[1]. Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet 2016;388:73-85.
[2]. Monitoring of Cancer Incidence in Japan - Survival 2009-2011 Report (Center for Cancer Control and Information Services, National Cancer Center, 2020)
[3]. Matsuda T, Ajiki W, Marugame T, et al. Population-based survival of cancer patients diagnosed between 1993 and 1999 in Japan: a chronological and international comparative study. Jpn J Clin Oncol 2011;41:40-51.
[4]. Cancer Statistics. Cancer Information Service, National Cancer Center, Japan (National Cancer Registry, Ministry of Health, Labour and Welfare)
[5]. Kanno A, Masamune A, Hanada K, et al. Multicenter study of early pancreatic cancer in Japan. Pancreatology 2018;18:61-67.
[6]. Egawa S, Toma H, Ohigashi H, et al. Japan pancreatic cancer registry; 30th year anniversary: Japan Pancreas Society. Pancreas 2012;41:985-992.
[7]. Bengtsson A, Andersson R, Ansari D. The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data. Sci Rep 2020;10:16425.
[8]. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-1825.
[9]. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-1703.
[10]. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-566.
[11]. von Mehren M, Brennan MF, Patel S, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097-1104.
[12]. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-2972.
[13]. Bryant KL, Mancias JD, Kimmelman AC, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014;39:91-100.
[14]. McCormick F. KRAS as a therapeutic target. Clin Cancer Res 2015;21:1797-1801.
[15]. Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J 2012;18:492-501.
[16]. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418-429.
[17]. Erkan M, Adler G, Apte MV, et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 2012;61:172-178.
[18]. Kikuta K, Masamune A, Watanabe T, et al. Pancreatic stellate cells promote epithelial- mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 2010;403:380-384.
[19]. Hamada S, Masamune A, Takikawa T, et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun 2012;421:349-354.
[20]. Masamune A, Shimosegawa T. Pancreatic stellate cells--multi-functional cells in the pancreas. Pancreatology 2013;13:102-105.
[21]. 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;324:1457-1461.
[22]. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma- associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014;25:719-734.
[23]. Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014;25:735-747.
[24]. Mizutani Y, Kobayashi H, Iida T, et al. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res 2019;79:5367-5381.
[25]. Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80-93.
[26]. Guillaumond F, Iovanna JL, Vasseur S. Pancreatic tumor cell metabolism: focus on glycolysis and its connected metabolic pathways. Arch Biochem Biophys 2014;545:69- 73.
[27]. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell 2020;38:167-197.
[28]. Yu JH, Kim H. Oxidative stress and cytokines in the pathogenesis of pancreatic cancer. J Cancer Prev 2014;19:97-102.
[29]. Hiraga R, Kato M, Miyagawa S, et al. Nox4-derived ROS signaling contributes to TGF- β-induced epithelial-mesenchymal transition in pancreatic cancer cells. Anticancer Res 2013;33:4431-4438.
[30]. Baird L, and Yamamoto M. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol 2020;40:e00099-20.
[31]. Suzuki T, Yamamoto M. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. J Biol Chem 2017;292:16817-16824.
[32]. Taguchi K, and Yamamoto M. The KEAP1-NRF2 system as a molecular target of cancer treatment. Cancers (Basel) 2020;13:46.
[33]. Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res 2018;24:3087-3096.
[34]. Fukutomi T, Takagi K, Mizushima T, et al. Kinetic, thermodynamic and structural characterizations of association between Nrf2-DLGex degron and Keap1. Mol Cell Biol 2018;34:832-846.
[35]. Kerins MJ, Ooi A. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci Rep 2018;8:12846.
[36]. Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997;236:313-322.
[37]. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469-483.
[38]. Hamada S, Taguchi K, Masamune A, et al. Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. Carcinogenesis 2017;38:661-670.
[39]. DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011;475:106-109.
[40]. Chio IIC, Jafarnejad SM, Ponz-Sarvise M, et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 2016;166:963-976.
[41]. Maruyama A, Tsukamoto S, Nishikawa K, et al. Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements. Arch Biochem Biophys 2008;477:139-145.
[42]. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012;2:401–404.
[43]. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:pl1.
[44]. Hoadley KA, Yau C, Hinoue T, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 2018;173:291–304.
[45]. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998;43:128-133.
[46]. Satoh M, Masamune A, Sakai Y, et al. Establishment and characterization of a simian virus 40-immortalized rat pancreatic stellate cell line. Tohoku J Exp Med 2002;198:55- 69.
[47]. Wang X, Spandidos A, Wang H, et al. PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update. Nucleic Acids Res 2012;40:D1144- 1149.
[48]. Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010:12:213-223.
[49]. Masamune A, Kikuta K, Satoh M, et al. Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells. J Pharmacol Exp Ther 2002;302:36-42.
[50]. Jesnowski R, Fürst 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;85:1276-1291.
[51]. Suklabaidya S, Das B, Ali SA, et al. Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia. Oncotarget 2016;7:41825-41842.
[52]. Feng H, Moriyama T, Ohuchida K, et al. N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions. J Exp Clin Cancer Res 2021;40:133.
[53]. Mukhopadhyay S, Goswami D, Adiseshaiah PP, et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res 2020;80:1630-1643.
[54]. Sherman MH. Stellate cells in tissue repair, inflammation, and cancer. Annu Rev Cell Dev Biol 2018;34:333-355.
[55]. Ishida K, Kaji K, Sato S, et al. Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway. J Nutr Biochem 2020;89:108573.
[56]. Dwivedi DK, Jena G, Kumar V. Dimethyl fumarate protects thioacetamide-induced liver damage in rats: Studies on Nrf2, NLRP3, and NF-kappaB. J Biochem Mol Toxicol 2020;34:e22476.
[57]. Yoshida N, Masamune A, Hamada S, et al. Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer. Cancer Lett 2017;390:103-114.
[58]. Hamada S, Masamune A, Yoshida N, et al. IL-6/STAT3 plays a regulatory role in the interaction between pancreatic stellate cells and cancer cells. Dig Dis Sci 2016;61:1561-1571.
[59]. Nagathihalli NS, Castellanos JA, VanSaun MN, et al. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget 2016;7:65982-65992.
[60]. Hiebert P, Wietecha MS, Cangkrama M, et al. Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome. Dev Cell 2018;46:145-161.
[61]. Kang JI, Kim DH, Sung KW, et al. p62-Induced cancer-associated fibroblast activation via the Nrf2-ATF6 pathway promotes lung tumorigenesis. Cancers (Basel) 2021;13:864.
[62]. Matsumoto R, Hamada S, Tanaka Y, et al. Nrf2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression. J Pharmacol Exp Ther 2021:JPET-AR-2021-000744.
[63]. Bruck R, Genina O, Aeed H, et al. Halofuginone to prevent and treat thioacetamide- induced liver fibrosis in rats. Hepatology 2001;33:379-386.
[64]. de Jonge MJ, Dumez H, Verweij J, et al. Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. Eur J Cancer 2006;42:1768-1774.
[65]. Turgeman T, Hagai Y, Huebner K, et al. Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone. Neuromuscul Disord 2008;18:857-68.
[66]. Adler A, Lifshitz Z, Gordon M, et al. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. J Antimicrob Chemother 2017;72:2219-2224.
[67]. Hamada S, Matsumoto R, Tanaka Y, et al. Nrf2 activation sensitizes K-Ras mutant pancreatic cancer cells to glutaminase inhibition. Int J Mol Sci 2021;22:1870.