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Stromal Inflammation in Pancreatic Cancer: Mechanisms and Translational Applications

  • Kathleen A. Boyle
  • Michael A. James
  • Susan Tsai
  • Douglas B. Evans
  • Michael B. Dwinell
Reference work entry

Abstract

Pancreatic ductal adenocarcinoma is the most severe form of pancreatic cancer because of pronounced inflammation and desmoplasia leading to hypoxia, metabolic reprogramming, and immune suppression that ultimately promote tumor growth and metastasis. The conventional wisdom is that patient survival is hobbled by the inability of currently available therapies to penetrate the tumor and its dense stromal microenvironment. The pancreatic cancer stromal microenvironment is a heterogeneous population of cancer cells, immune cells, cancer-associated fibroblasts, vascular endothelial cells, and neurons. While a detailed understanding of the cells, mediators, and receptors influencing stromal dynamism continues to emerge, interactions between these cells influence tumor suppression as well as tumor promotion. The specific roles for the inflamed stroma in pancreatic cancer immune evasion, progression, metastasis, and therapeutic resistance likely depend on stage of tumor development and distinct biophysical features within the dynamic cellular micro-niches of the tumor. Uncovering the stromal mechanisms of tumor development and progression should prompt the discovery of key windows of opportunity for multimodal therapies in pancreatic cancer.

Keywords

Inflammation Stellate Cell Cytokine Desmoplasia Cancer-Associated Fibroblast T Cell Tumor-Associated Macrophage Immune Evasion Stromal Remodeling 

Notes

Acknowledgments

The authors thank past and present members of the Dwinell Laboratory as well as Dr. Ishan Roy, Dr. Bryon Johnson, and Dr. Edna Cukierman for constructive conversations about mucosal inflammation and stromal interactions within the pancreatic cancer microenvironment. Work in the laboratory is supported by the National Cancer Institute (U01 CA178960) and continuing philanthropic support from the Bobbie Nick Voss Charitable Foundation and the We Care Fund. The authors gratefully acknowledge and apologize to numerous colleagues whose excellent work could not be cited due to space restrictions.

In memory of Martin F. Kagnoff, MD who succumbed to complications of pancreatic cancer in 2014. His enduring legacy and passion for understanding the pathophysiologic mechanisms of mucosal inflammation remain an inspiration to his trainees and colleagues.

Disclosures MBD is cofounder and has financial interests in Protein Foundry, LLC, a biotech startup that manufactures recombinant chemokines for biomedical research. MBD has been granted a patent [US Patent 8,404,640] for the use of recombinant CXCL12 as an antitumor agent.

References

  1. 1.
    Tsai S, Evans DB. Therapeutic advances in localized pancreatic cancer. JAMA Surg. 2016;151(9):862–8.CrossRefGoogle Scholar
  2. 2.
    Erkan M, Reiser-Erkan C, Michalski CW, Deucker S, Sauliunaite D, Streit S, et al. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia. 2009;11(5):497–508.CrossRefGoogle Scholar
  3. 3.
    Seshacharyulu P, Baine MJ, Souchek JJ, Menning M, Kaur S, Yan Y, et al. Biological determinants of radioresistance and their remediation in pancreatic cancer. Biochim Biophys Acta. 2017;1868(1):69–92.PubMedGoogle Scholar
  4. 4.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRefGoogle Scholar
  5. 5.
    Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.CrossRefGoogle Scholar
  6. 6.
    Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–47.CrossRefGoogle Scholar
  7. 7.
    Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6(8):2969–72.Google Scholar
  8. 8.
    Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67(19):9518–27.CrossRefGoogle Scholar
  9. 9.
    Bhanot UK, Moller P. Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis. Lab Investig. 2009;89(5):489–97.CrossRefGoogle Scholar
  10. 10.
    Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579–96.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Bachem MG, Schunemann M, Ramadani M, Siech M, Beger H, Buck A, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005;128(4):907–21.CrossRefGoogle Scholar
  12. 12.
    Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115(2):421–32.CrossRefGoogle Scholar
  13. 13.
    Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol. 2009;7(11 Suppl):S48–54.CrossRefGoogle Scholar
  14. 14.
    Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol. 2012;22(4):275–81.CrossRefGoogle Scholar
  15. 15.
    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.CrossRefGoogle Scholar
  16. 16.
    Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell. 2012;21(6):822–35.CrossRefGoogle Scholar
  17. 17.
    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16(3):183–94.CrossRefGoogle Scholar
  18. 18.
    Strouch MJ, Cheon EC, Salabat MR, Krantz SB, Gounaris E, Melstrom LG, et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res. 2010;16(8):2257–65.CrossRefGoogle Scholar
  19. 19.
    Cai SW, Yang SZ, Gao J, Pan K, Chen JY, Wang YL, et al. Prognostic significance of mast cell count following curative resection for pancreatic ductal adenocarcinoma. Surgery. 2011;149(4):576–84.CrossRefGoogle Scholar
  20. 20.
    Schonhuber N, Seidler B, Schuck K, Veltkamp C, Schachtler C, Zukowska M, et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med. 2014;20(11):1340–7.CrossRefGoogle Scholar
  21. 21.
    von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, et al. Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res. 2001;7(3 Suppl):925s–32s.Google Scholar
  22. 22.
    McAllister F, Bailey JM, Alsina J, Nirschl CJ, Sharma R, Fan H, et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell. 2014;25(5):621–37.CrossRefGoogle Scholar
  23. 23.
    Zhang Y, Yan W, Mathew E, Bednar F, Wan S, Collins MA, et al. CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol Res. 2014;2(5):423–35.CrossRefGoogle Scholar
  24. 24.
    Byrne WL, Mills KH, Lederer JA, O'Sullivan GC. Targeting regulatory T cells in cancer. Cancer Res. 2011;71(22):6915–20.CrossRefGoogle Scholar
  25. 25.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.CrossRefGoogle Scholar
  26. 26.
    Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009;182(3):1746–55.CrossRefGoogle Scholar
  27. 27.
    Wang X, Lang M, Zhao T, Feng X, Zheng C, Huang C, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. Oncogene. 2016;Google Scholar
  28. 28.
    Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB, et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 2016;6(3):247–55.CrossRefGoogle Scholar
  29. 29.
    Barber MD, Fearon KC, Ross JA. Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer. Clin Sci (Lond). 1999;96(1):83–7.CrossRefGoogle Scholar
  30. 30.
    Okada S, Okusaka T, Ishii H, Kyogoku A, Yoshimori M, Kajimura N, et al. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol. 1998;28(1):12–5.CrossRefGoogle Scholar
  31. 31.
    Roy I, McAllister DM, Gorse E, Dixon K, Piper CT, Zimmerman NP, et al. Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased Agonism and Bioenergetic signaling. Cancer Res. 2015;75(17):3529–42.CrossRefGoogle Scholar
  32. 32.
    Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, et al. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J Exp Clin Cancer Res. 2016;35:27.CrossRefGoogle Scholar
  33. 33.
    Young MR. Th17 cells in protection from tumor or promotion of tumor progression. J Clin Cell Immunol. 2016;7(3):431.CrossRefGoogle Scholar
  34. 34.
    Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(1):105–20.CrossRefGoogle Scholar
  35. 35.
    Tjomsland V, Spangeus A, Valila J, Sandstrom P, Borch K, Druid H, et al. Interleukin 1alpha sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts. Neoplasia. 2011;13(8):664–75.CrossRefGoogle Scholar
  36. 36.
    Tracey KJ, Lowry SF, Cerami A. Cachectin: a hormone that triggers acute shock and chronic cachexia. J Infect Dis. 1988;157(3):413–20.CrossRefGoogle Scholar
  37. 37.
    Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS. Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem. 2004;279(33):34643–54.CrossRefGoogle Scholar
  38. 38.
    Subramanian G, Schwarz RE, Higgins L, McEnroe G, Chakravarty S, Dugar S, et al. Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. Cancer Res. 2004;64(15):5200–11.CrossRefGoogle Scholar
  39. 39.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.CrossRefGoogle Scholar
  40. 40.
    Roy I, Zimmerman NP, Mackinnon AC, Tsai S, Evans DB, Dwinell MB. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One. 2014;9(3):e90400.CrossRefGoogle Scholar
  41. 41.
    Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT, Takekoshi T, Hwang ST, et al. Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc Natl Acad Sci U S A. 2011;108(43):17655–60.CrossRefGoogle Scholar
  42. 42.
    Ziarek JJ, Kleist AB, London N, Raveh B, Montpas N, Bonneterre J, et al. Structural basis for chemokine recognition by a G protein-coupled receptor and implications for receptor activation. Sci Signal. 2017;10(471)CrossRefGoogle Scholar
  43. 43.
    Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.CrossRefGoogle Scholar
  44. 44.
    Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, et al. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res. 2003;63(21):7451–61.PubMedGoogle Scholar
  45. 45.
    Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–62.CrossRefGoogle Scholar
  46. 46.
    Cacalano G, Lee J, Kikly K, Ryan AM, Pitts-Meek S, Hultgren B, et al. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science. 1994;265(5172):682–4.CrossRefGoogle Scholar
  47. 47.
    Kleeff J, Kusama T, Rossi DL, Ishiwata T, Maruyama H, Friess H, et al. Detection and localization of Mip-3alpha/LARC/exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer. 1999;81(4):650–7.CrossRefGoogle Scholar
  48. 48.
    Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999;99(1):23–33.CrossRefGoogle Scholar
  49. 49.
    Nakata B, Fukunaga S, Noda E, Amano R, Yamada N, Hirakawa K. Chemokine receptor CCR7 expression correlates with lymph node metastasis in pancreatic cancer. Oncology. 2008;74(1–2):69–75.CrossRefGoogle Scholar
  50. 50.
    Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990;347(6294):669–71.CrossRefGoogle Scholar
  51. 51.
    Roy I, Boyle KA, Vonderhaar EP, Zimmerman NP, Gorse E, Mackinnon AC, et al. Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. Lab Investig. 2017;97(3):302–17.CrossRefGoogle Scholar
  52. 52.
    Provenzano PP, Inman DR, Eliceiri KW, Trier SM, Keely PJ. Contact guidance mediated three-dimensional cell migration is regulated by rho/ROCK-dependent matrix reorganization. Biophys J. 2008;95(11):5374–84.CrossRefGoogle Scholar
  53. 53.
    Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.CrossRefGoogle Scholar
  54. 54.
    Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418–29.CrossRefGoogle Scholar
  55. 55.
    Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.CrossRefGoogle Scholar
  56. 56.
    Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T, et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One. 2007;2(11):e1155.CrossRefGoogle Scholar
  57. 57.
    Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK, Takebe N, et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res. 2014;20(23):5937–45.CrossRefGoogle Scholar
  58. 58.
    Hwang RF, Moore TT, Hattersley MM, Scarpitti M, Yang B, Devereaux E, et al. Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer. Mol Cancer Res. 2012;10(9):1147–57.CrossRefGoogle Scholar
  59. 59.
    Hidalgo M. New insights into pancreatic cancer biology. Ann Oncol. 2012;23(Suppl 10):x135–8.CrossRefGoogle Scholar
  60. 60.
    Takada M, Yamamoto M, Saitoh Y. The significance of CD44 in human pancreatic cancer: I. High expression of CD44 in human pancreatic adenocarcinoma. Pancreas. 1994;9(6):748–52.CrossRefGoogle Scholar
  61. 61.
    Hofmann M, Rudy W, Gunthert U, Zimmer SG, Zawadzki V, Zoller M, et al. A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. Cancer Res. 1993;53(7):1516–21.PubMedGoogle Scholar
  62. 62.
    Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22(12):2848–54.CrossRefGoogle Scholar
  63. 63.
    De Oliveira T, Abiatari I, Raulefs S, Sauliunaite D, Erkan M, Kong B, et al. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol Cancer. 2012;11:19.CrossRefGoogle Scholar
  64. 64.
    Grunwald B, Vandooren J, Gerg M, Ahomaa K, Hunger A, Berchtold S, et al. Systemic ablation of MMP-9 triggers invasive growth and metastasis of pancreatic cancer via deregulation of IL6 expression in the bone marrow. Mol Cancer Res. 2016;14(11):1147–58.CrossRefGoogle Scholar
  65. 65.
    Sawey ET, Johnson JA, Crawford HC. Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway. Proc Natl Acad Sci U S A. 2007;104(49):19327–32.CrossRefGoogle Scholar
  66. 66.
    Froeling FE, Feig C, Chelala C, Dobson R, Mein CE, Tuveson DA, et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology. 2011;141(4):1486–97. e1–14CrossRefGoogle Scholar
  67. 67.
    Stromnes IM, DelGiorno KE, Greenberg PD, Hingorani SR. Stromal reengineering to treat pancreas cancer. Carcinogenesis. 2014;35(7):1451–60.CrossRefGoogle Scholar
  68. 68.
    Cukierman G. Simultaneous multi-channel immunofluorescence analysis 2017. Available from: https://github.com/cukie/SIA_CUKIE
  69. 69.
    Couvelard A, O'Toole D, Leek R, Turley H, Sauvanet A, Degott C, et al. Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas. Histopathology. 2005;46(6):668–76.CrossRefGoogle Scholar
  70. 70.
    Nguyen NC, Taalab K, Osman MM. Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness. Clin Cancer Res. 2010;16(1):367. author reply 567CrossRefGoogle Scholar
  71. 71.
    Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555–9.CrossRefGoogle Scholar
  72. 72.
    Palam LR, Gore J, Craven KE, Wilson JL, Korc M. Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma. Cell Death Dis. 2015;6:e1913.CrossRefGoogle Scholar
  73. 73.
    James MA, Vikis HG, Tate E, Rymaszewski AL, You M. CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis. Cancer Res. 2014;74(4):1116–27.CrossRefGoogle Scholar
  74. 74.
    Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P, et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 2010;17(4):666–76.CrossRefGoogle Scholar
  75. 75.
    Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer. 2015;14:179.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kathleen A. Boyle
    • 1
  • Michael A. James
    • 2
  • Susan Tsai
    • 2
  • Douglas B. Evans
    • 2
  • Michael B. Dwinell
    • 1
    • 2
  1. 1.Pancreatic Cancer Program, Department of Microbiology and ImmunologyMCW Cancer Center, Medical College of WisconsinMilwaukeeUSA
  2. 2.Pancreatic Cancer Program, Department of SurgeryMCW Cancer Center, Medical College of WisconsinMilwaukeeUSA

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