefGoogle Scholar
  189. Pevzner V, Wolf I, Burgstahler R, Förster R, Lipp M (1999) Regulation of expression of chemokine receptor BLR1/CXCR5 during B cell maturation. Curr Top Microbiol Immunol 246:79–84PubMedGoogle Scholar
  190. Publicover J, Gaggar A, Nishimura S, Van Horn CM, Goodsell A, Muench MO, Reinhardt RL, van Rooijen N, Wakil AE, Peters M, Cyster JG, Erle DJ, Rosenthal P, Cooper S, Baron JL (2013) Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B. J Clin Invest 123(9):3728–3739PubMedPubMedCentralCrossRefGoogle Scholar
  191. Qi C, Li B, Guo S, Wei B, Shao C, Li J, Yang Y, Zhang Q, Li J, He X, Wang L, Zhang Y (2015) P-Selectin-Mediated Adhesion between Platelets and Tumor Cells Promotes Intestinal Tumorigenesis in Apc(Min/+) Mice. Int J Biol Sci 11(6):679–687PubMedPubMedCentralCrossRefGoogle Scholar
  192. Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, Gerard C, Lefkowitz RJ (2010a) Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc Natl Acad Sci U S A 107(2):628–632PubMedPubMedCentralCrossRefGoogle Scholar
  193. Rajagopal S, Rajagopal K, Lefkowitz RJ (2010b) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9(5):373–386PubMedPubMedCentralCrossRefGoogle Scholar
  194. Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, Warnick E, Whiteside T, Osborne J, Kim H, Day R, Troetschel M, Finn OJ (2005) Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother 54(3):254–264PubMedCrossRefGoogle Scholar
  195. Rammensee HG, Falk K, Rötzschke O (1993) Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11:213–244PubMedCrossRefGoogle Scholar
  196. Rapraeger AC, Krufka A, Olwin BB (1991) Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252(5013):1705–1708PubMedCrossRefGoogle Scholar
  197. Ray P, Lewin SA, Mihalko LA, Lesher-Perez SC, Takayama S, Luker KE, Luker GD (2012) Secreted CXCL12 (SDF-1) forms dimers under physiological conditions. Biochem J 442(2):433–442PubMedPubMedCentralCrossRefGoogle Scholar
  198. Razis E, Kalogeras KT, Kotoula V, Eleftheraki AG, Nikitas N, Kronenwett R, Timotheadou E, Christodoulou C, Pectasides D, Gogas H, Wirtz RM, Makatsoris T, Bafaloukos D, Aravantinos G, Televantou D, Pavlidis N, Fountzilas G (2012) Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression. Clin Breast Cancer 12(3):183–193PubMedCrossRefGoogle Scholar
  199. Rodríguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191PubMedPubMedCentralCrossRefGoogle Scholar
  200. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849PubMedCrossRefGoogle Scholar
  201. Roland CL, Dineen SP, Toombs JE, Carbon JG, Smith CW, Brekken RA, Barnett CC Jr (2010) Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts. Exp Biol Med (Maywood) 235(2):263–270CrossRefGoogle Scholar
  202. Romain B, Hachet-Haas M, Rohr S, Brigand C, Galzi JL, Gaub MP, Pencreach E, Guenot D (2014) Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. Mol Cancer 13:58PubMedPubMedCentralCrossRefGoogle Scholar
  203. Rosenbaum J, Blazejewski S, Préaux AM, Mallat A, Dhumeaux D, Mavier P (1995) Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts. Gastroenterology 109(6):1986–1996PubMedCrossRefGoogle Scholar
  204. Rossi JF, Négrier S, James ND, Kocak I, Hawkins R, Davis H, Prabhakar U, Qin X, Mulders P, Berns B (2010) A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer 103(8):1154–1162PubMedPubMedCentralCrossRefGoogle Scholar
  205. Ryschich E, Nötzel T, Hinz U, Autschbach F, Ferguson J, Simon I, Weitz J, Fröhlich B, Klar E, Büchler MW, Schmidt J (2005) Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. Clin Cancer Res 11(2 Pt 1):498–504PubMedGoogle Scholar
  206. Sadanandam A, Varney ML, Singh RK (2008) Identification of semaphorin 5A interacting protein by applying apriori knowledge and peptide complementarity related to protein evolution and structure. Genomics Proteomics Bioinformatics 6(3–4):163–174PubMedCrossRefGoogle Scholar
  207. Sadanandam A, Sidhu SS, Wullschleger S, Singh S, Varney ML, Yang CS, Ashour AE, Batra SK, Singh RK (2012) Secreted semaphorin 5A suppressed pancreatic tumor burden but increased metastasis and endothelial cell proliferation. Br J Cancer 107(3):501–507PubMedPubMedCentralCrossRefGoogle Scholar
  208. Saito T, Tomida M (2005) Generation of inhibitory DNA aptamers against human hepatocyte growth factor. DNA Cell Biol 24(10):624–633PubMedCrossRefGoogle Scholar
  209. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562PubMedCrossRefGoogle Scholar
  210. Sakamoto K, Haga Y, Yoshimura R, Egami H, Yokoyama Y, Akagi M (1987) Comparative effectiveness of the tumor diagnostics, CA 19-9, CA 125 and carcinoembryonic antigen in patients with diseases of the digestive system. Gut 28(3):323–329PubMedPubMedCentralCrossRefGoogle Scholar
  211. Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, Wang-Gillam A, Eberlein TJ, Denardo DG, Goedegebuure SP, Linehan DC (2013) Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 19(13):3404–3415PubMedPubMedCentralCrossRefGoogle Scholar
  212. Santiago B, Gutierrez-Cañas I, Dotor J, Palao G, Lasarte JJ, Ruiz J, Prieto J, Borrás-Cuesta F, Pablos JL (2005) Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. J Invest Dermatol 125(3):450–455PubMedCrossRefGoogle Scholar
  213. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A (2011) Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 102(6):1193–1200PubMedCrossRefGoogle Scholar
  214. Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P, Schirner M, Wiedenmann B, Rosewicz S (2003) Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 125(3):891–905PubMedCrossRefGoogle Scholar
  215. Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S (2013) Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24(1):130–137PubMedCrossRefGoogle Scholar
  216. Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H (2000) The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses. Immunol Rev 174:35–46PubMedCrossRefGoogle Scholar
  217. Shen B, Zheng MQ, Lu JW, Jiang Q, Wang TH, Huang XE (2013) CXCL12-CXCR4 promotes proliferation and invasion of pancreatic cancer cells. Asian Pac J Cancer Prev 14(9):5403–5408PubMedCrossRefGoogle Scholar
  218. Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, Xiong Q, Wang B, Li XC, Xie K (2001) Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 61(10):4143–4154PubMedGoogle Scholar
  219. Shi WD, Meng ZQ, Chen Z, Lin JH, Zhou ZH, Liu LM (2009) Identification of liver metastasis-related genes in a novel human pancreatic carcinoma cell model by microarray analysis. Cancer Lett 283(1):84–91PubMedCrossRefGoogle Scholar
  220. Shi C, Washington MK, Chaturvedi R, Drosos Y, Revetta FL, Weaver CJ, Buzhardt E, Yull FE, Blackwell TS, Sosa-Pineda B, Whitehead RH, Beauchamp RD, Wilson KT, Means AL (2014a) Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction. Lab Invest 94(4):409–421PubMedPubMedCentralCrossRefGoogle Scholar
  221. Shi W, Meng Z, Chen Z, Hua Y, Gao H, Wang P, Lin J, Zhou Z, Luo J, Liu L (2014b) RNA interference against MDM2 suppresses tumor growth and metastasis in pancreatic carcinoma SW1990HM cells. Mol Cell Biochem 387(1–2):1–8PubMedCrossRefGoogle Scholar
  222. Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T, Oike Y, Endo M, Ibusuki M, Hiraki A, Nakayama H, Yoshitake Y, Shinohara M, Ando Y (2009) Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res 15(17):5426–5434PubMedCrossRefGoogle Scholar
  223. Shinriki S, Jono H, Ueda M, Ota K, Ota T, Sueyoshi T, Oike Y, Ibusuki M, Hiraki A, Nakayama H, Shinohara M, Ando Y (2011) Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in humanoral squamous cell carcinoma. J Pathol 225(1):142–150PubMedCrossRefGoogle Scholar
  224. Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166PubMedPubMedCentralCrossRefGoogle Scholar
  225. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumor-associated macrophages are a distinct M2 polarised population promoting tumor progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727PubMedCrossRefGoogle Scholar
  226. Siegel R, Ma J, Zou Z (2014) Jemal A (2014) Cancer statistics. CA Cancer J Clin 64(1):9–29PubMedCrossRefGoogle Scholar
  227. Singh S, Srivastava SK, Bhardwaj A, Owen LB, Singh AP (2010) CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer 103(11):1671–1679PubMedPubMedCentralCrossRefGoogle Scholar
  228. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4(6):567–579PubMedCrossRefGoogle Scholar
  229. Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172PubMedCrossRefGoogle Scholar
  230. Stegner D, Dütting S, Nieswandt B (2014) Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 133(Suppl 2):S149–S157PubMedCrossRefGoogle Scholar
  231. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711PubMedCrossRefGoogle Scholar
  232. Stenner F, Liewen H, Göttig S, Henschler R, Markuly N, Kleber S, Faust M, Mischo A, Bauer S, Zweifel M, Knuth A, Renner C, Wadle A (2013) RP1 is a phosphorylation target of CK2 and is involved in cell adhesion. PLoS ONE 8(7):e67595PubMedPubMedCentralCrossRefGoogle Scholar
  233. Stephens LA, Gray D, Anderton SM (2005) CD4+ CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci U S A 102(48):17418–17423PubMedPubMedCentralCrossRefGoogle Scholar
  234. Suciu-Foca N, Feirt N, Zhang QY, Vlad G, Liu Z, Lin H, Chang CC, Ho EK, Colovai AI, Kaufman H, D’Agati VD, Thaker HM, Remotti H, Galluzzo S, Cinti P, Rabitti C, Allendorf J, Chabot J, Caricato M, Coppola R, Berloco P, Cortesini R (2007) Soluble Ig-like transcript 3 inhibits tumor allograft rejection in humanized SCID mice and T cell responses in cancer patients. J Immunol 178(11):7432–7441PubMedCrossRefGoogle Scholar
  235. Sudha T, Phillips P, Kanaan C, Linhardt RJ, Borsig L, Mousa SA (2012) Inhibitory effect of non-anticoagulant heparin (S-NACH) on pancreatic cancer cell adhesion and metastasis in human umbilical cord vessel segment and in mouse model. Clin Exp Metastasis 29(5):431–439PubMedCrossRefGoogle Scholar
  236. Sung B, Jhurani S, Ahn KS, Mastuo Y, Yi T, Guha S, Liu M, Aggarwal BB (2008) Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells. Cancer Res 68(21):8938–8944PubMedCrossRefGoogle Scholar
  237. Takada A, Ohmori K, Takahashi N, Tsuyuoka K, Yago A, Zenita K, Hasegawa A, Kannagi R (1991) Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. Biochem Biophys Res Commun 179(2):713–719PubMedCrossRefGoogle Scholar
  238. Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M, Kannagi R (1993) Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res 53(2):354–361PubMedGoogle Scholar
  239. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310PubMedPubMedCentralCrossRefGoogle Scholar
  240. Tamamura H, Omagari A, Hiramatsu K, Gotoh K, Kanamoto T, Xu Y, Kodama E, Matsuoka M, Hattori T, Yamamoto N, Nakashima H, Otaka A, Fujii N (2001) Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140. Bioorg Med Chem Lett 11(14):1897–1902PubMedCrossRefGoogle Scholar
  241. Tamamura H, Tsutsumi H, Masuno H, Fujii N (2007) Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra- and pentapeptide-scaffolds towards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Curr Med Chem 14(1):93–102PubMedCrossRefGoogle Scholar
  242. Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS, Linehan DC (2009) Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 182(3):1746–17455PubMedPubMedCentralCrossRefGoogle Scholar
  243. Tao J, Xiang JJ, Li D, Deng N, Wang H, Gong YP (2010) Selection and characterization of a human neutralizing antibody to human fibroblast growth factor-2. Biochem Biophys Res Commun 394(3):767–773PubMedCrossRefGoogle Scholar
  244. Tarp MA, Clausen H (2008) Mucin-type O-glycosylation and its potential use in drug and vaccine development. Biochim Biophys Acta 1780(3):546–563PubMedCrossRefGoogle Scholar
  245. Ten Kate M, Hofland LJ, van Grevenstein WM, van Koetsveld PV, Jeekel J, van Eijck CH (2004) Influence of proinflammatory cytokines on the adhesion of human colon carcinoma cells to lung microvascular endothelium. Int J Cancer 112(6):943–950PubMedCrossRefGoogle Scholar
  246. Ten Kate M, van der Wal JB, Sluiter W, Hofland LJ, Jeekel J, Sonneveld P, van Eijck CH (2006) The role of superoxide anions in the development of distant tumor recurrence. Br J Cancer 95(11):1497–1503PubMedPubMedCentralCrossRefGoogle Scholar
  247. Ten Kate M, Aalbers AG, Sluiter W, Hofland LJ, Sonneveld P, Jeekel J, Van Eijck CH (2007) Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium. Anticancer Res 27(1A):17–22PubMedGoogle Scholar
  248. Teraoka H, Sawada T, Nishihara T, Yashiro M, Ohira M, Ishikawa T, Nishino H, Hirakawa K (2001) Enhanced VEGF production and decreased immunogenicity induced by TGF-beta 1 promote liver metastasis of pancreatic cancer. Br J Cancer 85(4):612–617PubMedPubMedCentralCrossRefGoogle Scholar
  249. Théret N, Musso O, Campion JP, Turlin B, Loréal O, L’Helgoualc’h A, Clément B (1997) Overexpression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 in liver from patients with gastrointestinal adenocarcinoma and no detectable metastasis. Int J Cancer 74(4):426–432PubMedCrossRefGoogle Scholar
  250. Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+ CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164(1):183–190PubMedCrossRefGoogle Scholar
  251. Tien YW, Wu YM, Lin WC, Lee HS, Lee PH (2009) Pancreatic carcinoma cells stimulate proliferation and matrix synthesis of hepatic stellate cells. J Hepatol 51(2):307–314PubMedCrossRefGoogle Scholar
  252. Tímár J, Tóvári J, Rásó E, Mészáros L, Bereczky B, Lapis K (2005) Platelet-mimicry of cancer cells: epiphenomenon with clinical significance. Oncology 69(3):185–201PubMedCrossRefGoogle Scholar
  253. Timmers M, Vekemans K, Vermijlen D, Asosingh K, Kuppen P, Bouwens L, Wisse E, Braet F (2004) Interactions between rat colon carcinoma cells and Kupffer cells during the onset of hepatic metastasis. Int J Cancer 112(5):793–802PubMedCrossRefGoogle Scholar
  254. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266(18):11947–11954PubMedGoogle Scholar
  255. Tözeren A, Kleinman HK, Grant DS, Morales D, Mercurio AM, Byers SW (1995) E-selectin-mediated dynamic interactions of breast- and colon-cancer cells with endothelial-cell monolayers. Int J Cancer 60(3):426–431PubMedCrossRefGoogle Scholar
  256. Tsuji F, Seki I, Aono H, Odani N, Mizutani K, Okamoto M, Sasano M (2007) Bucillamine mechanism inhibiting IL-1beta-induced VEGF production from fibroblast-like synoviocytes. Int Immunopharmacol 7(12):1569–1576PubMedCrossRefGoogle Scholar
  257. Uotani H, Yamashita I, Nagata T, Kishimoto H, Kashii Y, Tsukada K (2001) Induction of E-selectin after partial hepatectomy promotes metastases to liver in mice. J Surg Res 96(2):197–203PubMedCrossRefGoogle Scholar
  258. Vasilyeva ED, Kaledin V, Nikolin VP, Popova NA, Kirilyuk IA, Grigor’ev IA (2012) Accelerated rejection of the second transplants of immunogenic tumor in mice under inhibition of indoleamine 2,3-dioxygenase activity by ethyl pyruvate. Exp Oncol 34(1):66–68PubMedGoogle Scholar
  259. Veldkamp CT, Peterson FC, Pelzek AJ, Volkman BF (2005) The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin. Protein Sci 14(4):1071–1081PubMedPubMedCentralCrossRefGoogle Scholar
  260. Venkatasubbarao K, Choudary A, Freeman JW (2005) Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3(Tyr705) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases. Cancer Res 65(7):2861–2871PubMedCrossRefGoogle Scholar
  261. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378(9791):607–620PubMedPubMedCentralCrossRefGoogle Scholar
  262. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, Corringham RE, Zaki MH, Nemeth JA, Orlowski RZ (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 13(21):6469–6478PubMedCrossRefGoogle Scholar
  263. Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, Orlowski RZ (2009) Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 145(4):481–490PubMedPubMedCentralCrossRefGoogle Scholar
  264. Waghray M, Yalamanchili M, di Magliano MP, Simeone DM (2013) Deciphering the role of stroma in pancreatic cancer. Curr Opin Gastroenterol 29(5):537–543PubMedPubMedCentralCrossRefGoogle Scholar
  265. Wang C, Lin S, Nie Y, Jia X, Wang J, Xiao J, Wu J, Li X, Wu X (2010) Mechanism of antitumor effect of a novel bFGF binding peptide on human colon cancer cells. Cancer Sci 101(5):1212–1218PubMedCrossRefGoogle Scholar
  266. Wang L, Park H, Chhim S, Ding Y, Jiang W, Queen C, Kim KJ (2012) A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther 11(4):864–872PubMedPubMedCentralCrossRefGoogle Scholar
  267. Wang B, Wang W, Niu W, Liu E, Liu X, Wang J, Peng C, Liu S, Xu L, Wang L, Niu J (2014) SDF-1/CXCR4 axis promotes directional migration of colorectal cancer cells through upregulation of integrin αvβ6. Carcinogenesis 35(2):282–291PubMedCrossRefGoogle Scholar
  268. Weekes CD, Song D, Arcaroli J, Wilson LA, Rubio-Viqueira B, Cusatis G, Garrett-Mayer E, Messersmith WA, Winn RA, Hidalgo M (2012) Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer. Neoplasia 14(8):690–701PubMedPubMedCentralCrossRefGoogle Scholar
  269. 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):319–329PubMedCrossRefGoogle Scholar
  270. 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):2030–2038PubMedCrossRefGoogle Scholar
  271. Weiss L, Orr FW, Honn KV (1988) Interactions of cancer cells with the microvasculature during metastasis. FASEB J 2(1):12–21PubMedGoogle Scholar
  272. Wen SW, Ager EI, Christophi C (2013) Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther 14(7):606–613PubMedPubMedCentralCrossRefGoogle Scholar
  273. Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, Brody JR (2008) Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg 206(5):849–854PubMedCrossRefGoogle Scholar
  274. Wu X, Yan Q, Huang Y, Huang H, Su Z, Xiao J, Zeng Y, Wang Y, Nie C, Yang Y, Li X (2010) Isolation of a novel basic FGF-binding peptide with potent antiangiogenetic activity. J Cell Mol Med 14(1–2):351–356PubMedPubMedCentralCrossRefGoogle Scholar
  275. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Klimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA Jr, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B (2011) Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A 108(52):21188–21193PubMedPubMedCentralCrossRefGoogle Scholar
  276. Wu X, Huang H, Wang C, Lin S, Huang Y, Wang Y, Liang G, Yan Q, Xiao J, Wu J, Yang Y, Li X (2013) Identification of a novel peptide that blocks basic fibroblast growth factor-mediated cell proliferation. Oncotarget 4(10):1819–1828PubMedPubMedCentralCrossRefGoogle Scholar
  277. Xiong HQ, Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K (2011) NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer 108(2):181–188CrossRefGoogle Scholar
  278. Xu K, Gao H, Shu HK (2011) Celecoxib can induce vascular endothelial growth factor expression and tumor angiogenesis. Mol Cancer The 10(1):138–147CrossRefGoogle Scholar
  279. Xu X, Wang Y, Chen J, Ma H, Shao Z, Chen H, Jin G (2012) High expression of CX3CL1/CX3CR1 axis predicts a poor prognosis of pancreatic ductal adenocarcinoma. J Gastrointest Surg 16(8):1493–1498PubMedCrossRefGoogle Scholar
  280. Yachida S, Iacobuzio-Donahue CA (2009) The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med 133:413–422PubMedGoogle Scholar
  281. Yachida S, Iacobuzio-Donahue CA (2013) Evolution and dynamics of pancreatic cancer progression. Oncogene 32(45):5253–5260PubMedCrossRefGoogle Scholar
  282. Yadav VR, Sung B, Prasad S, Kannappan R, Cho SG, Liu M, Chaturvedi MM, Aggarwal BB (2010) Celastrol suppresses invasion of colon and pancreatic cancer cells through the downregulation of expression of CXCR4 chemokine receptor. J Mol Med (Berl) 88(12):1243–1253CrossRefGoogle Scholar
  283. Yamada S, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Mori H, Arakawa Y, Kanamoto M, Iwahashi S, Saito Y (2014) CXC receptor 4 and stromal cell-derived factor 1 in primary tumors and liver metastases of colorectal cancer. J Surg Res 187(1):107–112PubMedCrossRefGoogle Scholar
  284. Yamahira A, Narita M, Iwabuchi M, Uchiyama T, Iwaya S, Ohiwa R, Nishizawa Y, Suzuki T, Yokoyama Y, Hashimoto S, Takizawa J, Sone H, Takahashi M (2014) Activation of the leukemia plasmacytoid dendritic cell line PMDC05 by Toho-1, a novel IDO inhibitor. Anticancer Res 34(8):4021–4028PubMedGoogle Scholar
  285. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S, Yui R, Yamao J, Kim S, Kwon AH (2012) Circulating CD4+ CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas 41(3):409–415PubMedCrossRefGoogle Scholar
  286. Yamauchi H, Kikuchi Y, Kakizaki K (1995) Relation between the stromal volume and liver metastasis in ductal cell carcinoma of the pancreas. Tohoku J Exp Med 177(2):179–181PubMedCrossRefGoogle Scholar
  287. Yang Q, Zhang F, Ding Y, Huang J, Chen S, Wu Q, Wang Z, Wang Z, Chen C (2014) Antitumour activity of the recombination polypeptide GST-NT21MP is mediated by inhibition of CXCR4 pathway in breast cancer. Br J Cancer 110(5):1288–1297PubMedPubMedCentralCrossRefGoogle Scholar
  288. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64(4):841–848PubMedCrossRefGoogle Scholar
  289. Yezhelyev MV, Koehl G, Guba M, Brabletz T, Jauch KW, Ryan A, Barge A, Green T, Fennell M, Bruns CJ (2004) Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice. Clin Cancer Res 10(23):8028–8036PubMedCrossRefGoogle Scholar
  290. Yoshidome H, Kohno H, Shida T, Kimura F, Shimizu H, Ohtsuka M, Nakatani Y, Miyazaki M (2009) Significance of monocyte chemoattractant protein-1 in angiogenesis and survival in colorectal liver metastases. Int J Oncol 34(4):923–930PubMedCrossRefGoogle Scholar
  291. Yoshimoto K, Tajima H, Ohta T, Okamoto K, Sakai S, Kinoshita J, Furukawa H, Makino I, Hayashi H, Nakamura K, Oyama K, Inokuchi M, Nakagawara H, Itoh H, Fujita H, Takamura H, Ninomiya I, Kitagawa H, Fushida S, Fujimura T, Wakayama T, Iseki S, Shimizu K (2012) Increased E-selectin in hepatic ischemia-reperfusion injury mediates liver metastasis of pancreatic cancer. Oncol Rep 28(3):791–796PubMedPubMedCentralGoogle Scholar
  292. Yu Y, Gao S, Li Q, Wang C, Lai X, Chen X, Wang R, Di J, Li T, Wang W, Wu X (2012) The FGF2-binding peptide P7 inhibits melanoma growth in vitro and in vivo. J Cancer Res Clin Oncol 138(8):1321–1328PubMedCrossRefGoogle Scholar
  293. Zabel BA, Wang Y, Lewén S, Berahovich RD, Penfold ME, Zhang P, Powers J, Summers BC, Miao Z, Zhao B, Jalili A, Janowska-Wieczorek A, Jaen JC, Schall TJ (2009) Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 183(5):3204–3211PubMedCrossRefGoogle Scholar
  294. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J (2005) Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci U S A 102(11):4091–4096PubMedPubMedCentralCrossRefGoogle Scholar
  295. Zeng J, Cai S, Yi Y, He Y, Wang Z, Jiang G, Li X, Du J (2009) Prevention of spontaneous tumor development in a ret transgenic mouse model by ret peptide vaccination with indoleamine 2,3-dioxygenase inhibitor 1-methyl tryptophan. Cancer Res 69(9):3963–3970PubMedCrossRefGoogle Scholar
  296. Zervos EE, Shafii AE, Haq M, Rosemurgy AS (1999a) Matrix metalloproteinase inhibition suppresses MMP-2 activity and activation of PANC-1 cells in vitro. J Surg Res 84(2):162–167PubMedCrossRefGoogle Scholar
  297. Zervos EE, Shafii AE, Rosemurgy AS (1999b) Matrix metalloproteinase (MMP) inhibition selectively decreases type II MMP activity in a murine model of pancreatic cancer. J Surg Res 81(1):65–68PubMedCrossRefGoogle Scholar
  298. Zhou N, Luo Z, Luo J, Fan X, Cayabyab M, Hiraoka M, Liu D, Han X, Pesavento J, Dong CZ, Wang Y, An J, Kaji H, Sodroski JG, Huang Z (2002) Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines. J Biol Chem 277(20):17476–17485PubMedCrossRefGoogle Scholar
  299. Zhu A, Zhan W, Liang Z, Yoon Y, Yang H, Grossniklaus HE, Xu J, Rojas M, Lockwood M, Snyder JP, Liotta DC, Shim H (2010) Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity. J Med Chem 53(24):8556–8568PubMedPubMedCentralCrossRefGoogle Scholar
  300. Zubeldia IG, Bleau AM, Redrado M, Serrano D, Agliano A, Gil-Puig C, Vidal-Vanaclocha F, Lecanda J, Calvo A (2013) Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFβ1-targeting peptides P17 and P144. Exp Cell Res 319(3):12–22PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan HospitalFudan UniversityShanghaiChina

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