Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma

International Journal of Cancer

Volumn 132, Issue 5, 2013, Pages 993-1003

  Tang, Dong ^a   Wang, Daorong ^a   Yuan, Zhongxu ^b   Xue, Xiaofeng ^b   Zhang, Ye ^b   An, Yong ^b   Chen, Jianmin ^b   Tu, Min ^b   Lu, Zipeng ^b   Wei, Jishu ^b   Jiang, Kuirong ^b   Miao, Yi ^b  

^a NORTHERN JIANGSU PEOPLE S HOSPITAL   (China)

^b THE FIRST AFFILIATED HOSPITAL OF NANJING MEDICAL UNIVERSITY   (China)

Author keywords

pancreatic ductal adenocarcinoma; pancreatic stellate cells; tumor microenvironment

Indexed keywords

ANTINEOPLASTIC AGENT; BOSENTAN; CHEMOTACTIC FACTOR; CYTOKINE; GAMMA INTERFERON; GROWTH FACTOR; HALOFUGINONE; RETINOIC ACID; SARIDEGIB;

CANCER INVASION; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CANCER RESISTANCE; CARCINOGENESIS; CELL ACTIVATION; CELL INTERACTION; CYTOKINE PRODUCTION; DESMOPLASIA; DRUG TARGETING; EXTRACELLULAR MATRIX; HUMAN; HYPOXIA; IMMUNOSURVEILLANCE; MALIGNANT TRANSFORMATION; METASTASIS; NONHUMAN; PANCREAS ADENOCARCINOMA; PANCREATIC STELLATE CELL; PHYSICAL DISEASE BY ETIOLOGY AND PATHOGENESIS; PRIORITY JOURNAL; REVIEW; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT;

CARCINOMA, PANCREATIC DUCTAL; CELL COMMUNICATION; CELL TRANSFORMATION, NEOPLASTIC; HUMANS; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; PANCREATIC NEOPLASMS; PANCREATIC STELLATE CELLS; TUMOR MICROENVIRONMENT;

EID: 84872852392     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.27715     Document Type: Review

References (137)

1. Apte MV, Wilson JS,. Dangerous liaisons: pancreatic stellate cells and pancreatic ductal adenocarcinoma cells. J Gastroenterol Hepatol 2012; 27 (Suppl 2): 69-74.
2. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009; 27: 3778-85.
3. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic ductal adenocarcinoma: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007; 25: 2212-17.
4. Vaccaro V, Sperduti I, Milella M,. FOLFIRINOX versus gemcitabine for metastatic pancreatic ductal adenocarcinoma. N Engl J Med 2011; 365: 768-9; author reply 769.
5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic ductal adenocarcinoma. N Engl J Med 2011; 364: 1817-25.
6. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic ductal adenocarcinoma: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960-6.
7. Kleeff J, Beckhove P, Esposito I, et al. Pancreatic ductal adenocarcinoma microenvironment. Int J Cancer 2007; 121: 699-705.
8. Hanahan D, Weinberg RA,. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-74.
9. Lohr M,. Is it possible to survive pancreatic ductal adenocarcinoma? Nat Clin Pract Gastroenterol Hepatol 2006; 3: 236-7.
10. Li X, Ma Q, Xu Q, et al. Targeting the cancer-stroma interaction: a potential approach for pancreatic ductal adenocarcinoma treatment. Curr Pharm Des 2012.
11. Erkan M, Reiser-Erkan C, Michalski CW, et al. The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. Curr Mol Med 2012; 12: 288-303.
12. Masamune A, Kikuta K, Watanabe T, et al. Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic ductal adenocarcinoma. Am J Physiol Gastrointest Liver Physiol 2008; 295: G709-17.
13. Xu Z, Vonlaufen A, Phillips PA, et al. Role of pancreatic stellate cells in pancreatic ductal adenocarcinoma metastasis. Am J Pathol 2010; 177: 2585-96.
14. Jiang X, Abiatari I, Kong B, et al. Pancreatic islet and stellate cells are the main sources of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 in pancreatic ductal adenocarcinoma. Pancreatology 2009; 9: 165-72.
15. Tang D, Yuan Z, Xue X, et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic ductal adenocarcinoma. Int J Cancer 2012; 130: 2337-48.
16. Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115: 421-32.
17. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998; 43: 128-33.
18. Jaster R,. Molecular regulation of pancreatic stellate cell function. Mol Cancer 2004; 3: 26.
19. Jesnowski R, Furst D, Ringel J, et al. Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine. Lab Invest 2005; 85: 1276-91.
20. Wehr AY, Furth EE, Sangar V, et al. Analysis of the human pancreatic stellate cell secreted proteome. Pancreas 2011; 40: 557-66.
21. Erkan M, Kleeff J, Gorbachevski A, et al. Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 2007; 132: 1447-64.
22. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999; 44: 534-41.
23. 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: 907-21.
24. Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 2008; 68: 918-26.
25. Vonlaufen A, Joshi S, Qu C, et al. Pancreatic stellate cells: partners in crime with pancreatic ductal adenocarcinoma cells. Cancer Res 2008; 68: 2085-93.
26. Lohr M, Schmidt C, Ringel J, et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 2001; 61: 550-5.
27. Apte MV, Park S, Phillips PA, et al. Desmoplastic reaction in pancreatic ductal adenocarcinoma: role of pancreatic stellate cells. Pancreas 2004; 29: 179-87.
28. Bachem MG, Zhou S, Buck K, et al. Pancreatic stellate cells - role in pancreas cancer. Langenbecks Arch Surg 2008; 393: 891-900.
29. Duner S, Lopatko Lindman J, Ansari D, et al. Pancreatic ductal adenocarcinoma: the role of pancreatic stellate cells in tumor progression. Pancreatology 2010; 10: 673-81.
30. Omary MB, Lugea A, Lowe AW, Pandol SJ,. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007; 117: 50-9.
31. Lohr M, Trautmann B, Gottler M, et al. Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins. Br J Cancer 1994; 69: 144-51.
32. Masamune A, Watanabe T, Kikuta K, et al. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol 2009; 7: S48-54.
33. Matthaios D, Zarogoulidis P, Balgouranidou I, et al. Molecular pathogenesis of pancreatic ductal adenocarcinoma and clinical perspectives. Oncology 2011; 81: 259-72.
34. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic ductal adenocarcinoma. International Pancreatitis Study Group. N Engl J Med 1993; 328: 1433-7.
35. Algul H, Treiber M, Lesina M, et al. Mechanisms of disease: chronic inflammation and cancer in the pancreas - a potential role for pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol 2007; 4: 454-62.
36. Lowenfels AB, Maisonneuve P,. Risk factors for pancreatic ductal adenocarcinoma. J Cell Biochem 2005; 95: 649-56.
37. Whitcomb DC, Pogue-Geile K,. Pancreatitis as a risk for pancreatic ductal adenocarcinoma. Gastroenterol Clin North Am 2002; 31: 663-78.
38. Dvorak HF,. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650-9.
39. Apte M, Pirola R, Wilson J,. The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid Redox Signal 2011; 15: 2711-22.
40. Masamune A, Shimosegawa T,. Signal transduction in pancreatic stellate cells. J Gastroenterol 2009; 44: 249-60.
41. Binkley CE, Zhang L, Greenson JK, et al. The molecular basis of pancreatic fibrosis: common stromal gene expression in chronic pancreatitis and pancreatic adenocarcinoma. Pancreas 2004; 29: 254-63.
42. Shimosegawa T, Kume K, Satoh K,. Chronic pancreatitis and pancreatic ductal adenocarcinoma: prediction and mechanism. Clin Gastroenterol Hepatol 2009; 7: S23-8.
43. Mori K, Shibanuma M, Nose K,. Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 2004; 64: 7464-72.
44. Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005; 436: 123-7.
45. Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30: 1073-81.
46. Hussain SP, Hofseth LJ, Harris CC,. Radical causes of cancer. Nat Rev Cancer 2003; 3: 276-85.
47. Grivennikov SI, Greten FR, Karin M,. Immunity, inflammation, and cancer. Cell 2010; 140: 883-99.
48. Sakurai T, Kudo M, Fukuta N, et al. Involvement of angiotensin II and reactive oxygen species in pancreatic fibrosis. Pancreatology 2011;(11 Suppl 2): 7-13.
49. Masamune A, Watanabe T, Kikuta K, et al. NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2008; 294: G99-G108.
50. Asaumi H, Watanabe S, Taguchi M, et al. Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species. Am J Physiol Gastrointest Liver Physiol 2007; 293: G972-8.
51. Ikenaga N, Ohuchida K, Mizumoto K, et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic ductal adenocarcinoma. Gastroenterology 2010; 139: 1041-51, 51 e1-8.
52. Mathison A, Liebl A, Bharucha J, et al. Pancreatic stellate cell models for transcriptional studies of desmoplasia-associated genes. Pancreatology 2010; 10: 505-16.
53. Kanno A, Satoh K, Masamune A, et al. Periostin, secreted from stromal cells, has biphasic effect on cell migration and correlates with the epithelial to mesenchymal transition of human pancreatic ductal adenocarcinoma cells. Int J Cancer 2008; 122: 2707-18.
54. Ruan K, Bao S, Ouyang G,. The multifaceted role of periostin in tumorigenesis. Cell Mol Life Sci 2009; 66: 2219-30.
55. Nguyen DX, Bos PD, Massague J,. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009; 9: 274-84.
56. De Bock K, Mazzone M, Carmeliet P,. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Rev Clin Oncol 2011; 8: 393-404.
57. Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871-90.
58. Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic ductal adenocarcinoma. Cancer Res 2009; 69: 5820-8.
59. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148: 349-61.
60. Joost S, Almada LL, Rohnalter V, et al. GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma cells. Cancer Res 2012; 72: 88-99.
61. Kikuta K, Masamune A, Watanabe T, et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells. Biochem Biophys Res Commun 2010; 403: 380-4.
62. Fujita H, Ohuchida K, Mizumoto K, et al. Tumor-stromal interactions with direct cell contacts enhance proliferation of human pancreatic carcinoma cells. Cancer Sci 2009; 100: 2309-17.
63. Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic ductal adenocarcinoma. Clin Cancer Res 2007; 13: 4769-76.
64. Javle MM, Gibbs JF, Iwata KK, et al. Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic ductal adenocarcinoma. Ann Surg Oncol 2007; 14: 3527-33.
65. Nelson CM, Khauv D, Bissell MJ, et al. Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem 2008; 105: 25-33.
66. Gao Z, Wang X, Wu K, et al. Pancreatic stellate cells increase the invasion of human pancreatic ductal adenocarcinoma cells through the stromal cell-derived factor-1/CXCR4 axis. Pancreatology 2010; 10: 186-93.
67. Li X, Ma Q, Xu Q, et al. SDF-1/CXCR4 signaling induces pancreatic ductal adenocarcinoma cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett 2012; 322: 169-76.
68. Onoue T, Uchida D, Begum NM, et al. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol 2006; 29: 1133-8.
69. Erkan M, Reiser-Erkan C, Michalski CW, et al. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 2009; 11: 497-508.
70. Yang AD, Camp ER, Fan F, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res 2006; 66: 46-51.
71. Lee H, Lim C, Lee J, et al. TGF-beta signaling preserves RECK expression in activated pancreatic stellate cells. J Cell Biochem 2008; 104: 1065-74.
72. Valcourt U, Kowanetz M, Niimi H, et al. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005; 16: 1987-2002.
73. Gui T, Sun Y, Shimokado A, et al. The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-beta-Induced Epithelial-Mesenchymal Transition. J Signal Transduct 2012; 2012: 289243.
74. Horiguchi K, Shirakihara T, Nakano A, et al. Role of Ras signaling in the induction of snail by transforming growth factor-beta. J Biol Chem 2009; 284: 245-53.
75. Karger A, Fitzner B, Brock P, et al. Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells. Cell Signal 2008; 20: 1865-72.
76. Liu BC, Li MX, Zhang JD, et al. Inhibition of integrin-linked kinase via a siRNA expression plasmid attenuates connective tissue growth factor-induced human proximal tubular epithelial cells to mesenchymal transition. Am J Nephrol 2008; 28: 143-51.
77. Liu XC, Liu BC, Zhang XL, et al. Role of ERK1/2 and PI3-K in the regulation of CTGF-induced ILK expression in HK-2 cells. Clin Chim Acta 2007; 382: 89-94.
78. Kayed H, Jiang X, Keleg S, et al. Regulation and functional role of the Runt-related transcription factor-2 in pancreatic ductal adenocarcinoma. Br J Cancer 2007; 97: 1106-15.
79. Chimge NO, Baniwal SK, Little GH, et al. Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res 2011; 13: R127.
80. Pandol S, Edderkaoui M, Gukovsky I, et al. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2009; 7: S44-7.
81. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic ductal adenocarcinoma. Science 2009; 324: 1457-61.
82. Armstrong T, Packham G, Murphy LB, et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res 2004; 10: 7427-37.
83. Sohara N, Znoyko I, Levy MT, et al. Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate. J Hepatol 2002; 37: 214-21.
84. Wirtz D, Konstantopoulos K, Searson PC,. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat Rev Cancer 2011; 11: 512-22.
85. Farrow B, Berger DH, Rowley D,. Tumor-derived pancreatic stellate cells promote pancreatic ductal adenocarcinoma cell invasion through release of thrombospondin-2. J Surg Res 2009; 156: 155-60.
86. Bissell MJ, Radisky D,. Putting tumours in context. Nat Rev Cancer 2001; 1: 46-54.
87. Kalluri R, Zeisberg M,. Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392-401.
88. Langley RR, Fidler IJ,. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 2007; 28: 297-321.
89. Folkman J,. Angiogenesis. Annu Rev Med 2006; 57: 1-18.
90. Ide T, Kitajima Y, Miyoshi A, et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic ductal adenocarcinoma cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer 2006; 119: 2750-9.
91. Cui P, Yu M, Peng X, et al. Melatonin prevents human pancreatic carcinoma cell PANC-1-induced human umbilical vein endothelial cell proliferation and migration by inhibiting vascular endothelial growth factor expression. J Pineal Res 2012; 52: 236-43.
92. Schuch G, Kisker O, Atala A, et al. Pancreatic tumor growth is regulated by the balance between positive and negative modulators of angiogenesis. Angiogenesis 2002; 5: 181-90.
93. Zhou J, Zhang ZX, Zhao H, et al. Anti-angiogenesis by lentivirus-mediated small interfering RNA silencing of angiopoietin-2 gene in pancreatic carcinoma. Technol Cancer Res Treat 2011; 10: 361-9.
94. Zhang W, Erkan M, Abiatari I, et al. Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells. Cancer Biol Ther 2007; 6: 218-27.
95. Weis SM, Cheresh DA,. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005; 437: 497-504.
96. Byrne AM, Bouchier-Hayes DJ, Harmey JH,. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 2005; 9: 777-94.
97. Watanabe K, Hasegawa Y, Yamashita H, et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest 2004; 114: 898-907.
98. Ramachandran V, Arumugam T, Hwang RF, et al. Adrenomedullin is expressed in pancreatic ductal adenocarcinoma and stimulates cell proliferation and invasion in an autocrine manner via the adrenomedullin receptor, ADMR. Cancer Res 2007; 67: 2666-75.
99. Phillips PA, McCarroll JA, Park S, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut 2003; 52: 275-82.
100. Ribatti D,. Endogenous inhibitors of angiogenesis: a historical review. Leuk Res 2009; 33: 638-44.
101. Willimsky G, Blankenstein T,. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437: 141-6.
102. Stewart CA, Trinchieri G,. Reinforcing suppression using regulators: a new link between STAT3, IL-23, and Tregs in tumor immunosuppression. Cancer Cell 2009; 15: 81-3.
103. Markiewski MM, DeAngelis RA, Benencia F, et al. Modulation of the antitumor immune response by complement. Nat Immunol 2008; 9: 1225-35.
104. Arum CJ, Anderssen E, Viset T, et al. Cancer immunoediting from immunosurveillance to tumor escape in microvillus-formed niche: a study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer. Neoplasia 2010; 12: 434-42.
105. Clark CE, Beatty GL, Vonderheide RH,. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett 2009; 279: 1-7.
106. Schmitz-Winnenthal FH, Volk C, Z'Graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic ductal adenocarcinoma patients. Cancer Res 2005; 65: 10079-87.
107. Kubuschok B, Xie X, Jesnowski R, et al. Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis. Int J Cancer 2004; 109: 568-75.
108. Esposito I, Menicagli M, Funel N, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004; 57: 630-6.
109. Seicean A, Popa D, Mocan T, et al. Th1 and Th2 profiles in patients with pancreatic ductal adenocarcinoma compared with chronic pancreatitis. Pancreas 2009; 38: 594-5.
110. Valastyan S, Weinberg RA,. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275-92.
111. Peinado H, Lavotshkin S, Lyden D,. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 2011; 21: 139-46.
112. Phillips PA, Wu MJ, Kumar RK, et al. Cell migration: a novel aspect of pancreatic stellate cell biology. Gut 2003; 52: 677-82.
113. Paget S,. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8: 98-101.
114. Shek FW, Benyon RC, Walker FM, et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 2002; 160: 1787-98.
115. Yang C, Zeisberg M, Mosterman B, et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology 2003; 124: 147-59.
116. Tien YW, Wu YM, Lin WC, et al. Pancreatic carcinoma cells stimulate proliferation and matrix synthesis of hepatic stellate cells. J Hepatol 2009; 51: 307-14.
117. Kordes C, Sawitza I, Haussinger D,. Hepatic and pancreatic stellate cells in focus. Biol Chem 2009; 390: 1003-12.
118. Psaila B, Lyden D,. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009; 9: 285-93.
119. Kaplan RN, Rafii S, Lyden D,. Preparing the «soil»: the premetastatic niche. Cancer Res 2006; 66: 11089-93.
120. Miyamoto H, Murakami T, Tsuchida K, et al. Tumor-stroma interaction of human pancreatic ductal adenocarcinoma: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004; 28: 38-44.
121. Muerkoster S, Wegehenkel K, Arlt A, et al. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 2004; 64: 1331-7.
122. Boehrer S, Nowak D, Hoelzer D, et al. Novel agents aiming at specific molecular targets increase chemosensitivity and overcome chemoresistance in hematopoietic malignancies. Curr Pharm Des 2006; 12: 111-28.
123. Wang F, Liu R, Lee SW, et al. Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene 2007; 26: 2006-16.
124. Couvelard A, O'Toole D, Leek R, 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: 668-76.
125. Wilson WR, Hay MP,. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11: 393-410.
126. Milane L, Ganesh S, Shah S, et al. Multi-modal strategies for overcoming tumor drug resistance: hypoxia, the Warburg effect, stem cells, and multifunctional nanotechnology. J Control Release 2011; 155: 237-47.
127. Rohwer N, Cramer T,. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 2011; 14: 191-201.
128. Koninger J, Giese NA, di Mola FF, et al. Overexpressed decorin in pancreatic ductal adenocarcinoma: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res 2004; 10: 4776-83.
129. Mantoni TS, Lunardi S, Al-Assar O, et al. Pancreatic stellate cells radioprotect pancreatic ductal adenocarcinoma cells through beta1-integrin signaling. Cancer Res 2011; 71: 3453-8.
130. Talukdar R, Tandon RK,. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol 2008; 23: 34-41.
131. Lonardo E, Hermann PC, Mueller MT, et al. Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic ductal adenocarcinoma stem cells and provides a target for combined drug therapy. Cell Stem Cell 2011; 9: 433-46.
132. Erkan M, Adler G, Apte MV, et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 2012; 61: 172-8.
133. Bhatia V, Kim SO, Aronson JF, et al. Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis. Regul Pept 2012; 175: 49-60.
134. Lange F, Rateitschak K, Fitzner B, et al. Studies on mechanisms of interferon-gamma action in pancreatic ductal adenocarcinoma using a data-driven and model-based approach. Mol Cancer 2011; 10: 13.
135. Froeling FE, Feig C, Chelala C, et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 2011; 141: 1486-97, 97 e1-14.
136. Spector I, Honig H, Kawada N, et al. Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas 2010; 39: 1008-15.
137. Fitzner B, Brock P, Holzhuter SA, et al. Synergistic growth inhibitory effects of the dual endothelin-1 receptor antagonist bosentan on pancreatic stellate and cancer cells. Dig Dis Sci 2009; 54: 309-20.