Targets, Trials, and Travails in Pancreas Cancer

Authors: Kamel Izeradjene PhDa and Sunil R. Hingorani MD, PhDa
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  • a From the Clinical Research and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.

Pancreas cancer is a highly aggressive and rapidly fatal disease. The current standard of care for advanced disease improves survival modestly at best and provides palliation for a minority of patients. The need for new therapies is undisputed. This article describes new therapeutic strategies currently under investigation and discusses possible reasons that others have failed. New potential targets in the treatment of this formidable disease are suggested based on recent findings.

Correspondence: Sunil R. Hingorani, MD, PhD, Clinical Research and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, M5-C800, PO Box 19024, Seattle, WA 98109-1024. E-mail: srh@fhcrc.org
  • 1.

    Jemal A, Murray T, Samuels A et al.. Cancer statistics, 2003. CA Cancer J Clin 2003;53:526.

  • 2.

    Warshaw AL, Fernandez-del Castillo C. Pancreatic carcinoma. N Engl J Med 1992;326:455465.

  • 3.

    Burris HA III, Moore MJ, Andersen J et al.. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:24032413.

    • Search Google Scholar
    • Export Citation
  • 4.

    Allison DC, Piantadosi S, Hruban RH et al.. DNA content and other factors associated with ten-year survival after resection of pancreatic carcinoma. J Surg Oncol 1998;67:151159.

    • Search Google Scholar
    • Export Citation
  • 5.

    Yeo CJ, Cameron JL, Lillemoe KD et al.. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 2002;236:355366; discussion 366–368.

    • Search Google Scholar
    • Export Citation
  • 6.

    Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:29692972.

  • 7.

    Hruban RH, Iacobuzio-Donahue C, Wilentz RE et al.. Molecular pathology of pancreatic cancer. Cancer J 2001;7:251258.

  • 8.

    Kahn S, Yamamoto F, Almoguera C et al.. The c-K-ras gene and human cancer (review). Anticancer Res 1987;7:639652.

  • 9.

    Smit VT, Boot AJ, Smits AM et al.. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res 1988;16:77737782.

    • Search Google Scholar
    • Export Citation
  • 10.

    Hansel DE, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Annu Rev Genomics Hum Genet 2003;4:237256.

  • 11.

    Hruban RH, Wilentz RE, Goggins M et al.. Pathology of incipient pancreatic cancer. Ann Oncol 1999;10(suppl 4):911.

  • 12.

    Inoue S, Tezel E, Nakao A. Molecular diagnosis of pancreatic cancer. Hepatogastroenterology 2001;48:933938.

  • 13.

    Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988;195:255271.

  • 14.

    Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989;49:46824689. Erratum in Cancer Res 1990;50:4682–4689.

  • 15.

    Lemoine NR, Jain S, Hughes CM et al.. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992;102:230236.

  • 16.

    Hingorani SR, Petricoin EF, Maitra A et al.. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437450.

    • Search Google Scholar
    • Export Citation
  • 17.

    Feldmann G, Beaty R, Hruban RH, Maitra A. Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg 2007;14:224232.

    • Search Google Scholar
    • Export Citation
  • 18.

    Brat DJ, Lillemoe KD, Yeo CJ et al.. Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 1998;22:163169.

    • Search Google Scholar
    • Export Citation
  • 19.

    Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002;2:243247.

  • 20.

    Friday BB, Adjei AA. K-ras as a target for cancer therapy. Biochim Biophys Acta 2005;1756:127144.

  • 21.

    Yeh JJ, Der CJ. Targeting signal transduction in pancreatic cancer treatment. Expert Opin Ther Targets 2007;11:673694.

  • 22.

    Hingorani SR, Tuveson DA. Ras redux: rethinking how and where Ras acts. Current Opin Genet Dev 2003;13:613.

  • 23.

    End DW, Smets G, Todd AV et al.. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:131137.

    • Search Google Scholar
    • Export Citation
  • 24.

    Macdonald JS, McCoy S, Whitehead RP et al.. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest Oncology Group (SWOG 9924) study. Invest New Drugs 2005;23:485487.

    • Search Google Scholar
    • Export Citation
  • 25.

    Van Cutsem E, van de Velde H, Karasek P et al.. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22:14301438.

    • Search Google Scholar
    • Export Citation
  • 26.

    Mor A, Philips MR. Compartmentalized Ras/MAPK signaling. Annu Rev Immunol 2006;24:771800.

  • 27.

    Bhattacharyya M, Lemoine NR. Gene therapy developments for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:285298.

  • 28.

    Prenzel N, Fischer OM, Streit S et al.. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 2001;8:1131.

    • Search Google Scholar
    • Export Citation
  • 29.

    Hackel PO, Zwick E, Prenzel N. Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 1999;11:184189.

    • Search Google Scholar
    • Export Citation
  • 30.

    Ozawa F, Friess H, Tempia-Caliera A et al.. Growth factors and their receptors in pancreatic cancer. Teratog Carcinog Mutagen 2001;21:2744.

  • 31.

    Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006;12:52685272.

  • 32.

    Ueda S, Ogata S, Tsuda H et al.. The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 2004;29:e18.

    • Search Google Scholar
    • Export Citation
  • 33.

    Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:24452459.

    • Search Google Scholar
    • Export Citation
  • 34.

    Bruns CJ, Harbison MT, Davis DW et al.. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000;6:19361948.

    • Search Google Scholar
    • Export Citation
  • 35.

    Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. Drugs Today (Barc) 2005;41:107127.

    • Search Google Scholar
    • Export Citation
  • 36.

    Sclabas GM, Fujioka S, Schmidt C et al.. Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-kappaB signaling pathway with the anti-epidermal growth factor antibody IMC-C225. J Gastrointest Surg 2003;7:3743; discussion 43.

    • Search Google Scholar
    • Export Citation
  • 37.

    Xiong HQ, Rosenberg A, LoBuglio A et al.. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 2004;22:26102616.

    • Search Google Scholar
    • Export Citation
  • 38.

    Philip PA, Benedetti J, Fenoglio-Preiser C et al.. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study [abstract]. J Clin Oncol 2007;25(Suppl 1):199S. Abstract LBA4509.

    • Search Google Scholar
    • Export Citation
  • 39.

    Lynch TJ, Bell DW, Sordella R et al.. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:21292139.

    • Search Google Scholar
    • Export Citation
  • 40.

    Paez JG, Janne PA, Lee JC et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:14971500.

    • Search Google Scholar
    • Export Citation
  • 41.

    Tsao MS, Sakurada A, Cutz JC et al.. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133144.

  • 42.

    Moore MJ, Goldstein D, Hamm J et al.. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:19601966.

    • Search Google Scholar
    • Export Citation
  • 43.

    Hingorani SR, Wang L, Multani AS et al.. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469483.

    • Search Google Scholar
    • Export Citation
  • 44.

    Safran H, Iannitti D, Ramanathan R et al.. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004;22:706712.

    • Search Google Scholar
    • Export Citation
  • 45.

    Buchler P, Reber HA, Buchler MC et al.. Therapy for pancreatic cancer with a recombinant humanized anti-HER2 antibody (herceptin). J Gastrointest Surg 2001;5:139146.

    • Search Google Scholar
    • Export Citation
  • 46.

    Geyer CE, Forster J, Lindquist D et al.. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:27332743.

  • 47.

    Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev 2001;15:111127.

  • 48.

    Thayer SP, di Magliano MP, Heiser PW et al.. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851856.

  • 49.

    Miyamoto Y, Maitra A, Ghosh B et al.. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003;3:565576.

    • Search Google Scholar
    • Export Citation
  • 50.

    Wang MH, Ronsin C, Gesnel MC et al.. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 1994;266:117119.

    • Search Google Scholar
    • Export Citation
  • 51.

    Chen YQ, Zhou YQ, Fu LH et al.. Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais. Carcinogenesis 2002;23:18111819.

    • Search Google Scholar
    • Export Citation
  • 52.

    Zinser GM, Leonis MA, Toney K et al.. Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. Cancer Res 2006;66:1196711974.

    • Search Google Scholar
    • Export Citation
  • 53.

    Thomas RM, Toney K, Fenoglio-Preiser C et al.. The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. Cancer Res 2007;67:60756082.

    • Search Google Scholar
    • Export Citation
  • 54.

    Argani P, Iacobuzio-Donahue C, Ryu B et al.. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res 2001;7:38623868.

    • Search Google Scholar
    • Export Citation
  • 55.

    Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer—science driving clinical progress. Nat Rev Cancer 2005;5:459467.

  • 56.

    Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell 2005;122:67.

  • 57.

    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nature Rev Cancer 2006;6:259269.

  • 58.

    Gregory RI, Shiekhattar R. MicroRNA biogenesis and cancer. Cancer Res 2005;65:35093512.

  • 59.

    Bloomston M, Frankel WL, Petrocca F et al.. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007;297:19011908.

    • Search Google Scholar
    • Export Citation
  • 60.

    Lee EJ, Gusev Y, Jiang J et al.. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 2007;120:10461454.

  • 61.

    Almoguera C, Shibata D, Forrester K et al.. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549554.

  • 62.

    Johnson SM, Grosshans H, Shingara J et al.. RAS is regulated by the let-7 microRNA family. Cell 2005;120:635647.

  • 63.

    Mollenhauer J, Roether I, Kern HF. Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 1987;2:1424.

    • Search Google Scholar
    • Export Citation
  • 64.

    Hruban RH. Tumors of the pancreas. In: Hruban RH, Klimstra DS, Pitman MB, eds. Atlas of Tumor Pathology. Fourth Series ed. Washington, DC: Armed Forces Institute of Pathology; 2006.

    • Search Google Scholar
    • Export Citation
  • 65.

    Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972;175:409416.

  • 66.

    Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 2006;103:1249312498.

    • Search Google Scholar
    • Export Citation
  • 67.

    Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in latestage pancreatic islet tumors. Cancer Cell 2005;8:299309.

    • Search Google Scholar
    • Export Citation
  • 68.

    Inoue M, Hager JH, Ferrara N et al.. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002;1:193202.

    • Search Google Scholar
    • Export Citation
  • 69.

    Saif MW. Anti-angiogenesis therapy in pancreatic carcinoma. JOP 2006;7:163173.

  • 70.

    Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2003;2:18.

  • 71.

    Itakura J, Ishiwata T, Friess H et al.. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 1997;3:13091316.

    • Search Google Scholar
    • Export Citation
  • 72.

    Knoll MR, Rudnitzki D, Sturm J et al.. Correlation of postoperative survival and angiogenic growth factors in pancreatic carcinoma. Hepatogastroenterology 2001;48:11621165.

    • Search Google Scholar
    • Export Citation
  • 73.

    Niedergethmann M, Hildenbrand R, Wostbrock B et al.. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas 2002;25:122129.

    • Search Google Scholar
    • Export Citation
  • 74.

    Seo Y, Baba H, Fukuda T et al.. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000;88:22392245.

    • Search Google Scholar
    • Export Citation
  • 75.

    Hurwitz H, Fehrenbacher L, Novotny W et al.. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 76.

    Solorzano CC, Baker CH, Bruns CJ et al.. Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biother Radiopharm 2001;16:359370.

    • Search Google Scholar
    • Export Citation
  • 77.

    Kindler HL, Friberg G, Singh DA et al.. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23:80338040.

    • Search Google Scholar
    • Export Citation
  • 78.

    Ikeda N, Adachi M, Taki T et al.. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 1999;79:15531563.

  • 79.

    Maitra A, Ashfaq R, Gunn CR et al.. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 2002;118:194201.

    • Search Google Scholar
    • Export Citation
  • 80.

    Albazaz R, Verbeke CS, Rahman SH, McMahon MJ. Cyclooxygenase-2 expression associated with severity of PanIN lesions: a possible link between chronic pancreatitis and pancreatic cancer. Pancreatology 2005;5:361369.

    • Search Google Scholar
    • Export Citation
  • 81.

    Tseng WW, Deganutti A, Chen MN et al.. Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer. J Gastrointest Surg 2002;6:838843; discussion 844.

    • Search Google Scholar
    • Export Citation
  • 82.

    Wei D, Wang L, He Y et al.. 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 2004;64:20302038.

    • Search Google Scholar
    • Export Citation
  • 83.

    Funahashi H, Satake M, Dawson D et al.. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res 2007;67:70687071.

    • Search Google Scholar
    • Export Citation
  • 84.

    El-Rayes BF, Zalupski MM, Shields AF et al.. A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest New Drugs 2005;23:583590.

    • Search Google Scholar
    • Export Citation
  • 85.

    Xiong HQ, Plunkett W, Wolff R et al.. A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 2005;55:559564.

    • Search Google Scholar
    • Export Citation
  • 86.

    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nature Rev Cancer 2004;4:423436.

  • 87.

    Colleoni M, Rocca A, Sandri MT et al.. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;13:7380.

    • Search Google Scholar
    • Export Citation
  • 88.

    Mancuso P, Calleri A, Cassi C et al.. Circulating endothelial cells as a novel marker of angiogenesis. Advances in experimental medicine and biology 2003;522:8397.

    • Search Google Scholar
    • Export Citation
  • 89.

    Chue B. Interim results of a weekly, metronomic dosing of paclitaxel, oxaliplatin, leucovorin, 5-FU (POLF) in the treatment of metastatic pancreatic cancer (PC). J Clin Oncol 2007;25(Suppl 1):648S. Abstract 15175.

    • Search Google Scholar
    • Export Citation
  • 90.

    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev Cancer 2002;2:161174.

  • 91.

    Bramhall SR, Rosemurgy A, Brown PD et al.. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001;19:34473455.

    • Search Google Scholar
    • Export Citation
  • 92.

    Moore MJ, Hamm J, Dancey J et al.. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:32963302.

    • Search Google Scholar
    • Export Citation
  • 93.

    An Z, Wang X, Willmott N et al.. Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. Clin Exp Metastasis 1997;15:184195.

    • Search Google Scholar
    • Export Citation
  • 94.

    Bergers G, Javaherian K, Lo KM et al.. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 1999;284:808812.

  • 95.

    Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002;295:23872392.

  • 96.

    Benaud CM, Oberst M, Dickson RB, Lin CY. Deregulated activation of matriptase in breast cancer cells. Clin Exp Metastasis 2002;19:639649.

  • 97.

    Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev Cancer 2002;2:289300.

  • 98.

    List K, Szabo R, Molinolo A et al.. Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev 2005;19:19341950.

    • Search Google Scholar
    • Export Citation
  • 99.

    Galkin AV, Mullen L, Fox WD et al.. CVS-3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts. Prostate 2004;61:228235.

    • Search Google Scholar
    • Export Citation
  • 100.

    Apte MV, Park S, Phillips PA et al.. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004;29:179187.

  • 101.

    Bachem MG, Schunemann M, Ramadani M et al.. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907921.

    • Search Google Scholar
    • Export Citation
  • 102.

    Schneiderhan W, Diaz F, Fundel M et al.. Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci 2007;120(Pt 3):512519.

    • Search Google Scholar
    • Export Citation
  • 103.

    Clark CE, Hingorani SR, Mick R et al.. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:95189527.

    • Search Google Scholar
    • Export Citation
  • 104.

    Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006;66:605612.

  • 105.

    Tsutsui S, Yasuda K, Suzuki K et al.. Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 2005;14:425431.

    • Search Google Scholar
    • Export Citation
  • 106.

    Hamada I, Kato M, Yamasaki T et al.. Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma. Anticancer Res 2002;22:42814284.

    • Search Google Scholar
    • Export Citation
  • 107.

    Dirkx AE, Oude Egbrink MG, Wagstaff J, Griffioen AW. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 2006;80:11831196.

    • Search Google Scholar
    • Export Citation
  • 108.

    Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 2005;167:627635.

    • Search Google Scholar
    • Export Citation
  • 109.

    Joseph IB, Isaacs JT. Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents. J Natl Cancer Inst 1998;90:16481653.

    • Search Google Scholar
    • Export Citation
  • 110.

    Griffiths L, Binley K, Iqball S et al.. The macrophage—a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 2000;7:255262.

  • 111.

    Lei H, Ju DW, Yu Y et al.. Induction of potent antitumor response by vaccination with tumor lysate-pulsed macrophages engineered to secrete macrophage colony-stimulating factor and interferon-gamma. Gene Ther 2000;7:707713.

    • Search Google Scholar
    • Export Citation
  • 112.

    Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev Cancer 2005;5:263274.

  • 113.

    Almand B, Clark JI, Nikitina E et al.. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001;166:678689.

    • Search Google Scholar
    • Export Citation
  • 114.

    Bronte V, Serafini P, Apolloni E, Zanovello P. Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunother 2001;24:431446.

    • Search Google Scholar
    • Export Citation
  • 115.

    Saio M, Radoja S, Marino M, Frey AB. Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide. J Immunol 2001;167:55835593.

    • Search Google Scholar
    • Export Citation
  • 116.

    Bronte V, Apolloni E, Cabrelle A et al.. Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 2000;96:38383846.

    • Search Google Scholar
    • Export Citation
  • 117.

    Seung LP, Rowley DA, Dubey P, Schreiber H. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci U S A 1995;92:62546258.

    • Search Google Scholar
    • Export Citation
  • 118.

    Kusmartsev S, Cheng F, Yu B et al.. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 2003;63:44414449.

    • Search Google Scholar
    • Export Citation
  • 119.

    Curiel TJ, Coukos G, Zou L et al.. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942949.

    • Search Google Scholar
    • Export Citation
  • 120.

    Foss FM. DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. Clin Lymphoma 2000;1:110116; discussion 117.

  • 121.

    Rosenberg SA. Shedding light on immunotherapy for cancer. N Engl J Med 2004;350:14611463.

  • 122.

    Elliott GT, McLeod RA, Perez J, Von Eschen KB. Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol 1993;9:264272.

    • Search Google Scholar
    • Export Citation
  • 123.

    Jaffee EM, Schutte M, Gossett J et al.. Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. Cancer J Sci Am 1998;4:194203.

    • Search Google Scholar
    • Export Citation
  • 124.

    Rosenberg SA. The adoptive immunotherapy of cancer using the transfer of activated lymphoid cells and interleukin-2. Semin Oncol 1986;13:200206.

    • Search Google Scholar
    • Export Citation
  • 125.

    Hruban RH, Adsay NV, Albores-Saavedra J et al.. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 2006;66:95106.

    • Search Google Scholar
    • Export Citation
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