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Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Exploring Signaling Pathways and Pancreatic Cancer Treatment Approaches Using Genetic Models

Author(s): Shorooq Khader, Anita Thyagarajan and Ravi P. Sahu*

Volume 19, Issue 14, 2019

Page: [1112 - 1125] Pages: 14

DOI: 10.2174/1389557519666190327163644

Price: $65

Open Access Journals Promotions 2
Abstract

Despite available treatment options, the overall survival rates of pancreatic cancer patients remain dismal. Multiple counter-regulatory pathways have been identified and shown to be involved in interfering with the efficacy of therapeutic agents. In addition, various known genetic alterations in the cellular signaling pathways have been implicated in affecting the growth and progression of pancreatic cancer. Nevertheless, the significance of other unknown pathways is yet to be explored, which provides the rationale for the intervention of new approaches. Several experimental genetic models have been explored to define the impact of key signaling cascades, and their mechanisms in the pathophysiology as well as treatment approaches of pancreatic cancer. The current review highlights the recent updates, and significance of such genetic models in the therapeutic efficacy of anti-tumor agents including the standard chemotherapeutic agents, natural products, cell signaling inhibitors, immunebased therapies and the combination of these approaches in pancreatic cancer.

Keywords: Pancreatic cancer, genetic models, pancreatic cancer therapies, cellular signaling pathways, immune-based approaches, natural compounds.

Graphical Abstract
[1]
Balan, B.J.; Zygmanowska, E.; Radomska-Lesniewska, D.M. Disorders noticed during development of pancreatic cancer: Potential opportunities for early and effective diagnostics and therapy. Cent. Eur. J. Immunol., 2017, 42, 377-382.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66, 7-30.
[3]
van Erning, F.N.; Mackay, T.M.; van der Geest, L.G.M.; Groot Koerkamp, B.; van Laarhoven, H.W.M.; Bonsing, B.A.; Wilmink, J.W.; van Santvoort, H.C.; de Vos-Geelen, J.; van Eijck, C.H.J.; Busch, O.R.; Lemmens, V.E.; Besselink, M.G. Dutch pancreatic cancer group association of the location of pancreatic ductal adenocarcinoma (head, body, tail) with tumor stage, treatment, and survival: A population-based analysis. Acta Oncol., 2018, 57(12), 1655-1662.
[4]
Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic ductal adenocarcinoma: Current and evolving therapies. Int. J. Mol. Sci., 2017, 18(7)E1338
[5]
Bernard, V.; Fleming, J.; Maitra, A. Molecular and genetic basis of pancreatic carcinogenesis: Which concepts may be clinically relevant? Surg. Oncol. Clin. N. Am., 2016, 25, 227-238.
[6]
Soliman, G.A.; Steenson, S.M.; Etekpo, A.H. Effects of metformin and a mammalian target of rapamycin (mTOR) ATP-competitive inhibitor on targeted metabolomics in pancreatic cancer cell line. Metabolomics (Los Angel.), 2016, 6(3), 183.
[7]
Nevler, A.; Muller, A.J.; Sutanto-Ward, E.; DuHadaway, J.B.; Nagatomo, K.; Londin, E.; O’Hayer, K.; Cozzitorto, J.A.; Lavu, H.; Yeo, T.P.; Curtis, M.T.; Villatoro, T.; Leiby, B.E.; Mandik-Nayak, L.; Winter, J.M.; Yeo, C.J.; Prendergast, G.C.; Brody, J.R. Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers. Clin. Cancer Res., 2019, 25(2), 724-734.
[8]
Chung, W.J.; Daemen, A.; Cheng, J.H.; Long, J.E.; Cooper, J.E.; Wang, B.E.; Tran, C.; Singh, M.; Gnad, F.; Modrusan, Z.; Foreman, O.; Junttila, M.R. Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous. Proc. Natl. Acad. Sci. USA, 2017, 114, E10947-E10955.
[9]
Kopp, J.L.; Dubois, C.L.; Schaeffer, D.F.; Samani, A.; Taghizadeh, F.; Cowan, R.W.; Rhim, A.D.; Stiles, B.L.; Valasek, M.; Sander, M. Loss of pten and activation of kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice. Gastroenterology, 2018, 154, 1509-1523.
[10]
Colvin, E.K.; Scarlett, C.J. A historical perspective of pancreatic cancer mouse models. Semin. Cell Dev. Biol., 2014, 27, 96-105.
[11]
Zhao, X.; Wang, X.; Fang, L.; Lan, C.; Zheng, X.; Wang, Y.; Zhang, Y.; Han, X.; Liu, S.; Cheng, K.; Zhao, Y.; Shi, J.; Guo, J.; Hao, J.; Ren, H.; Nie, G. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer. Cancer Lett., 2017, 402, 61-70.
[12]
Ischenko, I.; Petrenko, O.; Hayman, M.J.A. MEK/PI3K/HDAC inhibitor combination therapy for KRAS mutant pancreatic cancer cells. Oncotarget, 2015, 6, 15814-15827.
[13]
Liao, J.; Hwang, S.H.; Li, H.; Yang, Y.; Yang, J.; Wecksler, A.T.; Liu, J.Y.; Hammock, B.D.; Yang, G.Y. Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM. Cancer Lett., 2016, 371, 187-193.
[14]
Huang, M.; Tang, S.N.; Upadhyay, G.; Marsh, J.L.; Jackman, C.P.; Shankar, S.; Srivastava, R.K. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting akt and sonic hedgehog pathways. PLoS One, 2014, 9e92161
[15]
Jun, E.; Hong, S.M.; Yoo, H.J.; Kim, M.B.; Won, J.S.; An, S.; Shim, I.K.; Chang, S.; Hoffman, R.M.; Kim, S.C. Genetic and metabolic comparison of orthotopic and heterotopic patient-derived pancreatic-cancer xenografts to the original patient tumors. Oncotarget, 2017, 9, 7867-7881.
[16]
Ma, J.; Hui, P.; Meng, W.; Wang, N.; Xiang, S. Ku70 inhibits gemcitabine-induced DNA damage and pancreatic cancer cell apoptosis. Biochem. Biophys. Res. Commun., 2017, 484, 746-752.
[17]
Jun, E.; Jung, J.; Jeong, S.Y.; Choi, E.K.; Kim, M.B.; Lee, J.S.; Hong, S.M.; Seol, H.S.; Hwang, C.; Hoffman, R.M.; Shim, I.K.; Chang, S.; Kim, S.C. Surgical and oncological factors affecting the successful engraftment of patient-derived xenografts in pancreatic ductal adenocarcinoma. Anticancer Res., 2016, 36, 517-521.
[18]
Lo, J.H.; Hao, L.; Muzumdar, M.D.; Raghavan, S.; Kwon, E.J.; Pulver, E.M.; Hsu, F.; Aguirre, A.J.; Wolpin, B.M.; Fuchs, C.S.; Hahn, W.C.; Jacks, T.; Bhatia, S.N. iRGD-guided tumor-penetrating nanocomplexes for therapeutic siRNA delivery to pancreatic cancer. Mol. Cancer Ther., 2018, 17(11), 2377-2388.
[19]
Kaur, K.; Chang, H.H.; Cook, J.; Eibl, G.; Jewett, A. Suppression of gingival NK cells in precancerous and cancerous stages of pancreatic cancer in KC and BLT-humanized mice. Front. Immunol., 2017, 8, 1606.
[20]
Holzapfel, B.M.; Thibaudeau, L.; Hesami, P.; Taubenberger, A.; Holzapfel, N.P.; Mayer-Wagner, S.; Power, C.; Clements, J.; Russell, P.; Hutmacher, D.W. Humanised xenograft models of bone metastasis revisited: Novel insights into species-specific mechanisms of cancer cell osteotropism. Cancer Metastasis Rev., 2013, 32, 129-145.
[21]
Rongvaux, A.; Willinger, T.; Martinek, J.; Strowig, T.; Gearty, S.V.; Teichmann, L.L.; Saito, Y.; Marches, F.; Halene, S.; Palucka, A.K.; Manz, M.G.; Flavell, R.A. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol., 2014, 32, 364-372.
[22]
Guo, X.; Zheng, L.; Jiang, J.; Zhao, Y.; Wang, X.; Shen, M.; Zhu, F.; Tian, R.; Shi, C.; Xu, M.; Li, X.; Peng, F.; Zhang, H.; Feng, Y.; Xie, Y.; Xu, X.; Jia, W.; He, R.; Xie, C.; Hu, J.; Ye, D.; Wang, M.; Qin, R. Blocking NF-kappaB Is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer. Clin. Cancer Res., 2016, 22, 5939-5950.
[23]
Basel, M.T.; Narayanan, S.; Ganta, C.; Shreshta, T.B.; Marquez, A.; Pyle, M.; Hill, J.; Bossmann, S.H.; Troyer, D.L. Developing a xenograft human tumor model in immunocompetent mice. Cancer Lett., 2018, 412, 256-263.
[24]
Mazur, P.K.; Herner, A.; Neff, F.; Siveke, J.T. Current methods in mouse models of pancreatic cancer. Methods Mol. Biol., 2015, 1267, 185-215.
[25]
Salzwedel, A.O.; Han, J.; LaRocca, C.J.; Shanley, R.; Yamamoto, M.; Davydova, J. Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer. Oncotarget, 2018, 9, 18041-18052.
[26]
Spyridopoulou, K.; Aindelis, G.; Lampri, E.; Giorgalli, M.; Lamprianidou, E.; Kotsianidis, I.; Tsingotjidou, A.; Pappa, A.; Kalogirou, O.; Chlichlia, K. Improving the subcutaneous mouse tumor model by effective manipulation of magnetic nanoparticles-treated implanted cancer cells. Ann. Biomed. Eng., 2018, 46(12), 1975-1987.
[27]
Bocci, G.; Buffa, F.; Canu, B.; Concu, R.; Fioravanti, A.; Orlandi, P.; Pisanu, T. A new biometric tool for three-dimensional subcutaneous tumor scanning in mice. In Vivo, 2014, 28, 75-80.
[28]
Jiang, Y.J.; Lee, C.L.; Wang, Q.; Zhou, Z.W.; Yang, F.; Jin, C.; Fu, D.L. Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel. World J. Gastroenterol., 2014, 20, 9476-9485.
[29]
Krempley, B.D.; Yu, K.H. Preclinical models of pancreatic ductal adenocarcinoma. Chin. Clin. Oncol, 2017, 6, 25.
[30]
Song, S.Y.; Kim, K.P.; Jeong, S.Y.; Park, J.; Park, J.; Jung, J.; Chung, H.K.; Lee, S.W.; Seo, M.H.; Lee, J.S.; Jung, K.H.; Choi, E.K. Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: Phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model. Oncotarget, 2016, 7, 77348-77357.
[31]
Condeelis, J.; Weissleder, R. In vivo imaging in cancer. Cold Spring Harb. Perspect. Biol., 2010, 2a003848
[32]
Noguchi, K.; Konno, M.; Eguchi, H.; Kawamoto, K.; Mukai, R.; Nishida, N.; Koseki, J.; Wada, H.; Akita, H.; Satoh, T.; Marubashi, S.; Nagano, H.; Doki, Y.; Mori, M.; Ishii, H. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Oncol. Lett., 2018, 16, 1892-1898.
[33]
Thomas, R.M.; Gharaibeh, R.Z.; Gauthier, J.; Beveridge, M.; Pope, J.L.; Guijarro, M.V.; Yu, Q.; He, Z.; Ohland, C.; Newsome, R.; Trevino, J.; Hughes, S.J.; Reinhard, M.; Winglee, K.; Fodor, A.A.; Zajac-Kaye, M.; Jobin, C. Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models. Carcinogenesis, 2018, 39(8), 1068-1078.
[34]
Hamada, S.; Taguchi, K.; Masamune, A.; Yamamoto, M.; Shimosegawa, T. Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. Carcinogenesis, 2017, 38, 661-670.
[35]
Husain, K.; Centeno, B.A.; Chen, D.T.; Hingorani, S.R.; Sebti, S.M.; Malafa, M.P. Vitamin E delta-tocotrienol prolongs survival in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) transgenic mouse model of pancreatic cancer. Cancer Prev. Res. (Phila.), 2013, 6, 1074-1083.
[36]
Nguyen, H.H.; Aronchik, I.; Brar, G.A.; Nguyen, D.H.; Bjeldanes, L.F.; Firestone, G.L. The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing. Proc. Natl. Acad. Sci. USA, 2008, 105, 19750-19755.
[37]
Nakagawa-Goto, K.; Yamada, K.; Nakamura, S.; Chen, T.H.; Chiang, P.C.; Bastow, K.F.; Wang, S.C.; Spohn, B.; Hung, M.C.; Lee, F.Y.; Lee, F.C.; Lee, K.H. Antitumor agents. 258. Syntheses and evaluation of dietary antioxidant--taxoid conjugates as novel cytotoxic agents. Bioorg. Med. Chem. Lett., 2007, 17, 5204-5209.
[38]
Wormann, S.M.; Song, L.; Ai, J.; Diakopoulos, K.N.; Kurkowski, M.U.; Gorgulu, K.; Ruess, D.; Campbell, A.; Doglioni, C.; Jodrell, D.; Neesse, A.; Demir, I.E.; Karpathaki, A.P.; Barenboim, M.; Hagemann, T.; Rose-John, S.; Sansom, O.; Schmid, R.M.; Protti, M.P.; Lesina, M.; Algul, H. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology, 2016, 151, 180-193.
[39]
Singh, M.; Lima, A.; Molina, R.; Hamilton, P.; Clermont, A.C.; Devasthali, V.; Thompson, J.D.; Cheng, J.H.; Bou Reslan, H.; Ho, C.C.; Cao, T.C.; Lee, C.V.; Nannini, M.A.; Fuh, G.; Carano, R.A.; Koeppen, H.; Yu, R.X.; Forrest, W.F.; Plowman, G.D.; Johnson, L. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat. Biotechnol., 2010, 28, 585-593.
[40]
Kao, C.T.; Aziz, M.; Kasi, A. Pathological complete response in pancreatic adenocarcinoma with FOLFIRINOX. BMJ Case Rep, 2018. 2018.
[41]
Tong, H.; Fan, Z.; Liu, B.; Lu, T. The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: A systematic review and meta-analysis. Sci. Rep., 2018, 8, 8666.
[42]
Kim, J.H.; Lee, S.C.; Oh, S.Y.; Song, S.Y.; Lee, N.; Nam, E.M.; Lee, S.; Hwang, I.G.; Lee, H.R.; Lee, K.T.; Bae, S.B.; Kim, H.J.; Jang, J.S.; Lim, D.H.; Lee, H.W.; Kang, S.Y.; Kang, J.H. Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic cancer: A phase II study. Cancer Commun. (Lond), 2018, 38, 32.
[43]
Luu, A.M.; Herzog, T.; Hoehn, P.; Reinacher-Schick, A.; Munding, J.; Uhl, W.; Braumann, C. FOLFIRINOX treatment leading to pathologic complete response of a locally advanced pancreatic cancer. J. Gastrointest. Oncol., 2018, 9, E9-E12.
[44]
Erstad, D.J.; Sojoodi, M.; Taylor, M.S.; Ghoshal, S.; Razavi, A.A.; Graham-O’Regan, K.A.; Bardeesy, N.; Ferrone, C.R.; Lanuti, M.; Caravan, P.; Tanabe, K.K.; Fuchs, B.C. Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. Dis. Model. Mech., 2018, 11(7)
[http://dx.doi.org/10.1242/dmm.034793]
[45]
Verma, R.K.; Yu, W.; Shrivastava, A.; Shankar, S.; Srivastava, R.K. alpha-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (Kras(G12D), and Kras(G12D)/tp53R270H) mice. Sci. Rep., 2016, 6, 32743.
[46]
Weyandt, J.D.; Lampson, B.L.; Tang, S.; Mastrodomenico, M.; Cardona, D.M.; Counter, C.M. Wild-type hras suppresses the earliest stages of tumorigenesis in a genetically engineered mouse model of pancreatic cancer. PLoS One, 2015, 10e0140253
[47]
Botta, G.P.; Reichert, M.; Reginato, M.J.; Heeg, S.; Rustgi, A.K.; Lelkes, P.I. ERK2-regulated TIMP1 induces hyperproliferation of K-Ras(G12D)-transformed pancreatic ductal cells. Neoplasia, 2013, 15, 359-372.
[48]
D’Costa, Z.; Jones, K.; Azad, A.; van Stiphout, R.; Lim, S.Y.; Gomes, A.L.; Kinchesh, P.; Smart, S.C.; McKenna, W.G.; Buffa, F.M.; Sansom, O.J.; Muschel, R.J.; O’Neill, E.; Fokas, E. Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer. Cancer Res., 2017, 77(21), 5952-5962.
[49]
Chow, J.Y.; Ban, M.; Wu, H.L.; Nguyen, F.; Huang, M.; Chung, H.; Dong, H.; Carethers, J.M. TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2010, 298, G275-G282.
[50]
Setia, S.; Sanyal, S.N. Nuclear factor kappa B: A pro-inflammatory, transcription factor-mediated signalling pathway in lung carcinogenesis and its inhibition by nonsteroidal anti-inflammatory drugs. J. Environ. Pathol. Toxicol. Oncol., 2012, 31, 27-37.
[51]
Yip-Schneider, M.T.; Wu, H.; Stantz, K.; Agaram, N.; Crooks, P. A.; Schmidt, C.M. Dimethylaminoparthenolide and gemcitabine: A survival study using a genetically engineered mouse model of pancreatic cancer. BMC Cancer, 2013. 13, 194-2407-13-194.
[52]
Orozco, C.A.; Martinez-Bosch, N.; Guerrero, P.E.; Vinaixa, J.; Dalotto-Moreno, T.; Iglesias, M.; Moreno, M.; Djurec, M.; Poirier, F.; Gabius, H.J.; Fernandez-Zapico, M.E.; Hwang, R.F.; Guerra, C.; Rabinovich, G.A.; Navarro, P. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc. Natl. Acad. Sci. USA, 2018, 115, E3769-E3778.
[53]
Lu, Z.; Weniger, M.; Jiang, K.; Boeck, S.; Zhang, K.; Bazhin, A.; Miao, Y.; Werner, J. DHaese, J.G. Therapies targeting the tumor stroma and the vegf/vegfr axis in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Target. Oncol., 2018, 13(4), 447-459.
[54]
Frese, K.K.; Neesse, A.; Cook, N.; Bapiro, T.E.; Lolkema, M.P.; Jodrell, D.I.; Tuveson, D.A. Nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov., 2012, 2, 260-269.
[55]
Miller, B.W.; Morton, J.P.; Pinese, M.; Saturno, G.; Jamieson, N.B.; McGhee, E.; Timpson, P.; Leach, J.; McGarry, L.; Shanks, E.; Bailey, P.; Chang, D.; Oien, K.; Karim, S.; Au, A.; Steele, C.; Carter, C.R.; McKay, C.; Anderson, K.; Evans, T.R.; Marais, R.; Springer, C.; Biankin, A.; Erler, J.T.; Sansom, O.J. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: Inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol. Med., 2015, 7, 1063-1076.
[56]
Whatcott, C.J.; Ng, S.; Barrett, M.T.; Hostetter, G.; Von Hoff, D.D.; Han, H. Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. PLoS One, 2017, 12e0183871
[57]
Carapuca, E.F.; Gemenetzidis, E.; Feig, C.; Bapiro, T.E.; Williams, M.D.; Wilson, A.S.; Delvecchio, F.R.; Arumugam, P.; Grose, R.P.; Lemoine, N.R.; Richards, F.M.; Kocher, H.M. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. J. Pathol., 2016, 239, 286-296.
[58]
Jacobetz, M.A.; Chan, D.S.; Neesse, A.; Bapiro, T.E.; Cook, N.; Frese, K.K.; Feig, C.; Nakagawa, T.; Caldwell, M.E.; Zecchini, H.I.; Lolkema, M.P.; Jiang, P.; Kultti, A.; Thompson, C.B.; Maneval, D.C.; Jodrell, D.I.; Frost, G.I.; Shepard, H.M.; Skepper, J.N.; Tuveson, D.A. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut, 2013, 62, 112-120.
[59]
Rucki, A.A.; Xiao, Q.; Muth, S.; Chen, J.; Che, X.; Kleponis, J.; Sharma, R.; Anders, R.A.; Jaffee, E.M.; Zheng, L. Dual inhibition of hedgehog and c-met pathways for pancreatic cancer treatment. Mol. Cancer Ther., 2017, 16, 2399-2409.
[60]
Feng, B.; Zhou, F.; Hou, B.; Wang, D.; Wang, T.; Fu, Y.; Ma, Y.; Yu, H.; Li, Y. Binary cooperative prodrug nanoparticles improve immunotherapy by synergistically modulating immune tumor microenvironment. Adv. Mater., 2018.e1803001
[61]
Beatty, G.L.; Chiorean, E.G.; Fishman, M.P.; Saboury, B.; Teitelbaum, U.R.; Sun, W.; Huhn, R.D.; Song, W.; Li, D.; Sharp, L.L.; Torigian, D.A.; O’Dwyer, P.J.; Vonderheide, R.H. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science, 2011, 331, 1612-1616.
[62]
Zhang, H.; Song, Y.; Zhou, C.; Bai, Y.; Yuan, D.; Pan, Y.; Shao, C. Blocking endogenous H2S signaling attenuated radiation-induced long-term metastasis of residual HepG2 cells through inhibition of EMT. Radiat. Res., 2018, 190(4), 374-384.
[63]
Aiello, N.M.; Maddipati, R.; Norgard, R.J.; Balli, D.; Li, J.; Yuan, S.; Yamazoe, T.; Black, T.; Sahmoud, A.; Furth, E.E.; Bar-Sagi, D.; Stanger, B.Z. EMT Subtype influences epithelial plasticity and mode of cell migration. Dev. Cell, 2018, 45, 681-695.e4.
[64]
Meng, Q.; Shi, S.; Liang, C.; Liang, D.; Hua, J.; Zhang, B.; Xu, J.; Yu, X. Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3beta/Snail signaling. Oncogene, 2018, 37(44), 5843-5857.
[65]
Su, Y.; Li, J.; Witkiewicz, A.K.; Brennan, D.; Neill, T.; Talarico, J.; Radice, G.L. N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. Oncogene, 2012, 31, 4484-4489.
[66]
Banerjee, S.; Modi, S.; McGinn, O.; Zhao, X.; Dudeja, V.; Ramakrishnan, S.; Saluja, A.K. Impaired synthesis of stromal components in response to minnelide improves vascular function, drug delivery, and survival in pancreatic cancer. Clin. Cancer Res., 2016, 22, 415-425.
[67]
Koikawa, K.; Ohuchida, K.; Ando, Y.; Kibe, S.; Nakayama, H.; Takesue, S.; Endo, S.; Abe, T.; Okumura, T.; Iwamoto, C.; Moriyama, T.; Nakata, K.; Miyasaka, Y.; Ohtsuka, T.; Nagai, E.; Mizumoto, K.; Hashizume, M.; Nakamura, M. Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma. Cancer Lett., 2018, 425, 65-77.
[68]
Sarper, M.; Cortes, E.; Lieberthal, T.J.; Del, R.H.A. ATRA modulates mechanical activation of TGF-beta by pancreatic stellate cells. Sci. Rep., 2016, 6, 27639.
[69]
Froeling, F.E.; Feig, C.; Chelala, C.; Dobson, R.; Mein, C.E.; Tuveson, D.A.; Clevers, H.; Hart, I.R.; Kocher, H.M. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology, 2011. 141, 1486-97, 1497.e1-14.
[70]
Liby, K.T.; Royce, D.B.; Risingsong, R.; Williams, C.R.; Maitra, A.; Hruban, R.H.; Sporn, M.B. Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. Cancer Prev. Res. (Phila.), 2010, 3, 1427-1434.
[71]
Akimoto, M.; Maruyama, R.; Kawabata, Y.; Tajima, Y.; Takenaga, K. Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERKdependent necroptosis. Cell. Death Dis.,2018, 9, 804-018-0851-z.
[72]
Chen, C.; Xiao, W.; Huang, L.; Yu, G.; Ni, J.; Yang, L.; Wan, R.; Hu, G. Shikonin induces apoptosis and necroptosis in pancreatic cancer via regulating the expression of RIP1/RIP3 and synergizes the activity of gemcitabine. Am. J. Transl. Res., 2017, 9, 5507-5517.
[73]
Xie, Y.; Zhu, S.; Zhong, M.; Yang, M.; Sun, X.; Liu, J.; Kroemer, G.; Lotze, M.; Zeh, H.J., III; Kang, R.; Tang, D. Inhibition of aurora kinase an induces necroptosis in pancreatic carcinoma. Gastroenterology, 2017, 153(5), 1429-1443.e5.
[74]
Weber, K.; Roelandt, R.; Bruggeman, I.; Estornes, Y.; Vandenabeele, P. Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. Commun. Biol., 2018, 6.
[75]
Zhou, J.E.; Yu, J.; Gao, L.; Sun, L.; Peng, T.; Wang, J.; Zhu, J.; Lu, W.; Zhang, L.; Yan, Z.; Yu, L. iNGR-modified liposomes for tumor vascular targeting and tumor tissue penetrating delivery in the treatment of glioblastoma. Mol. Pharm., 2017, 14, 1811-1820.
[76]
Miao, L.; Newby, J.M.; Lin, C.M.; Zhang, L.; Xu, F.; Kim, W.Y.; Forest, M.G.; Lai, S.K.; Milowsky, M.I.; Wobker, S.E.; Huang, L. The binding site barrier elicited by tumor-associated fibroblasts interferes disposition of nanoparticles in stroma-vessel type tumors. ACS Nano, 2016, 10(10), 9243-9258.
[77]
Chandra, D.; Selvanesan, B.C.; Yuan, Z.; Libutti, S.K.; Koba, W.; Beck, A.; Zhu, K.; Casadevall, A.; Dadachova, E.; Gravekamp, C. 32-Phosphorus selectively delivered by listeria to pancreatic cancer demonstrates a strong therapeutic effect. Oncotarget, 2017, 8, 20729-20740.
[78]
Bobrov, E.; Skobeleva, N.; Restifo, D.; Beglyarova, N.; Cai, K.Q.; Handorf, E.; Campbell, K.; Proia, D.A.; Khazak, V.; Golemis, E.A.; Astsaturov, I. Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models. Oncotarget, 2017, 8, 4399-4409.
[79]
Farr, N.; Wang, Y.N.; D’Andrea, S.; Starr, F.; Partanen, A.; Gravelle, K.M.; McCune, J.S.; Risler, L.J.; Whang, S.G.; Chang, A.; Hingorani, S.R.; Lee, D.; Hwang, J.H. Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: A pre-clinical study in a genetic model of pancreatic cancer. Int. J. Hyperthermia, 2018, 34(3), 284-291.
[80]
Jiang, H.; Hegde, S.; Knolhoff, B.L.; Zhu, Y.; Herndon, J.M.; Meyer, M.A.; Nywening, T.M.; Hawkins, W.G.; Shapiro, I.M.; Weaver, D.T.; Pachter, J.A.; Wang-Gillam, A.; DeNardo, D.G. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med., 2016, 22, 851-860.
[81]
Joensson, P.; Hotz, B.; Buhr, H.J.; Hotz, H.G. A novel antiangiogenic approach for adjuvant therapy of pancreatic carcinoma. Langenbecks Arch. Surg., 2011, 396, 535-541.
[82]
Gurlevik, E.; Fleischmann-Mundt, B.; Brooks, J.; Demir, I.E.; Steiger, K.; Ribback, S.; Yevsa, T.; Woller, N.; Kloos, A.; Ostroumov, D.; Armbrecht, N.; Manns, M.P.; Dombrowski, F.; Saborowski, M.; Kleine, M.; Wirth, T.C.; Oettle, H.; Ceyhan, G.O.; Esposito, I.; Calvisi, D.F.; Kubicka, S.; Kuhnel, F. Administration of gemcitabine after pancreatic tumor resection in mice induces an antitumor immune response mediated by natural killer cells. Gastroenterology, 2016, 151, 338-350.e7.
[83]
Renz, B.W.; Takahashi, R.; Tanaka, T.; Macchini, M.; Hayakawa, Y.; Dantes, Z.; Maurer, H.C.; Chen, X.; Jiang, Z.; Westphalen, C.B.; Ilmer, M.; Valenti, G.; Mohanta, S.K.; Habenicht, A.J.R.; Middelhoff, M.; Chu, T.; Nagar, K.; Tailor, Y.; Casadei, R.; Di Marco, M.; Kleespies, A.; Friedman, R.A.; Remotti, H.; Reichert, M.; Worthley, D.L.; Neumann, J.; Werner, J.; Iuga, A.C.; Olive, K.P.; Wang, T.C. Beta2 adrenergic-neurotrophin feedforward Loop Promotes Pancreatic Cancer. Cancer Cell, 2018, 33, 75-90.e7.
[84]
Ambree, O.; Ruland, C.; Scheu, S.; Arolt, V.; Alferink, J. Alterations of the innate immune system in susceptibility and resilience after social defeat stress. Front. Behav. Neurosci., 2018, 12, 141.
[85]
Clark, S.M.; Song, C.; Li, X.; Keegan, A.D.; Tonelli, L.H. CD8(+) T cells promote cytokine responses to stress. Cytokine, 2018, 113, 256-264.
[86]
Morran, D.C.; Wu, J.; Jamieson, N.B.; Mrowinska, A.; Kalna, G.; Karim, S.A.; Au, A.Y.; Scarlett, C.J.; Chang, D.K.; Pajak, M.Z.; Oien, K.A.; McKay, C.J.; Carter, C.R.; Gillen, G.; Champion, S.; Pimlott, S.L.; Anderson, K.I.; Evans, T.R.; Grimmond, S.M.; Biankin, A.V.; Sansom, O.J.; Morton, J.P. Targeting mTOR dependency in pancreatic cancer. Gut, 2014, 63, 1481-1489.
[87]
Konings, I.C.A.W.; Cahen, D.L.; Harinck, F.; Fockens, P.; van Hooft, J.E.; Poley, J.W.; Bruno, M.J. Evolution of features of chronic pancreatitis during endoscopic ultrasound-based surveillance of individuals at high risk for pancreatic cancer. Endosc. Int. Open, 2018, 6, E541-E548.
[88]
Ikuta, K.; Fukuda, A.; Ogawa, S.; Masuo, K.; Goto, N.; Hiramatsu, Y.; Tsuda, M.; Kimura, Y.; Matsumoto, Y.; Kimura, Y.; Maruno, T.; Kanda, K.; Nishi, K.; Takaori, K.; Uemoto, S.; Takaishi, S.; Chiba, T.; Nishi, E.; Seno, H. Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice. Gut, 2018. pii: gutjnl-2017-315425.
[89]
Mohammed, A.; Janakiram, N.B.; Madka, V.; Brewer, M.; Ritchie, R.L.; Lightfoot, S.; Kumar, G.; Sadeghi, M.; Patlolla, J.M.; Yamada, H.Y.; Cruz-Monserrate, Z.; May, R.; Houchen, C.W.; Steele, V.E.; Rao, C.V. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression. Oncotarget, 2015, 6, 15524-15539.
[90]
Mohammed, A.; Janakiram, N.B.; Li, Q.; Madka, V.; Ely, M.; Lightfoot, S.; Crawford, H.; Steele, V.E.; Rao, C.V. The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-KrasG12D/+ transgenic mouse model. Cancer Prev. Res. (Phila.), 2010, 3, 1417-1426.
[91]
Li, H.; Yang, A.L.; Chung, Y.T.; Zhang, W.; Liao, J.; Yang, G.Y. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10). Carcinogenesis, 2013, 34, 2090-2098.
[92]
Lee, J.J.; Perera, R.M.; Wang, H.; Wu, D.C.; Liu, X.S.; Han, S.; Fitamant, J.; Jones, P.D.; Ghanta, K.S.; Kawano, S.; Nagle, J.M.; Deshpande, V.; Boucher, Y.; Kato, T.; Chen, J.K.; Willmann, J.K.; Bardeesy, N.; Beachy, P.A. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl. Acad. Sci. USA, 2014, 111, E3091-E3100.
[93]
de Oliveira, M.R.; de Bittencourt Brasil, F.; Furstenau, C.R. Inhibition of the Nrf2/HO-1 axis suppresses the mitochondria-related protection promoted by gastrodin in human neuroblastoma cells exposed to paraquat. Mol. Neurobiol., 2019, 56(3), 2174-2184.
[94]
Song, Y.; Gao, L.; Tang, Z.; Li, H.; Sun, B.; Chu, P.; Qaed, E.; Ma, X.; Peng, J.; Wang, S.; Hu, M.; Tang, Z. Anticancer effect of SZC015 on pancreatic cancer via mitochondria-dependent apoptosis and the constitutive suppression of activated nuclear factor kappaB and STAT3 in vitro and in vivo. J. Cell. Physiol., 2018, 234(1), 777-788.
[95]
Sotgia, F.; Fiorillo, M.; Lisanti, M.P. Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics. Oncotarget, 2017, 8, 68730-68745.
[96]
Viale, A.; Pettazzoni, P.; Lyssiotis, C.A.; Ying, H.; Sanchez, N.; Marchesini, M.; Carugo, A.; Green, T.; Seth, S.; Giuliani, V.; Kost-Alimova, M.; Muller, F.; Colla, S.; Nezi, L.; Genovese, G.; Deem, A.K.; Kapoor, A.; Yao, W.; Brunetto, E.; Kang, Y.; Yuan, M.; Asara, J.M.; Wang, Y.A.; Heffernan, T.P.; Kimmelman, A.C.; Wang, H.; Fleming, J.B.; Cantley, L.C.; DePinho, R.A.; Draetta, G.F. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature, 2014, 514, 628-632.
[97]
Wang, Y.; Chen, Y.; Guan, L.; Zhang, H.; Huang, Y.; Johnson, C.H.; Wu, Z.; Gonzalez, F.J.; Yu, A.; Huang, P.; Wang, Y.; Yang, S.; Chen, P.; Fan, X.; Huang, M.; Bi, H. Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming. Cell Death Differ., 2018, 25, 733-746.
[98]
Chen, L.; Sun, Q.; Zhou, D.; Song, W.; Yang, Q.; Ju, B.; Zhang, L.; Xie, H.; Zhou, L.; Hu, Z.; Yao, H.; Zheng, S.; Wang, W. HINT2 triggers mitochondrial Ca(2+) influx by regulating the mitochondrial Ca(2+) uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett., 2017, 411, 106-116.
[99]
Schmohl, K.A.; Gupta, A.; Grunwald, G.K.; Trajkovic-Arsic, M.; Klutz, K.; Braren, R.; Schwaiger, M.; Nelson, P.J.; Ogris, M.; Wagner, E.; Siveke, J.T.; Spitzweg, C. Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene. Oncotarget, 2017, 8, 33393-33404.
[100]
Schmitz-Winnenthal, F.H.; Hohmann, N.; Schmidt, T.; Podola, L.; Friedrich, T.; Lubenau, H.; Springer, M.; Wieckowski, S.; Breiner, K.M.; Mikus, G.; Buchler, M.W.; Keller, A.V.; Koc, R.; Springfeld, C.; Knebel, P.; Bucur, M.; Grenacher, L.; Haefeli, W.E.; Beckhove, P. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. OncoImmunology, 2018, 7e1303584
[101]
Nishida, S.; Ishikawa, T.; Egawa, S.; Koido, S.; Yanagimoto, H.; Ishii, J.; Kanno, Y.; Kokura, S.; Yasuda, H.; Oba, M.S.; Sato, M.; Morimoto, S.; Fujiki, F.; Eguchi, H.; Nagano, H.; Kumanogoh, A.; Unno, M.; Kon, M.; Shimada, H.; Ito, K.; Homma, S.; Oka, Y.; Morita, S.; Sugiyama, H. Combination gemcitabine and WT1 peptide vaccination improves progression-free survival in advanced pancreatic ductal adenocarcinoma: A phase II randomized study. Cancer Immunol. Res., 2018.
[http://dx.doi.org/10.1158/2326-6066.CIR-17-0386]
[102]
Cappello, P.; Rolla, S.; Chiarle, R.; Principe, M.; Cavallo, F.; Perconti, G.; Feo, S.; Giovarelli, M.; Novelli, F. Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology, 2013, 144, 1098-1106.
[103]
Sahu, R.P.; Ferracini, M.; Travers, J.B. Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists. Mediators Inflamm., 2015, 2015820543
[104]
Sahu, R.P.; Harrison, K.A.; Weyerbacher, J.; Murphy, R.C.; Konger, R.L.; Garrett, J.E.; Chin-Sinex, H.J.; Johnston, M.E., II; Dynlacht, J.R.; Mendonca, M.; McMullen, K.; Li, G.; Spandau, D.F.; Travers, J.B. Radiation therapy generates platelet-activating factor agonists. Oncotarget, 2016, 7, 20788-20800.
[105]
Romer, E.; Thyagarajan, A.; Krishnamurthy, S.; Rapp, C.M.; Liu, L.; Fahy, K.; Awoyemi, A.; Sahu, R.P. Systemic platelet-activating factor-receptor agonism enhances non-melanoma skin cancer growth. Int. J. Mol. Sci., 2018, 19
[http://dx.doi.org/10.3390/ijms19103109]
[106]
Chammas, R.; de Sousa Andrade, L.N.; Jancar, S. Oncogenic effects of PAFR ligands produced in tumours upon chemotherapy and radiotherapy. Nat. Rev. Cancer, 2017, 17, 253.
[107]
Hackler, P.C.; Reuss, S.; Konger, R.L.; Travers, J.B.; Sahu, R.P. Systemic platelet-activating factor receptor activation augments experimental lung tumor growth and metastasis. Cancer Growth Metastasis, 2014, 7, 27-32.

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