Pancreatic cancer stroma: Understanding biology leads to new therapeutic strategies

World Journal of Gastroenterology

Volumn 20, Issue 9, 2014, Pages 2237-2246

  Rucki, Agnieszka Anna ^a   Zheng, Lei ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Cancer associated fibroblast; Fibroblast activation protein; Hepatic growth factor; Pancreatic ductal adenocarcinoma; Pancreatic stellate cells; Sonic hedgehog; Stroma; Tumor microenvironment

Indexed keywords

CANCER GROWTH FACTOR; HYALURONIDASE; INTERLEUKIN 10; INTERLEUKIN 17; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; ANTINEOPLASTIC AGENT;

ARTICLE; CANCER GROWTH; CANCER IMMUNOTHERAPY; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROBLAST; HISTOLOGY; HUMAN; IMMUNE RESPONSE; NATURAL KILLER CELL; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; REGULATORY T LYMPHOCYTE; STROMA; TUMOR MICROENVIRONMENT; TUMOR VOLUME; UPREGULATION; ANIMAL; DRUG DESIGN; DRUG EFFECTS; METABOLISM; MOLECULARLY TARGETED THERAPY; PANCREATIC NEOPLASMS; PATHOLOGY; SIGNAL TRANSDUCTION; STROMA CELL;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DESIGN; HUMANS; MOLECULAR TARGETED THERAPY; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION; STROMAL CELLS; TUMOR MICROENVIRONMENT;

EID: 84895891540     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i9.2237     Document Type: Article

References (105)

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10-29 [PMID: 22237781 DOI: 10.3322/ caac.20138]
2. Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res 2008; 149: 319-328 [PMID: 18639248]
3. Lewin CS, Allen RA, Amyes SG. Mechanisms of zidovudine resistance in bacteria. J Med Microbiol 1990; 33: 235-238 [PMID: 2124270]
4. Waghray M, Yalamanchili M, di Magliano MP, Simeone DM. Deciphering the role of stroma in pancreatic cancer. Curr Opin Gastroenterol 2013; 29: 537-543 [PMID: 23892539 DOI: 10.1097/MOG.0b013e328363affe]
5. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res 2012; 18: 4266-4276 [PMID: 22896693 DOI: 10.1158/1078-0432. ccr-11-3114]
6. Erkan M, Michalski CW, Rieder S, Reiser-Erkan C, Abiatari I, Kolb A, Giese NA, Esposito I, Friess H, Kleeff J. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2008; 6: 1155-1161 [PMID: 18639493 DOI: 10.1016/j.cgh.2008.05.006]
7. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, Mc-Intyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457-1461 [PMID: 19460966]
8. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O'Dwyer PJ, Vonderheide RH. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331: 1612-1616 [PMID: 21436454 DOI: 10.1126/science.1198443]
9. Heinemann V, Reni M, Ychou M, Richel DJ, Macarulla T, Ducreux M. Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. Cancer Treat Rev 2014; 40: 118-128 [PMID: 23849556 DOI: 10.1016/j.ctrv.2013.04.004]
10. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. 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: 2403-2413 [PMID: 9196156]
11. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825 [PMID: 21561347 DOI: 10.1056/NEJMoa1011923]
12. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grünert A, Adler G. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115: 421-432 [PMID: 9679048 DOI: 10.1016/S0016-5085(98)70209-4]
13. Bachem MG, Zhou S, Buck K, Schneiderhan W, Siech M. Pancreatic stellate cells--role in pancreas cancer. Langenbecks Arch Surg 2008; 393: 891-900 [PMID: 18204855 DOI: 10.1007/ s00423-008-0279-5]
14. Franco OE, Shaw AK, Strand DW, Hayward SW. Cancer associated fibroblasts in cancer pathogenesis. Semin Cell Dev Biol 2010; 21: 33-39 [PMID: 19896548 DOI: 10.1016/ j.semcdb.2009.10.010]
15. Spector I, Zilberstein Y, Lavy A, Nagler A, Genin O, Pines M. Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice. PLoS One 2012; 7: e41833 [PMID: 22848627 DOI: 10.1371/journal. pone.0041833]
16. Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 2013; 144: 1210-1219 [PMID: 23622130 DOI: 10.1053/j.gastro.2012.11.037]
17. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013; 73: 3007-3018 [PMID: 23514705 DOI: 10.1158/0008-5472.can-12-4601]
18. 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 2012; 421: 349-354 [PMID: 22510406 DOI: 10.1016/j.bbrc.2012.04.014]
19. Mace TA, Bloomston M, Lesinski GB. Pancreatic cancerassociated stellate cells: A viable target for reducing immunosuppression in the tumor microenvironment. Oncoimmunology 2013; 2: e24891 [PMID: 24073373 DOI: 10.4161/ onci.24891]
20. Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, Riches JC, Marshall JF, Chin-Aleong J, Chelala C, Gribben JG, Ramsay AG, Kocher HM. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013; 145: 1121-1132 [PMID: 23891972 DOI: 10.1053/j.gastro.2013.07.025]
21. Kadaba R, Birke H, Wang J, Hooper S, Andl CD, Di Maggio F, Soylu E, Ghallab M, Bor D, Froeling FE, Bhattacharya S, Rustgi AK, Sahai E, Chelala C, Sasieni P, Kocher HM. Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. J Pathol 2013; 230: 107-117 [PMID: 23359139 DOI: 10.1002/path.4172]
22. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, Buchler M, Friess H, McCarroll JA, Ke-ogh G, Merrett N, Pirola R, Wilson JS. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004; 29: 179-187 [PMID: 15367883]
23. Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther 2006; 5: 1640-1646 [PMID: 17106243]
24. Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E, Cheng JD. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer 2011; 11: 245 [PMID: 21668992 DOI: 10.1186/1471-2407-11-245]
25. Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci 2010; 123: 4195-4200 [PMID: 21123617 DOI: 10.1242/jcs.023820]
26. Apte MV, Yang L, Phillips PA, Xu Z, Kaplan W, Cowley M, Pirola RC, Wilson JS. Extracellular matrix composition significantly influences pancreatic stellate cell gene expression pattern: role of transgelin in PSC function. Am J Physiol Gastrointest Liver Physiol 2013; 305: G408-G417 [PMID: 23868411 DOI: 10.1152/ajpgi.00016.2013]
27. Dangi-Garimella S, Sahai V, Ebine K, Kumar K, Munshi HG. Three-dimensional collagen I promotes gemcitabine resistance in vitro in pancreatic cancer cells through HMGA2-dependent histone acetyltransferase expression. PLoS One 2013; 8: e64566 [PMID: 23696899 DOI: 10.1371/journal. pone.0064566]
28. Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S. Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004; 28: 38-44 [PMID: 14707728]
29. Michl P, Gress TM. Improving drug delivery to pancreatic cancer: breaching the stromal fortress by targeting hyaluronic acid. Gut 2012; 61: 1377-1379 [PMID: 22661496 DOI: 10.1136/gutjnl-2012-302604]
30. 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: 418-429 [PMID: 22439937 DOI: 10.1016/j.ccr.2012.01.007]
31. Assifi MM, Hines OJ. Anti-angiogenic agents in pancreatic cancer: a review. Anticancer Agents Med Chem 2011; 11: 464-469 [PMID: 21521158]
32. 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: 9518-9527 [PMID: 17909062 DOI: 10.1158/0008-5472. can-07-0175]
33. Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol 2013; 4: 210 [PMID: 23950747 DOI: 10.3389/fphys.2013.00210]
34. Mielgo A, Schmid MC. Impact of tumour associated macrophages in pancreatic cancer. BMB Rep 2013; 46: 131-138 [PMID: 23527856]
35. Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol 2013; 25: 200-205 [PMID: 23422836 DOI: 10.1016/ j.coi.2013.01.006]
36. Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013; 144: 1230-1240 [PMID: 23622132 DOI: 10.1053/j.gastro.2012.12.042]
37. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 2003; 170: 270-278 [PMID: 12496409]
38. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004; 172: 989-999 [PMID: 14707072]
39. Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006; 108: 804-811 [PMID: 16861339 DOI: 10.1182/blood-2006-02-002774]
40. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A. Macrophage polarization in tumour progression. Semin Cancer Biol 2008; 18: 349-355 [PMID: 18467122 DOI: 10.1016/ j.semcancer.2008.03.004]
41. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25: 9543-9553 [PMID: 16227604 DOI: 10.1128/mcb.25.21.9543-9553.2005]
42. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13: 2151-2157 [PMID: 17404099 DOI: 10.1158/1078-0432.ccr-06-2746]
43. Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, Laschinger M, W Büchler M, Friess H. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett 2008; 268: 98-109 [PMID: 18486325 DOI: 10.1016/j.canlet.2008.03.056]
44. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factorbeta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9: 641-649 [PMID: 18454151 DOI: 10.1038/ ni.1610]
45. Regateiro FS, Howie D, Nolan KF, Agorogiannis EI, Greaves DR, Cobbold SP, Waldmann H. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β. Eur J Immunol 2011; 41: 2955-2965 [PMID: 21770045 DOI: 10.1002/eji.201141512]
46. He S, Fei M, Wu Y, Zheng D, Wan D, Wang L, Li D. Distribution and clinical significance of th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients. Int J Mol Sci 2011; 12: 7424-7437 [PMID: 22174607 DOI: 10.3390/ijms12117424]
47. Qi W, Huang X, Wang J. Correlation between Th17 cells and tumor microenvironment. Cell Immunol 2013; 285: 18-22 [PMID: 24044962 DOI: 10.1016/j.cellimm.2013.06.001]
48. Greten TF, Zhao F, Gamrekelashvili J, Korangy F. Human Th17 cells in patients with cancer: Friends or foe? Oncoimmunology 2012; 1: 1438-1439 [PMID: 23243621 DOI: 10.4161/ onci.21245]
49. Ye J, Livergood RS, Peng G. The role and regulation of human Th17 cells in tumor immunity. Am J Pathol 2013; 182: 10-20 [PMID: 23159950 DOI: 10.1016/j.ajpath.2012.08.041]
50. Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, Wang X, Ryffel B, Sun B. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 2013; 191: 1835-1844 [PMID: 23842754 DOI: 10.4049/jimmunol.1203013]
51. Al-Muhsen S, Letuve S, Vazquez-Tello A, Pureza MA, Al-Jahdali H, Bahammam AS, Hamid Q, Halwani R. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils. Respir Res 2013; 14: 34 [PMID: 23496774 DOI: 10.1186/1465-9921-14-34]
52. Gao B, Waisman A. Th17 cells regulate liver fibrosis by targeting multiple cell types: many birds with one stone. Gastroenterology 2012; 143: 536-539 [PMID: 22842060 DOI: 10.1053/j.gastro.2012.07.031]
53. Murone M, Rosenthal A, de Sauvage FJ. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr Biol 1999; 9: 76-84 [PMID: 10021362 DOI: 10.1016/ S0960-9822(99)80018-9]
54. Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogen-esis. Proc Natl Acad Sci USA 2009; 106: 4254-4259 [PMID: 19246386]
55. Li X, Ma Q, Duan W, Liu H, Xu H, Wu E. Paracrine sonic hedgehog signaling derived from tumor epithelial cells: a key regulator in the pancreatic tumor microenvironment. Crit Rev Eukaryot Gene Expr 2012; 22: 97-108 [PMID: 22856428]
56. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008; 14: 5995-6004 [PMID: 18829478 DOI: 10.1158/1078-0432.ccr-08-0291]
57. Walter K, Omura N, Hong SM, Griffith M, Vincent A, Borges M, Goggins M. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancerassociated fibroblasts. Clin Cancer Res 2010; 16: 1781-1789 [PMID: 20215540 DOI: 10.1158/1078-0432.ccr-09-1913]
58. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030-1037 [PMID: 17283135 DOI: 10.1158/0008-5472.can-06-2030]
59. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390: 465-471 [PMID: 9393997 DOI: 10.1038/37284]
60. Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG, Gold LI, Korc M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993; 105: 1846-1856 [PMID: 8253361]
61. Jaschinski F, Rothhammer T, Jachimczak P, Seitz C, Schneider A, Schlingensiepen KH. The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-β2. Curr Pharm Biotechnol 2011; 12: 2203-2213 [PMID: 21619536]
62. Schnurr M, Duewell P. Breaking tumor-induced immunosuppression with 5'-triphosphate siRNA silencing TGFβ and activating RIG-I. Oncoimmunology 2013; 2: e24170 [PMID: 23762798 DOI: 10.4161/onci.24170]
63. Tahara H, Sato K, Yamazaki Y, Ohyama T, Horiguchi N, Hashizume H, Kakizaki S, Takagi H, Ozaki I, Arai H, Hirato J, Jesenofsky R, Masamune A, Mori M. Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation. Lab Invest 2013; 93: 720-732 [PMID: 23608755 DOI: 10.1038/labinvest. 2013.59]
64. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 2011; 102: 1193-1200 [PMID: 21366804 DOI: 10.1111/j.1349-7006.2011.01917.x]
65. He J, Sun X, Qian KQ, Liu X, Wang Z, Chen Y. Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7. Biochim Biophys Acta 2009; 1792: 56-60 [PMID: 19015026 DOI: 10.1016/j.bbadis.2008.10.010]
66. Creighton CJ, Gibbons DL, Kurie JM. The role of epithelialmesenchymal transition programming in invasion and metastasis: a clinical perspective. Cancer Manag Res 2013; 5: 187-195 [PMID: 23986650 DOI: 10.2147/cmar.s35171]
67. Lim J, Thiery JP. Epithelial-mesenchymal transitions: insights from development. Development 2012; 139: 3471-3486 [PMID: 22949611 DOI: 10.1242/dev.071209]
68. Kong D, Li Y, Wang Z, Sarkar FH. Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins? Cancers (Basel) 2011; 3: 716-729 [PMID: 21643534 DOI: 10.3390/cancers30100716]
69. de Graauw M, Tijdens I, Smeets MB, Hensbergen PJ, Deelder AM, van de Water B. Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin Activation. Mol Cell Biol 2008; 28: 1029-1040 [PMID: 18070928]
70. Lee MY, Chou CY, Tang MJ, Shen MR. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res 2008; 14: 4743-4750 [PMID: 18676743]
71. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818-829 [PMID: 18539112]
72. Ouyang G, Wang Z, Fang X, Liu J, Yang CJ. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol Life Sci 2010; 67: 2605-2618 [PMID: 20238234 DOI: 10.1007/s00018-010-0338-2]
73. Hiraga R, Kato M, Miyagawa S, Kamata T. Nox4-derived ROS signaling contributes to TGF-β-induced epithelial-mesenchymal transition in pancreatic cancer cells. Anticancer Res 2013; 33: 4431-4438 [PMID: 24123012]
74. Zheng L, Foley K, Huang L, Leubner A, Mo G, Olino K, Edil BH, Mizuma M, Sharma R, Le DT, Anders RA, Illei PB, Van Eyk JE, Maitra A, Laheru D, Jaffee EM. Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer. PLoS One 2011; 6: e19390 [PMID: 21572519]
75. Castellanos JA, Merchant NB, Nagathihalli NS. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther 2013; 6: 1261-1267 [PMID: 24049451 DOI: 10.2147/ott.s34670]
76. Yamada S, Fuchs BC, Fujii T, Shimoyama Y, Sugimoto H, Nomoto S, Takeda S, Tanabe KK, Kodera Y, Nakao A. Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery 2013; 154: 946-954 [PMID: 24075276 DOI: 10.1016/j.surg.2013.05.004]
77. Chen HT, Cai QC, Zheng JM, Man XH, Jiang H, Song B, Jin G, Zhu W, Li ZS. High expression of delta-like ligand 4 predicts poor prognosis after curative resection for pancreatic cancer. Ann Surg Oncol 2012; 19 Suppl 3: S464-S474 [PMID: 21822553 DOI: 10.1245/s10434-011-1968-9]
78. Yabuuchi S, Pai SG, Campbell NR, de Wilde RF, De Oliveira E, Korangath P, Streppel MM, Rasheed ZA, Hidalgo M, Maitra A, Rajeshkumar NV. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett 2013; 335: 41-51 [PMID: 23402814 DOI: 10.1016/j.canlet.2013.01.054]
79. Yu J, Ohuchida K, Mizumoto K, Ishikawa N, Ogura Y, Yamada D, Egami T, Fujita H, Ohashi S, Nagai E, Tanaka M. Overexpression of c-met in the early stage of pancreatic carcinogenesis; altered expression is not sufficient for progression from chronic pancreatitis to pancreatic cancer. World J Gastroenterol 2006; 12: 3878-3882 [PMID: 16804974]
80. Hage C, Rausch V, Giese N, Giese T, Schönsiegel F, Labsch S, Nwaeburu C, Mattern J, Gladkich J, Herr I. The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Cell Death Dis 2013; 4: e627 [PMID: 23661005 DOI: 10.1038/cddis.2013.158]
81. Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, Miyazaki K. The hypoxic environment in tumorstromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol 2007; 14: 2600-2607 [PMID: 17534684]
82. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86 [PMID: 23915189 DOI: 10.1186/1476-4598-12-86]
83. Chandler NM, Canete JJ, Callery MP. Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J Surg Res 2004; 118: 9-14 [PMID: 15093710 DOI: 10.1016/ s0022-4804(03)00354-8]
84. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5: 119-127 [PMID: 9918209]
85. Liou GY, Döppler H, Necela B, Krishna M, Crawford HC, Raimondo M, Storz P. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs. J Cell Biol 2013; 202: 563-577 [PMID: 23918941 DOI: 10.1083/jcb.201301001]
86. Carbone C, Melisi D. NF-κB as a target for pancreatic cancer therapy. Expert Opin Ther Targets 2012; 16 Suppl 2: S1-10 [PMID: 22443181 DOI: 10.1517/14728222.2011.645806]
87. Wong HH, Lemoine NR. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 2009; 6: 412-422 [PMID: 19506583 DOI: 10.1038/ nrgastro.2009.89]
88. Sobanko JF, Okman J, Miller C. Vismodegib: a hedgehog pathway inhibitor for locally advanced and metastatic basal cell carcinomas. J Drugs Dermatol 2013; 12: s154-s155 [PMID: 24085062]
89. Liss AS, Thayer SP. Therapeutic targeting of pancreatic stroma. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum (India): Transworld Research Network Transworld Research Network, 2012
90. Stephenson J, Richards DA, Wolpin BM, Becerra C, Hamm JT, Messersmith WA, Devens S, Cushing J, Goddard J, Schmalbach T, Fuchs CS. The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer. J Clin Oncol 2011; 29 suppl: Abstr 4114
91. Strimpakos AS, Saif MW. Update on phase I studies in advanced pancreatic adenocarcinoma. Hunting in darkness? JOP 2013; 14: 354-358 [PMID: 23846926 DOI: 10.6092/1590-8577/1664]
92. Oettle H, Hilbig A, Seufferlein T, Schmid RM, Luger T, von Wichert G, Schmaus S, Heinrichs H, Schlingensiepen K. Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma. J Clin Oncol 2009; 27 suppl: Abstr 4619
93. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg 2011; 253: 328-335 [PMID: 21217520 DOI: 10.1097/ SLA.0b013e3181fd271c]
94. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 2008; 14: 1455-1463 [PMID: 18316569 DOI: 10.1158/1078-0432.ccr-07-0371]
95. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013; 36: 382-389 [PMID: 23924790 DOI: 10.1097/CJI.0b013e31829fb7a2]
96. Diehl L, den Boer AT, Schoenberger SP, van der Voort EI, Schumacher TN, Melief CJ, Offringa R, Toes RE. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 1999; 5: 774-779 [PMID: 10395322 DOI: 10.1038/10495]
97. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330: 827-830 [PMID: 21051638]
98. LeBeau AM, Brennen WN, Aggarwal S, Denmeade SR. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther 2009; 8: 1378-1386 [PMID: 19417147 DOI: 10.1158/1535-7163. mct-08-1170]
99. Hofheinz RD, al-Batran SE, Hartmann F, Hartung G, Jäger D, Renner C, Tanswell P, Kunz U, Amelsberg A, Kuthan H, Stehle G. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 2003; 26: 44-48 [PMID: 12624517 DOI: 10.1159/000069863]
100. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L. 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: 3296-3302 [PMID: 12947065 DOI: 10.1200/ jco.2003.02.098]
101. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87: 161-167 [PMID: 12107836 DOI: 10.1038/sj.bjc.6600446]
102. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455-2465 [PMID: 22658128 DOI: 10.1056/NEJMoa1200694]
103. Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O'Dwyer PJ. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 2013; 19: 6286-6295 [PMID: 23983255 DOI: 10.1158/1078-0432.ccr-13-1320]
104. Venepalli NK, Goff L. Targeting the HGF-cMET Axis in Hepatocellular Carcinoma. Int J Hepatol 2013; 2013: 341636 [PMID: 23606971 DOI: 10.1155/2013/341636]
105. Arlt A, Schäfer H, Kalthoff H. The 'N-factors' in pancreatic cancer: functional relevance of NF-κB, NFAT and Nrf2 in pancreatic cancer. Oncogenesis 2012; 1: e35 [PMID: 23552468 DOI: 10.1038/oncsis.2012.35]