REFERENCES
2. Fokas E, O'Neill E, Gordon-Weeks A, Mukherjee S, McKenna WG, Muschel RJ. Pancreatic ductal adenocarcinoma: from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic. Biochim Biophys Acta 2015;1855:61-82.
3. Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 2015;12:319-34.
5. Adamska A, Domenichini A, Falasca M. Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci 2017;18:1338.
6. Lüttges J, Hahn S, Klöppel G. Where and when does pancreatic carcinoma start? Med Klin (Munich) 2004;99:191-5.
9. Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer 2013;32:312-24.
10. Salem AA, Mackenzie GG. Pancreatic cancer: a critical review of dietary risk. Nutr Res 2018;52:1-13.
11. Gupta S, Wang F, Holly EA, Bracci PM. Risk of pancreatic cancer by alcohol dose, duration, and pattern of consumption, including binge drinking: a population-based study. Cancer Causes Control 2010;21:1047-59.
12. Becker AE, Hernandez YG, Frucht H, Lucas AL. Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J Gastroenterol 2014;20:11182-98.
13. Wörmann SM, Algül H. Risk factors and therapeutic targets in pancreatic cancer. Front Oncol 2013;3:282.
14. Bliss LA, Witkowski ER, Yang CJ, Tseng JF. Outcomes in operative management of pancreatic cancer. J Surg Oncol 2014;110:592-8.
15. Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology 2001;60:8-18.
16. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6.
17. Mimeault M, Brand RE, Sasson AA, Batra SK. Recent advances on the molecular mechanisms involved in pancreatic cancer progression and therapies. Pancreas 2005;31:301-16.
18. Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 2012;18:2316-25.
19. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997;57:2140-3.
20. Karanikas M, Esempidis A, Chasan ZT, et al. Pancreatic cancer from molecular pathways to treatment opinion. J Cancer 2016;7:1328-39.
21. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997;88:593-602.
22. Brookes S, Rowe J, Ruas M, et al. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 2002;21:2936-45.
23. Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997;57:1731-4.
24. Nakashima H, Nakamura M, Yamaguchi H, et al. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 2006;66:7041-9.
25. Ling J, Kang Y, Zhao R, et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:105-20.
26. Gu D, Schlotman KE, Xie J. Deciphering the role of hedgehog signaling in pancreatic cancer. J Biomed Res 2016;30:353-60.
27. Tascilar M, Skinner HG, Rosty C, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2021;7:4115-21.
28. Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst 2018;110:1067-74.
29. Wong W, Raufi AG, Safyan RA, Bates SE, Manji GA. BRCA mutations in pancreas cancer: spectrum, current management, challenges and future prospects. Cancer Manag Res 2020;12:2731-42.
30. Cheng JQ, Ruggeri B, Klein WM, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 1996;93:3636-41.
31. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 1998;21:81-6.
32. Payne SN, Maher ME, Tran NH, et al. PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors. Oncogenesis 2015;4:e169.
33. Sivaram N, McLaughlin PA, Han HV, et al. Tumor-intrinsic PIK3CA represses tumor immunogenecity in a model of pancreatic cancer. J Clin Invest 2019;129:3264-76.
35. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020;17:153-68.
36. Chambard JC, Lefloch R, Pouysségur J, Lenormand P. ERK implication in cell cycle regulation. Biochim Biophys Acta 2007;1773:1299-310.
37. Huang L, Goodrow TL, Zhang SY, Klein-Szanto AJ, Chang H, Ruggeri BA. Deletion and mutation analyses of the P16/MTS-1 tumor suppressor gene in human ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor-derived cell lines than in primary ductal adenocarcinomas. Cancer Res 1996;56:1137-41.
38. Gerdes B, Ramaswamy A, Ziegler A, et al. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann Surg 2002;235:51-9.
39. Schmitt CA, Fridman JS, Yang M, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002;109:335-46.
40. Morton JP, Timpson P, Karim SA, et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci U S A 2010;107:246-51.
41. Kim MP, Li X, Deng J, et al. Oncogenic. KRAS :recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis.
42. Weissmueller S, Manchado E, Saborowski M, et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell 2014;157:382-94.
44. Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci 2018;14:111-23.
45. Lecanda J, Ganapathy V, D'Aquino-Ardalan C, et al. TGFbeta prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest. Cell Cycle 2009;8:742-56.
46. Adamska A, Elaskalani O, Emmanouilidi A, et al. Molecular and cellular mechanisms of chemoresistance in pancreatic cancer. Adv Biol Regul 2018;68:77-87.
47. Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998;58:4349-57.
48. Sousa Cavalcante L, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol 2014;741:8-16.
49. Binenbaum Y, Na'ara S, Gil Z. Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat 2015;23:55-68.
50. Hung SW, Mody HR, Govindarajan R. Overcoming nucleoside analog chemoresistance of pancreatic cancer: a therapeutic challenge. Cancer Lett 2012;320:138-49.
51. Skrypek N, Duchêne B, Hebbar M, Leteurtre E, van Seuningen I, Jonckheere N. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene 2013;32:1714-23.
52. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 2003;55:3-29.
53. Maréchal R, Mackey JR, Lai R, et al. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer 2010;116:5200-6.
54. Bergman AM, Eijk PP, Ruiz van Haperen VW, et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res 2005;65:9510-6.
55. Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res 2004;64:3761-6.
56. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene 2004;23:8571-80.
57. Singh K. . Therapeutic targeting of deregulated cell cycle and UPR in pancreatic cancer by tetrandrine. PhD, Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center at Shreveport, ProQuest, 2018.
58. Ebrahimi S, Hosseini M, Shahidsales S, et al. Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic cancer. Curr Med Chem 2017;24:1321-31.
59. Yamamoto S, Tomita Y, Hoshida Y, et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 2004;10:2846-50.
60. Parsons CM, Muilenburg D, Bowles TL, Virudachalam S, Bold RJ. The role of Akt activation in the response to chemotherapy in pancreatic cancer. Anticancer Res 2010;30:3279-89.
61. Ng SSW, Tsao MS, Chow S, Hedley DW. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 2000;60:5451-5.
63. Waghray M, Yalamanchili M, di Magliano MP, Simeone DM. Deciphering the role of stroma in pancreatic cancer. Curr Opin Gastroenterol 2013;29:537-43.
64. Nielsen MF, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016;22:2678-700.
65. Walter K, Omura N, Hong SM, et al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Cancer Res 2010;16:1781-9.
67. Li H, Zhang J, Chen SW, et al. Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. J Transl Med 2015;13:198.
68. Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer 2004;4:806-13.
69. Liang C, Shi S, Meng Q, et al. Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going. Exp Mol Med 2017;49:e406.
70. Kozono S, Ohuchida K, Eguchi D, et al. Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res 2013;73:2345-56.
71. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62:112-20.
72. 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;21:418-29.
73. Hingorani SR, Harris WP, Beck JT, et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res 2016;22:2848-54.
74. Alvarez R, Musteanu M, Garcia-Garcia E, et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 2013;109:926-33.
75. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.
76. Hotz HG, Reber HA, Hotz B, et al. Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth. J Gastrointest Surg 2001;5:131-8.
77. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457-61.
78. Olivares O, Mayers JR, Gouirand V, et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun 2017;8:16031.
79. Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol 2020;17:487-505.
80. Vennin C, Chin VT, Warren SC, et al. Australian Pancreatic Cancer Genome Initiative (APGI). Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med 2017;9:eaai8504.
81. Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 2016;22:851-60.
82. Aguilera KY, Huang H, Du W, et al. Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2017;16:2473-85.
83. Boucher MJ, Morisset J, Vachon PH, Reed JC, Lainé J, Rivard N. MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 2000;79:355-69.
84. Wang M, Lu X, Dong X, et al. pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression. World J Surg Oncol 2015;13:66.
85. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst) 2016;42:63-71.
86. Chien W, Ding LW, Sun QY, et al. Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells. Oncotarget 2014;5:4881-94.
87. Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 2004;4:966-77.
88. Yousefi H, Yuan J, Keshavarz-Fathi M, Murphy JF, Rezaei N. Immunotherapy of cancers comes of age. Expert Rev Clin Immunol 2017;13:1001-15.
89. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14:847-56.
90. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011;331:1612-6.
91. De Monte L, Reni M, Tassi E, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 2011;208:469-78.
92. Fukunaga A, Miyamoto M, Cho Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004;28:e26-31.
93. Schizas D, Charalampakis N, Kole C, et al. Immunotherapy for pancreatic cancer: a 2020 update. Cancer Treat Rev 2020;86:102016.
94. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828-33.
95. Kalyan A, Kircher SM, Mohindra NA, et al. Ipilimumab and gemcitabine for advanced pancreas cancer: a phase Ib study. J Clin Oncol 2016;34:e15747.
96. Luo W, Yang G, Luo W, et al. Novel therapeutic strategies and perspectives for metastatic pancreatic cancer: vaccine therapy is more than just a theory. Cancer Cell Int 2020;20:66.
97. Miyazawa M, Katsuda M, Maguchi H, et al. Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients. Int J Cancer 2017;140:973-82.
98. Mucciolo G, Roux C, Scagliotti A, Brugiapaglia S, Novelli F, Cappello P. The dark side of immunotherapy: pancreatic cancer. Cancer Drug Resist 2020;3:491-520.
99. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013;36:382-9.
100. Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol 2015;33:3124-9.
101. Salo-Mullen EE, O'Reilly EM, Kelsen DP, et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 2015;121:4382-8.
102. Waddell N, Pajic M, Patch AM, et al. Australian Pancreatic Cancer Genome Initiative. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495-501.
104. Gupta M, Iyer R, Fountzilas C. Poly(ADP-Ribose) Polymerase inhibitors in pancreatic cancer: a new treatment paradigms and future implications. Cancers (Basel) 2019;11:1980.
105. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317-27.
106. Zhu H, Wei M, Xu J, et al. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications. Mol Cancer 2020;19:49.
107. Leroux C, Konstantinidou G. Targeted therapies for pancreatic cancer: overview of current treatments and new opportunities for personalized oncology. Cancers (Basel) 2021;13:799.
108. Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach D. Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. International Journal of Radiation Oncology*Biology*Physics 1996;34:867-72.
109. Doyle TH, Mornex F, McKenna WG. The clinical implications of gemcitabine radiosensitization. Clin Cancer Res 2001;7:226-8.
110. Tuli R, Surmak AJ, Reyes J, et al. Radiosensitization of pancreatic cancer cells in vitro and in vivo through poly (ADP-ribose) polymerase inhibition with ABT-888. Transl Oncol ;2014:439-45.
111. Jiang Y, Dai H, Li Y, et al. PARP inhibitors synergize with gemcitabine by potentiating DNA damage in non-small-cell lung cancer. Int J Cancer 2019;144:1092-103.
112. Waissi W, Nicol A, Jung M, et al. Radiosensitizing pancreatic cancer with PARP inhibitor and gemcitabine: an in vivo and a whole-transcriptome analysis after proton or photon irradiation. Cancers (Basel) 2021;13:527.
113. Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014;211:1503-23.
114. Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer 2019;18:70.
115. Domen A, Quatannens D, Zanivan S, et al. Cancer-associated fibroblasts as a common orchestrator of therapy resistance in lung and pancreatic cancer. Cancers (Basel) 2021;13:987.
116. Wu Q, Tian Y, Zhang J, et al. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget 2017;8:102721-38.
117. Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013;145:1121-32.
118. Kumar V, Donthireddy L, Marvel D, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 2017;32:654-68.e5.
119. Francescone R, Barbosa Vendramini-Costa D, Franco-Barraza J, et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov 2021;11:446-79.
120. Cohen SJ, Alpaugh RK, Palazzo I, et al. Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas 2008;37:154-8.
121. Sunami Y, Böker V, Kleeff J. Targeting and reprograming cancer-associated fibroblasts and the tumor microenvironment in pancreatic cancer. Cancers (Basel) 2021;13:697.
122. Zhang Y, Recouvreux MV, Jung M, et al. Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness. Cancer Discov 2021;11:1808-25.
123. Davidson SM, Jonas O, Keibler MA, et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med 2017;23:235-41.
124. Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018;15:333-48.
