Information
References
Contents
Download
[1]Yauch RL, Settleman J. Recent advances in pathway-targeted cancerdrug therapies emerging from cancer genome analysis. Curr Opin Genet Dev 22, 45-9 (2012)
[2]Hidalgo M. Pancreatic cancer. N Engl J Med 362, 1605-17 (2010)
[3]Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment andfuture challenges. Nat Rev Clin Oncol 7, 163-72 (2010)
[4]Lombardi L, Troiano T, Silvestris N, Nanni L, Latiano TP, Di Maggio G. Combined modality treatments in pancreatic cancer. Expert Opin Ther Targets 16(Suppl. 2), S71-81 (2012)
[5]O’Reilly EM. Refinement of adjuvant therapy for pancreatic cancer. JAMA 304(10), 1124-5 (2010)
[6]Malik NK, May KS, Chandrasekhar R, Ma WW, Flaherty L, Iyer R. Treatment of locally advanced unresectable pancreatic cancer: a 10-yearexperience. J Gastrointest Oncol 3(4), 326-34 (2012)
[7]Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR. Improvements in survival and clinical benefit with gemcitabine as firstline therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6), 2403-13 (1997)
[8]Jones S, Zhang X, Wiilams Parsons D, Cheng-Ho Lin J, Leary RJ. Coresignalling pathways in human pancreatic cancers revealed by global genomicanalyses. Science 321(5897), 1801-6 (2008)
[9]Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The Pancreas Cancer Microenvironment. Clin Cancer Res 18, 4266-4276 (2012)
[10]Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9, 454-467 (2012)
[11]Chu GC, Kimmelman AC, Hezel AF, DePinho RA. Stromaliology of pancreatic cancer. J Cell Biochem 101, 887-907 (2007)
[12]Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18, 884-901 (2010)
[13]Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43,128–33 (1998)
[14]Vonlaufen A, Phillips PA, Yang L, Xu Z. Isolation of quiescent human pancreatic stellate cells: a promising in vitro tool for studies of human pancreatic stellate cell biology. Pancreatology 10, 434-443 (2010)
[15]Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115, 421-432 (1998)
[16]Bachem MG, Schünemann M, Ramadani M, Siech M, Beger H, Buck A, Zhou S, Schmid-Kotsas A, Adler G: Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907-921 (2005)
[17]Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117, 50-9 (2007)
[18]Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 3, 344 (2012)
[19]Xu Z, Pothula SP, Wilson JS, Apte MV. Pancreatic cancer and its stroma: A conspiracy theory. World J Gastroenterol 20(32), 11216-11229 (2014)
[20]Hamada S, Masamune A, Takikawa T, Suzuki N, Kikuta K, Hirota M. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells-Biochem Biophys Res Commun 421(2) 349-354 (2012)
[21]Kordes C, Sawitza I, Götze S, Häussinger D. Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 7, e51878 (2012)
[22]De Oliveira T, Abiatari I, Raulefs S, Sauliunaite D. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol Cancer 11, 19 (2012)
[23]Erkan M, Adler G, Apte MV, Bachem MG. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61,172-8 (2012)
[24]Bachem MG, Schünemann M, Ramadani M. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907-921 (2005)
[25]Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 68, 2085-2093 (2008)
[26]Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 177, 2585-2596 (2010)
[27]Nakao A, Harada A, Nonami T, Kaneko T, Takagi H. Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer.Pancreas 12(4), 357-61 (1996)
[28]Zhou Y, Zhou Q, Chen R. Pancreatic stellate cells promotes the perineural invasion in pancreatic cancer. Medical Hypotheses 78(6)811-813 (2012)
[29]Hamada S, Masamune A, Takikawa T, Suzuki N, Kikuta K, Hirota M, Hamada H, Kobune M, Satoh K, Shimosegawa T. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun 421, 349-354 (2012)
[30]Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210-1219 (2013)
[31]Fujiwara K, Ohuchida K, Ohtsuka T, Mizumoto K, Shindo K, Ikenaga N, Cui L, Takahata S, Aishima S, Tanaka M. Migratory activity of CD105+ pancreatic cancer cells is strongly enhanced by pancreatic stellate cells. Pancreas 42, 1283-1290 (2013)
[32]Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 6, 392-401 (2006)
[33]Bronsert P, Kohler I, Timme S, Kiefer S, Werner M, Schilling O. Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery 156, 97-108 (2014)
[34]Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell 25, 719-734 (2014)
[35]Hu M, Peluffo G, Chen H, Gelman R, Schnitt S, Polyak K. Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Natl Acad Sci USA 106, 3372-7 (2009)
[36]Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA. Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 44,509-17 (2008)
[37]Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol 21(1), 19-25 (2010)
[38]Mielgo A, Schmid MC. Impact of tumour associated macrophages in pancreatic cancer. BMB Rep 46(3), 131-8 (2013)
[39]Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22, 231-237 (2010)
[40]Greten FR, Eckmann L, Greten TF, Park JM, Li ZW. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296 (2004)
[41]Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749-759 (2005)
[42]Greten FR, Eckmann L, Greten TF, Park JM, Li ZW. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66, 11238-11246 (2006)
[43]Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4, e6562 (2009)
[44]Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol 33, 119-126 (2012)
[45]Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N. Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci 103, 2012-2020 (2012)
[46]Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE. Targeting tumor-infiltrating macrophages decreases tumor-Initiating cells, relieves immunosuppression and improves chemotherapeutic response. Cancer Res 73, 1128-1141 (2013)
[47]Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822-835 (2012)
[48]Narita Y, Wakita D, Ohkur T, Chamoto K, Nishimura T. Potential differentiation of tumor bearing mouse CD11b+Gr-1+ immature myeloid cells into both suppressor macrophages and immunostimulatory dendritic cells. Biomed Res 30, 7-15. 40 (2009)
[49]Kusmartsev S, Nagaraj S, Gabrilovich DI. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175, 4583-4592 (2005)
[50]Lewis JS, Landers RJ, Underwood JC, Harris AL. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 192,150-158 (2000)
[51]Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114, 623-633 (2004)
[52]Schmid MC, Avraamides CJ, Dippold HC, Franco I. A. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715-727 (2011)
[53]Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang SW. Combined blockade of integrin-alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res 71, 6965-6975 (2011)
[54]Tugues S, Honjo S, König C, Noguer O, Hedlund M, Botling J. Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization. Cancer Res 72, 1953-1963 (2012)
[55]Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239-252 (2009)
[56]Campbell AS, Albo D, Kimsey TF, White SL, Wang TN. Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion. J Surg Res 123, 96-101 (2005)
[57]Kimsey TF, Campbell AS, Albo D, Wilson M, Wang TN. Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion. Cancer J 10, 374-380 (2004)
[58]Cavel O, Shomron O, Shabtay A, Vital J, Trejo-Leider L, Weizman N. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res 72, 5733-5743 (2012)
[59]Ranieri G, Ammendola M, Patruno R, Celano G, Zito FA, Montemurro S. Tryptasepositive mast cells correlate with angiogenesis in early breast cancer patients. Int J Oncol 35(1),115–120 (2009)
[60]Esposito I, Menicagli M, Funel N. Inflammatory cells contribute to the generation of angiogenic phenotype in pancreatic ductal adenocarcionoma. J Clin Pathol 57,630-6 (2004)
[61]Theoharides TC. Mast Cells and Pancreatic Cancer. N Engl J Med 358 17,1860-1861 (2008)
[62]Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13,1211-8 (2007)
[63]Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002)
[64]Ribatti D, Ranieri G, Nico B, Benagiano V, Crivellato E. Tryptase and chymase are angiogenic in vivo in the chorioallantoic membrane assay. Int J Dev Biol 55(1) 99–102 (2011)
[65]Mangia A, Malfettone A, Rossi R, Paradiso A, Ranieri G, Simone G, Resta L. Tissue remodeling in breast cancer: human mast cell tryptase as an initiator of myofibroblast differentiation. Histopathology 58(7)1096–1106 (2011)
[66]Ranieri G, Gadaleta-Caldarola G, Goffredo V, Patruno R, Mangia A. Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development. Curr Med Chem 19(7)938–944 (2012)
[67]Ma Y, Ullrich SE. Intratumoral mast cells promote the growth of pancreatic cancer. Oncoimmunology 1(2), Article ID e25964 (2013)
[68]Ma Y, Hwang RF, Logsdon CD, Ullrich SE. Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res 73(13)3927–3937 (2013)
[69]Ammendola M, Sacco R, Sammarco G, Donato G, Zuccalà V, Luposella M. Mast Cells Density Positive to Tryptase Correlates with Angiogenesis in Pancreatic Ductal Adenocarcinoma Patients Having Undergone Surgery. Gastroenterol Res Pract 2014,951957 (2014)
[70]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 67, 9518-27 (2007)
[71]Schmitz-Winnenthal FH, Volk C, Z’graggen K, Galindo L, Nummer D, Ziouta Y. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 65, 10079-87 (2005)
[72]Schmitz-Winnenthal FH, Escobedo LV, Beckhove P, Schirrmacher V, Bucur M, Ziouta Y, Volk C, Schmied B, Koch M, Antolovic D, Weitz J, B€uchler MW. Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-gamma. Int J Oncol 28, 1419-28 (2006)
[73]Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90, 1-50 (2006)
[74]Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 22, 329-360 (2004)
[75]Schreiber RD, Pace JL, Russell SW, Altman A, Katz DH. Macrophage-activating factor produced by a T cell hybridoma: physiochemical and biosynthetic resemblance to gamma-interferon. J Immunol 131, 826-832 (1983)
[76]Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 33, 2956-2967 (2014)
[77]Ademmer K, Ebert M, Muller-Ostermeyer F, Friess H, Buchler MW, Schubert W. Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+cells and CD8+CD103+ cells by multi-epitope imaging. Clin Exp Immunol 112, 21-26 (1998)
[78]Kim JS, Park YS, Kim JY, Kim YG, Kim YJ, Lee HK. Inhibition of human pancreatic tumor growth by cytokine-induced killer cells in nude mouse xenograft model. Immune Netw 12, 247-252 (2012)
[79]Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108, 914-923 (2013)
[80]Pignatelli M, Ansari TW, Gunter P, Liu D, Hirano S, Takeichi M. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymphnode metastasis, high grade, and advanced stage. J Pathol 174, 243-248 (1994)
[81]Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846-1856 (1993)
[82]Gnerlich JL, Mitchem JB, Weir JS, Sankpal NV, Kashiwagi H, Belt BA. Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer. J Immunol 185, 4063-4071 (2010)
[83]He S, Fei M, Wu Y, Zheng D, Wan D, Wang L. Distribution and clinical significance of th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients. Int J Mol Sci 12, 7424-7437 (2011)
[84]Vizio B, Novarino A, Giacobino A, Cristiano C, Prati A, Ciuffreda L. Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. Exp Ther Med 4, 70-78 (2012)
[85]Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12, 298-306 (2012)
[86]Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60, 1419-1430 (2011)
[87]Tassi E, Gavazzi F, Albarello L, Senyukov V, Longhi R, Dellabona P. Carcinoembryonic antigen-specific but not antiviral CD4t T cell immunity is impaired in pancreatic carcinoma patients. J Immunol 181, 6595–6603 (2008)
[88]Qin FX. Dynamic behavior and function of Foxp3+ regulatory T cells in tumor bearing host. Cell Mol Immunol 6(1), 3-13 (2009)
[89]Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 57(1), 183-94 (2013)
[90]Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M. Clinical roles of increased populations of Foxp3+CD4 T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 33(4), 386-90 (2006)
[91]Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12(18), 5423-34 (2006)
[92]Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S. Circulating CD4+CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas 41(3), 409-15 (2012)
Article Metrics
Download
- Contents
Information
Download
Contents
Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Role of the tumor microenvironment in pancreatic adenocarcinoma
1 Interventional Center, TongRen Hospital affiliated to Shanghai Jiaotong University School of Medicine, No. 786, Yuyuan Road, Shanghai 200050, China
2 Institute of Medical Intervention Engineering, Tongji University, North Zhongshan Road, Shanghai, China
Abstract
Pancreatic cancer is a devastating disease with proclivity for early metastasis, which accounts for its poor prognosis. The clinical problem of pancreatic cancer is its resistance to conventional therapies, such as chemotherapy or radiation. Based upon these challenges, the focus of research on pancreatic cancer has shifted gradually towards the tumor microenvironment. The cancer microenvironment consists of various components, including fibroblasts, endothelial cells, immune cells, and endocrine cells, that interact with each other, and with the cancer cells in a complex fashion. Evidence is accumulating that the cancer microenvironment plays an active role in disease progression, and efforts are being made to target this interplay between cancer cells and host cells, to improve the prognosis of the disease. In the present review, we describe the cellular microenvironment of pancreatic ductal adenocarcinoma (PDA), the major type of pancreatic cancer. Our hope is that a better understanding of the cellular microenvironment of PDA will eventually lead to better treatments for this disease.
Keywords
- Tumor Microenvironment
- Cellular Components
- Pancreatic Ductal Adenocarcinoma
- Review
References
- [1] Yauch RL, Settleman J. Recent advances in pathway-targeted cancerdrug therapies emerging from cancer genome analysis. Curr Opin Genet Dev 22, 45-9 (2012)
- [2] Hidalgo M. Pancreatic cancer. N Engl J Med 362, 1605-17 (2010)
- [3] Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment andfuture challenges. Nat Rev Clin Oncol 7, 163-72 (2010)
- [4] Lombardi L, Troiano T, Silvestris N, Nanni L, Latiano TP, Di Maggio G. Combined modality treatments in pancreatic cancer. Expert Opin Ther Targets 16(Suppl. 2), S71-81 (2012)
- [5] O’Reilly EM. Refinement of adjuvant therapy for pancreatic cancer. JAMA 304(10), 1124-5 (2010)
- [6] Malik NK, May KS, Chandrasekhar R, Ma WW, Flaherty L, Iyer R. Treatment of locally advanced unresectable pancreatic cancer: a 10-yearexperience. J Gastrointest Oncol 3(4), 326-34 (2012)
- [7] Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR. Improvements in survival and clinical benefit with gemcitabine as firstline therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6), 2403-13 (1997)
- [8] Jones S, Zhang X, Wiilams Parsons D, Cheng-Ho Lin J, Leary RJ. Coresignalling pathways in human pancreatic cancers revealed by global genomicanalyses. Science 321(5897), 1801-6 (2008)
- [9] Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The Pancreas Cancer Microenvironment. Clin Cancer Res 18, 4266-4276 (2012)
- [10] Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9, 454-467 (2012)
- [11] Chu GC, Kimmelman AC, Hezel AF, DePinho RA. Stromaliology of pancreatic cancer. J Cell Biochem 101, 887-907 (2007)
- [12] Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18, 884-901 (2010)
- [13] Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43,128–33 (1998)
- [14] Vonlaufen A, Phillips PA, Yang L, Xu Z. Isolation of quiescent human pancreatic stellate cells: a promising in vitro tool for studies of human pancreatic stellate cell biology. Pancreatology 10, 434-443 (2010)
- [15] Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115, 421-432 (1998)
- [16] Bachem MG, Schünemann M, Ramadani M, Siech M, Beger H, Buck A, Zhou S, Schmid-Kotsas A, Adler G: Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907-921 (2005)
- [17] Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117, 50-9 (2007)
- [18] Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 3, 344 (2012)
- [19] Xu Z, Pothula SP, Wilson JS, Apte MV. Pancreatic cancer and its stroma: A conspiracy theory. World J Gastroenterol 20(32), 11216-11229 (2014)
- [20] Hamada S, Masamune A, Takikawa T, Suzuki N, Kikuta K, Hirota M. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells-Biochem Biophys Res Commun 421(2) 349-354 (2012)
- [21] Kordes C, Sawitza I, Götze S, Häussinger D. Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 7, e51878 (2012)
- [22] De Oliveira T, Abiatari I, Raulefs S, Sauliunaite D. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol Cancer 11, 19 (2012)
- [23] Erkan M, Adler G, Apte MV, Bachem MG. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61,172-8 (2012)
- [24] Bachem MG, Schünemann M, Ramadani M. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907-921 (2005)
- [25] Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 68, 2085-2093 (2008)
- [26] Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 177, 2585-2596 (2010)
- [27] Nakao A, Harada A, Nonami T, Kaneko T, Takagi H. Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer.Pancreas 12(4), 357-61 (1996)
- [28] Zhou Y, Zhou Q, Chen R. Pancreatic stellate cells promotes the perineural invasion in pancreatic cancer. Medical Hypotheses 78(6)811-813 (2012)
- [29] Hamada S, Masamune A, Takikawa T, Suzuki N, Kikuta K, Hirota M, Hamada H, Kobune M, Satoh K, Shimosegawa T. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun 421, 349-354 (2012)
- [30] Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210-1219 (2013)
- [31] Fujiwara K, Ohuchida K, Ohtsuka T, Mizumoto K, Shindo K, Ikenaga N, Cui L, Takahata S, Aishima S, Tanaka M. Migratory activity of CD105+ pancreatic cancer cells is strongly enhanced by pancreatic stellate cells. Pancreas 42, 1283-1290 (2013)
- [32] Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 6, 392-401 (2006)
- [33] Bronsert P, Kohler I, Timme S, Kiefer S, Werner M, Schilling O. Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery 156, 97-108 (2014)
- [34] Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell 25, 719-734 (2014)
- [35] Hu M, Peluffo G, Chen H, Gelman R, Schnitt S, Polyak K. Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Natl Acad Sci USA 106, 3372-7 (2009)
- [36] Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA. Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 44,509-17 (2008)
- [37] Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol 21(1), 19-25 (2010)
- [38] Mielgo A, Schmid MC. Impact of tumour associated macrophages in pancreatic cancer. BMB Rep 46(3), 131-8 (2013)
- [39] Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22, 231-237 (2010)
- [40] Greten FR, Eckmann L, Greten TF, Park JM, Li ZW. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296 (2004)
- [41] Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749-759 (2005)
- [42] Greten FR, Eckmann L, Greten TF, Park JM, Li ZW. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66, 11238-11246 (2006)
- [43] Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4, e6562 (2009)
- [44] Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol 33, 119-126 (2012)
- [45] Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N. Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci 103, 2012-2020 (2012)
- [46] Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE. Targeting tumor-infiltrating macrophages decreases tumor-Initiating cells, relieves immunosuppression and improves chemotherapeutic response. Cancer Res 73, 1128-1141 (2013)
- [47] Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822-835 (2012)
- [48] Narita Y, Wakita D, Ohkur T, Chamoto K, Nishimura T. Potential differentiation of tumor bearing mouse CD11b+Gr-1+ immature myeloid cells into both suppressor macrophages and immunostimulatory dendritic cells. Biomed Res 30, 7-15. 40 (2009)
- [49] Kusmartsev S, Nagaraj S, Gabrilovich DI. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175, 4583-4592 (2005)
- [50] Lewis JS, Landers RJ, Underwood JC, Harris AL. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 192,150-158 (2000)
- [51] Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114, 623-633 (2004)
- [52] Schmid MC, Avraamides CJ, Dippold HC, Franco I. A. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715-727 (2011)
- [53] Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang SW. Combined blockade of integrin-alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res 71, 6965-6975 (2011)
- [54] Tugues S, Honjo S, König C, Noguer O, Hedlund M, Botling J. Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization. Cancer Res 72, 1953-1963 (2012)
- [55] Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239-252 (2009)
- [56] Campbell AS, Albo D, Kimsey TF, White SL, Wang TN. Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion. J Surg Res 123, 96-101 (2005)
- [57] Kimsey TF, Campbell AS, Albo D, Wilson M, Wang TN. Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion. Cancer J 10, 374-380 (2004)
- [58] Cavel O, Shomron O, Shabtay A, Vital J, Trejo-Leider L, Weizman N. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res 72, 5733-5743 (2012)
- [59] Ranieri G, Ammendola M, Patruno R, Celano G, Zito FA, Montemurro S. Tryptasepositive mast cells correlate with angiogenesis in early breast cancer patients. Int J Oncol 35(1),115–120 (2009)
- [60] Esposito I, Menicagli M, Funel N. Inflammatory cells contribute to the generation of angiogenic phenotype in pancreatic ductal adenocarcionoma. J Clin Pathol 57,630-6 (2004)
- [61] Theoharides TC. Mast Cells and Pancreatic Cancer. N Engl J Med 358 17,1860-1861 (2008)
- [62] Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13,1211-8 (2007)
- [63] Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002)
- [64] Ribatti D, Ranieri G, Nico B, Benagiano V, Crivellato E. Tryptase and chymase are angiogenic in vivo in the chorioallantoic membrane assay. Int J Dev Biol 55(1) 99–102 (2011)
- [65] Mangia A, Malfettone A, Rossi R, Paradiso A, Ranieri G, Simone G, Resta L. Tissue remodeling in breast cancer: human mast cell tryptase as an initiator of myofibroblast differentiation. Histopathology 58(7)1096–1106 (2011)
- [66] Ranieri G, Gadaleta-Caldarola G, Goffredo V, Patruno R, Mangia A. Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development. Curr Med Chem 19(7)938–944 (2012)
- [67] Ma Y, Ullrich SE. Intratumoral mast cells promote the growth of pancreatic cancer. Oncoimmunology 1(2), Article ID e25964 (2013)
- [68] Ma Y, Hwang RF, Logsdon CD, Ullrich SE. Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res 73(13)3927–3937 (2013)
- [69] Ammendola M, Sacco R, Sammarco G, Donato G, Zuccalà V, Luposella M. Mast Cells Density Positive to Tryptase Correlates with Angiogenesis in Pancreatic Ductal Adenocarcinoma Patients Having Undergone Surgery. Gastroenterol Res Pract 2014,951957 (2014)
- [70] 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 67, 9518-27 (2007)
- [71] Schmitz-Winnenthal FH, Volk C, Z’graggen K, Galindo L, Nummer D, Ziouta Y. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 65, 10079-87 (2005)
- [72] Schmitz-Winnenthal FH, Escobedo LV, Beckhove P, Schirrmacher V, Bucur M, Ziouta Y, Volk C, Schmied B, Koch M, Antolovic D, Weitz J, B€uchler MW. Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-gamma. Int J Oncol 28, 1419-28 (2006)
- [73] Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90, 1-50 (2006)
- [74] Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 22, 329-360 (2004)
- [75] Schreiber RD, Pace JL, Russell SW, Altman A, Katz DH. Macrophage-activating factor produced by a T cell hybridoma: physiochemical and biosynthetic resemblance to gamma-interferon. J Immunol 131, 826-832 (1983)
- [76] Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 33, 2956-2967 (2014)
- [77] Ademmer K, Ebert M, Muller-Ostermeyer F, Friess H, Buchler MW, Schubert W. Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+cells and CD8+CD103+ cells by multi-epitope imaging. Clin Exp Immunol 112, 21-26 (1998)
- [78] Kim JS, Park YS, Kim JY, Kim YG, Kim YJ, Lee HK. Inhibition of human pancreatic tumor growth by cytokine-induced killer cells in nude mouse xenograft model. Immune Netw 12, 247-252 (2012)
- [79] Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108, 914-923 (2013)
- [80] Pignatelli M, Ansari TW, Gunter P, Liu D, Hirano S, Takeichi M. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymphnode metastasis, high grade, and advanced stage. J Pathol 174, 243-248 (1994)
- [81] Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846-1856 (1993)
- [82] Gnerlich JL, Mitchem JB, Weir JS, Sankpal NV, Kashiwagi H, Belt BA. Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer. J Immunol 185, 4063-4071 (2010)
- [83] He S, Fei M, Wu Y, Zheng D, Wan D, Wang L. Distribution and clinical significance of th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients. Int J Mol Sci 12, 7424-7437 (2011)
- [84] Vizio B, Novarino A, Giacobino A, Cristiano C, Prati A, Ciuffreda L. Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. Exp Ther Med 4, 70-78 (2012)
- [85] Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12, 298-306 (2012)
- [86] Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60, 1419-1430 (2011)
- [87] Tassi E, Gavazzi F, Albarello L, Senyukov V, Longhi R, Dellabona P. Carcinoembryonic antigen-specific but not antiviral CD4t T cell immunity is impaired in pancreatic carcinoma patients. J Immunol 181, 6595–6603 (2008)
- [88] Qin FX. Dynamic behavior and function of Foxp3+ regulatory T cells in tumor bearing host. Cell Mol Immunol 6(1), 3-13 (2009)
- [89] Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 57(1), 183-94 (2013)
- [90] Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M. Clinical roles of increased populations of Foxp3+CD4 T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 33(4), 386-90 (2006)
- [91] Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12(18), 5423-34 (2006)
- [92] Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S. Circulating CD4+CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas 41(3), 409-15 (2012)
