{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:50:17Z","timestamp":1773964217171,"version":"3.50.1"},"reference-count":376,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network","award":["813834; H2020-MSCA-ITN-2018"],"award-info":[{"award-number":["813834; H2020-MSCA-ITN-2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.<\/jats:p>","DOI":"10.3390\/cancers13236135","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T22:18:42Z","timestamp":1638829122000},"page":"6135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-1413","authenticated-orcid":false,"given":"Tiago M. A.","family":"Carvalho","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Daria","family":"Di Molfetta","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Maria Raffaella","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Tomas","family":"Koltai","sequence":"additional","affiliation":[{"name":"Via Pier Capponi 6, 50132 Florence, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-6117","authenticated-orcid":false,"given":"Khalid O.","family":"Alfarouk","sequence":"additional","affiliation":[{"name":"Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munwarah 42316, Saudi Arabia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-5908","authenticated-orcid":false,"given":"Stephan J.","family":"Reshkin","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2011-9135","authenticated-orcid":false,"given":"Rosa A.","family":"Cardone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(20)30974-0","article-title":"Pancreatic cancer","volume":"395","author":"Mizrahi","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4846","DOI":"10.3748\/wjg.v24.i43.4846","article-title":"Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes","volume":"24","author":"McGuigan","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1097\/00006676-200411000-00003","article-title":"The molecular basis of pancreatic fibrosis: Common stromal gene expression in chronic pancreatitis and pancreatic adenocarcinoma","volume":"29","author":"Binkley","year":"2004","journal-title":"Pancreas"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"188461","DOI":"10.1016\/j.bbcan.2020.188461","article-title":"Therapeutic resistance of pancreatic cancer: Roadmap to its reversal","volume":"1875","author":"Yu","year":"2021","journal-title":"Biochim. Biophys. Acta. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.3390\/cancers6042137","article-title":"Desmoplasia and chemoresistance in pancreatic cancer","volume":"6","author":"Schober","year":"2014","journal-title":"Cancers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"021004","DOI":"10.1115\/1.4034991","article-title":"The Solid Mechanics of Cancer and Strategies for Improved Therapy","volume":"139","author":"Stylianopoulos","year":"2017","journal-title":"J. Biomech. Eng."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cell.2011.05.040","article-title":"Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis","volume":"146","author":"Goetz","year":"2011","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1083\/jcb.201704053","article-title":"Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin","volume":"216","author":"Erdogan","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1158\/0008-5472.CAN-14-1903","article-title":"Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis","volume":"75","author":"Stanisavljevic","year":"2015","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ccr.2012.01.007","article-title":"Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma","volume":"21","author":"Provenzano","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Adamska, A., Domenichini, A., and Falasca, M. (2017). Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071338"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1006\/clin.1993.1012","article-title":"T cell recognition of human tumors: Implications for molecular immunotherapy of cancer","volume":"66","author":"Ioannides","year":"1993","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1016\/j.pan.2015.02.013","article-title":"Pancreatic cancer: The microenvironment needs attention too!","volume":"15","author":"Apte","year":"2015","journal-title":"Pancreatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e5541","DOI":"10.1097\/MD.0000000000005541","article-title":"Role of immune cells in pancreatic cancer from bench to clinical application: An updated review","volume":"95","author":"Chang","year":"2016","journal-title":"Medicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12935-015-0221-1","article-title":"Resistance to cancer chemotherapy: Failure in drug response from ADME to P-gp","volume":"15","author":"Alfarouk","year":"2015","journal-title":"Cancer Cell Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yeldag, G., Rice, A., and del R\u00edo Hern\u00e1ndez, A. (2018). Chemoresistance and the self-maintaining tumor microenvironment. Cancers, 10.","DOI":"10.3390\/cancers10120471"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"59950","DOI":"10.18632\/oncotarget.19048","article-title":"The molecular mechanisms of chemoresistance in cancers","volume":"8","author":"Zheng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1097\/MOG.0b013e328363affe","article-title":"Deciphering the role of stroma in pancreatic cancer","volume":"29","author":"Waghray","year":"2013","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19396","DOI":"10.18632\/oncotarget.25036","article-title":"Advanced pancreatic cancer: A meta-analysis of clinical trials over thirty years","volume":"9","author":"Hall","year":"2018","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/00006676-200410000-00002","article-title":"Desmoplastic reaction in pancreatic cancer: Role of pancreatic stellate cells","volume":"29","author":"Apte","year":"2004","journal-title":"Pancreas"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/bjc.2013.706","article-title":"Pancreatic stellate cells promote hapto-migration of cancer cells through collagen I-mediated signalling pathway","volume":"110","author":"Lu","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","article-title":"Cancer-associated stromal fibroblasts promote pancreatic tumor progression","volume":"68","author":"Hwang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_25","first-page":"673","article-title":"Pancreatic cancer: The role of pancreatic stellate cells in tumor progression","volume":"10","author":"Lindman","year":"2010","journal-title":"Pancreatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cell.2014.08.007","article-title":"Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy","volume":"159","author":"Sherman","year":"2014","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/path.4727","article-title":"Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma","volume":"239","author":"Gemenetzidis","year":"2016","journal-title":"J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1053\/j.gastro.2013.07.025","article-title":"Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma","volume":"145","author":"Clear","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"602","DOI":"10.3109\/00365521.2013.777776","article-title":"The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice","volume":"48","author":"Masamune","year":"2013","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_30","unstructured":"Whatcott, C.J., Posner, R.G., Von Hoff, D.D., and Han, H. (2012). Desmoplasia and chemoresistance in pancreatic cancer. Pancreatic Cancer and Tumor Microenvironment, Transworld Research Network."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1067\/msy.2002.119192","article-title":"Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas","volume":"131","author":"Yen","year":"2002","journal-title":"Surgery"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0016-5085(98)70209-4","article-title":"Identification, culture, and characterization of pancreatic stellate cells in rats and humans","volume":"115","author":"Bachem","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1136\/gut.44.4.534","article-title":"Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis","volume":"44","author":"Apte","year":"1999","journal-title":"Gut"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/sj.bjc.6602141","article-title":"Overexpression of TGF-\u03b2 by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer","volume":"91","author":"Aoyagi","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_35","first-page":"550","article-title":"Transforming growth factor-\u03b21 induces desmoplasia in an experimental model of human pancreatic carcinoma","volume":"61","author":"Schmidt","year":"2001","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s12307-019-00223-3","article-title":"Cancer-associated fibroblasts enhance survival and progression of the aggressive pancreatic tumor Via FGF-2 and CXCL8","volume":"12","author":"Awaji","year":"2019","journal-title":"Cancer Microenviron."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1007\/s00268-004-7147-4","article-title":"Desmoplastic reaction influences pancreatic cancer growth behavior","volume":"28","author":"Hartel","year":"2004","journal-title":"World J. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1158\/0008-5472.CAN-19-2080","article-title":"Tumor Cell-Derived IL-1\u03b2 Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer","volume":"80","author":"Das","year":"2020","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Stern, R. (2008). Hyaluronidases in cancer biology. Hyaluronan Cancer Biol., 207\u2013220.","DOI":"10.1016\/B978-012374178-3.10012-2"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/03008200802143190","article-title":"Extracellular matrix: A matter of life and death","volume":"49","author":"Marastoni","year":"2008","journal-title":"Connect. Tissue Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1002\/ijc.21677","article-title":"Fibronectin as target for tumor therapy","volume":"118","author":"Kaspar","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1158\/1535-7163.MCT-06-0686","article-title":"Tumor-stroma interactions in pancreatic ductal adenocarcinoma","volume":"6","author":"Mahadevan","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_43","unstructured":"Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). The extracellular matrix of animals. Molecular Biology of the Cell, Garland Science. [4th ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1097\/00006676-199511000-00007","article-title":"Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis","volume":"11","author":"Imamura","year":"1995","journal-title":"Pancreas"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/00006676-198701000-00003","article-title":"Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro","volume":"2","author":"Mollenhauer","year":"1987","journal-title":"Pancreas"},{"key":"ref_46","first-page":"1321","article-title":"Immunohistochemical expression of extracellular matrix proteins and adhesion molecules in pancreatic carcinoma","volume":"48","author":"Linder","year":"2001","journal-title":"Hepatogastroenterology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cellsig.2004.02.007","article-title":"TGF-\u03b2 and TNF-\u03b1: Antagonistic cytokines controlling type I collagen gene expression","volume":"16","author":"Verrecchia","year":"2004","journal-title":"Cell. Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-10671-w","article-title":"Collagen complexity spatially defines microregions of total tissue pressure in pancreatic cancer","volume":"7","author":"Nieskoski","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1096\/fasebj.6.7.1563592","article-title":"Hyaluronan","volume":"6","author":"Laurent","year":"1992","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ccr.2012.03.002","article-title":"Targeting tumor architecture to favor drug penetration: A new weapon to combat chemoresistance in pancreatic cancer?","volume":"21","author":"Yu","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/bjc.2012.569","article-title":"Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer","volume":"108","author":"Provenzano","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1067\/msy.2000.106587","article-title":"Role of hyaluronan in acute pancreatitis","volume":"127","author":"Johnsson","year":"2000","journal-title":"Surgery"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.neo.2016.10.001","article-title":"Hyaluronan-derived swelling of solid tumors, the contribution of collagen and cancer cells, and implications for cancer therapy","volume":"18","author":"Voutouri","year":"2016","journal-title":"Neoplasia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"817613","DOI":"10.1155\/2014\/817613","article-title":"Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment","volume":"2014","author":"Kultti","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/gutjnl-2012-302529","article-title":"Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer","volume":"62","author":"Jacobetz","year":"2013","journal-title":"Gut"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/BF00690290","article-title":"Fibronectin and integrins in invasion and metastasis","volume":"14","author":"Akiyama","year":"1995","journal-title":"Cancer Metastasis Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/iwj.12109","article-title":"Role of fibronectin in normal wound healing","volume":"12","author":"Lenselink","year":"2015","journal-title":"Int. Wound J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1242\/dev.119.4.1079","article-title":"Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin","volume":"119","author":"George","year":"1993","journal-title":"Development"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1242\/jcs.00059","article-title":"Fibronectin at a glance","volume":"115","author":"Pankov","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1755-1536-4-21","article-title":"Plasma and cellular fibronectin: Distinct and independent functions during tissue repair","volume":"4","author":"To","year":"2011","journal-title":"Fibrogenes. Tissue Repair"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.biocel.2003.12.003","article-title":"Tissue repair and the dynamics of the extracellular matrix","volume":"36","author":"Midwood","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ng1060","article-title":"A molecular signature of metastasis in primary solid tumors","volume":"33","author":"Ramaswamy","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Forciniti, S., Dalla Pozza, E., Greco, M.R., Amaral Carvalho, T.M., Rolando, B., Ambrosini, G., Carmona-Carmona, C.A., Pacchiana, R., Di Molfetta, D., and Donadelli, M. (2021). Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010029"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5011","DOI":"10.1158\/0008-5472.CAN-16-2704","article-title":"Posttranscriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors","volume":"77","author":"Chand","year":"2017","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1136\/gutjnl-2019-319984","article-title":"DNA damage repair as a target in pancreatic cancer: State-of-the-art and future perspectives","volume":"70","author":"Perkhofer","year":"2021","journal-title":"Gut"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1002\/ijc.24573","article-title":"CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells","volume":"125","author":"Hong","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0014-5793(02)03262-3","article-title":"CD44 signaling through focal adhesion kinase and its anti-apoptotic effect","volume":"528","author":"Fujita","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2174\/1568009043333032","article-title":"The Akt pathway: Molecular targets for anti-cancer drug development","volume":"4","author":"Mitsiades","year":"2004","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fmolb.2019.00160","article-title":"Extracellular matrix in the tumor microenvironment and its impact on cancer therapy","volume":"6","author":"Henke","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1073\/pnas.1018892108","article-title":"Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors","volume":"108","author":"Chauhan","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1111\/febs.14471","article-title":"Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome","volume":"285","author":"Biondani","year":"2018","journal-title":"FEBS J."},{"key":"ref_72","first-page":"2497","article-title":"Role of extracellular matrix assembly in interstitial transport in solid tumors","volume":"60","author":"Netti","year":"2000","journal-title":"Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.bpj.2009.07.009","article-title":"Selective filtering of particles by the extracellular matrix: An electrostatic bandpass","volume":"97","author":"Lieleg","year":"2009","journal-title":"Biophys. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1158\/1535-7163.MCT-10-0470","article-title":"Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models","volume":"9","author":"Thompson","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S1357-2725(97)00128-3","article-title":"Transforming growth factor-beta (TGF-beta)","volume":"30","author":"Clark","year":"1998","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.2174\/138920111798808356","article-title":"Transforming growth factor beta in pancreatic cancer","volume":"12","author":"Hilbig","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1042\/bj3570249","article-title":"Transforming growth factor \u03b2-1 enhances Smad transcriptional activity through activation of p8 gene expression","volume":"357","author":"Vasseur","year":"2001","journal-title":"Biochem. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10495","DOI":"10.1074\/jbc.M110.195628","article-title":"Pancreatic cancer cells respond to type I collagen by inducing snail expression to promote membrane type 1 matrix metalloproteinase-dependent collagen invasion","volume":"286","author":"Shields","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_79","first-page":"799","article-title":"Transforming growth factor beta receptor I inhibitor sensitizes drug-resistant pancreatic cancer cells to gemcitabine","volume":"32","author":"Kim","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.drup.2008.04.002","article-title":"Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance","volume":"11","author":"Toole","year":"2008","journal-title":"Drug Resist. Updates"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1111\/j.1365-2133.2010.09699.x","article-title":"4-Methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors","volume":"162","author":"Edward","year":"2010","journal-title":"Br. J. Dermatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/j.yexcr.2009.03.002","article-title":"4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3","volume":"315","author":"Kultti","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/ijc.26014","article-title":"Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo","volume":"130","author":"Urakawa","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1002\/ijc.22349","article-title":"Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice","volume":"120","author":"Hajime","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.bbrc.2006.05.037","article-title":"Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL)","volume":"345","author":"Morohashi","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00280-005-0016-5","article-title":"4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells","volume":"57","author":"Nakazawa","year":"2006","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1136\/gutjnl-2012-302604","article-title":"Improving drug delivery to pancreatic cancer: Breaching the stromal fortress by targeting hyaluronic acid","volume":"61","author":"Michl","year":"2012","journal-title":"Gut"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/BF01236386","article-title":"Effects of hyaluronidase on doxorubicin penetration into squamous carcinoma multicellular tumor spheroids and its cell lethality","volume":"120","author":"Kohno","year":"1994","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1096\/fj.07-9150com","article-title":"Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin","volume":"22","author":"Magzoub","year":"2008","journal-title":"FASEB J."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Koltai, T., Reshkin, S.J., Carvalho, T., and Cardone, R.A. (2021). Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083953"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/carcin\/bgq280","article-title":"Hedgehog signaling and therapeutics in pancreatic cancer","volume":"32","author":"Kelleher","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"14048","DOI":"10.1074\/jbc.M611089200","article-title":"Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells","volume":"282","author":"Ji","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1158\/1078-0432.CCR-08-0291","article-title":"Sonic hedgehog promotes desmoplasia in pancreatic cancer","volume":"14","author":"Bailey","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e2996","DOI":"10.1097\/MD.0000000000002996","article-title":"Hedgehog signaling in pancreatic fibrosis and cancer","volume":"95","author":"Bai","year":"2016","journal-title":"Medicine"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1158\/1535-7163.MCT-08-0573","article-title":"An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer","volume":"7","author":"Feldmann","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/B978-0-12-394622-5.00016-X","article-title":"Aberrations and therapeutics involving the developmental pathway Hedgehog in pancreatic cancer","volume":"88","author":"Kelleher","year":"2012","journal-title":"Vitam. Horm."},{"key":"ref_97","first-page":"1387","article-title":"Agents targeting the Hedgehog pathway for pancreatic cancer treatment","volume":"11","author":"Bisht","year":"2010","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1126\/science.1171362","article-title":"Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer","volume":"324","author":"Olive","year":"2009","journal-title":"Science"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1200\/jco.2012.30.4_suppl.213","article-title":"A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer","volume":"30","author":"Richards","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1136\/gut.2005.064543","article-title":"Vitamin A inhibits pancreatic stellate cell activation: Implications for treatment of pancreatic fibrosis","volume":"55","author":"McCarroll","year":"2006","journal-title":"Gut"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1053\/j.gastro.2011.06.047","article-title":"Retinoic acid\u2013induced pancreatic stellate cell quiescence reduces paracrine Wnt\u2013\u03b2-catenin signaling to slow tumor progression","volume":"141","author":"Froeling","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms12630","article-title":"ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion","volume":"7","author":"Chronopoulos","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.2165\/11207710-000000000-00000","article-title":"Pirfenidone","volume":"71","author":"Carter","year":"2011","journal-title":"Drugs"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1183\/09031936.00005209","article-title":"Pirfenidone in idiopathic pulmonary fibrosis","volume":"35","author":"Taniguchi","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1016\/S0140-6736(11)60405-4","article-title":"Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials","volume":"377","author":"Noble","year":"2011","journal-title":"Lancet"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0168-8278(02)00272-6","article-title":"Pirfenidone effectively reverses experimental liver fibrosis","volume":"37","author":"Sandoval","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"24506","DOI":"10.18632\/oncotarget.15534","article-title":"Pirfenidone normalizes the tumor microenvironment to improve chemotherapy","volume":"8","author":"Polydorou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1165\/rcmb.2016-0217OC","article-title":"A novel antifibrotic mechanism of nintedanib and pirfenidone. Inhibition of collagen fibril assembly","volume":"57","author":"Ishikawa","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1046\/j.1365-2249.1998.00618.x","article-title":"Pirfenidone induces intercellular adhesion molecule-1 (ICAM-1) down-regulation on cultured human synovial fibroblasts","volume":"113","author":"Kaneko","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1034\/j.1600-6143.2002.020201.x","article-title":"Pirfenidone treatment decreases transforming growth factor-\u03b21 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity","volume":"2","author":"Shihab","year":"2002","journal-title":"Am. J. Transplant."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0014-2999(02)01758-2","article-title":"A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-\u03b1 at the translational level","volume":"446","author":"Nakazato","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1096\/fj.201600892RR","article-title":"Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors","volume":"31","author":"Didiasova","year":"2017","journal-title":"FASEB J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0014-2999(02)01757-0","article-title":"Pirfenidone suppresses tumor necrosis factor-\u03b1, enhances interleukin-10 and protects mice from endotoxic shock","volume":"446","author":"Oku","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1158\/0008-5472.CAN-12-3180","article-title":"Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells","volume":"73","author":"Kozono","year":"2013","journal-title":"Cancer Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1159\/000496831","article-title":"Antifibrotic agent pirfenidone suppresses proliferation of human pancreatic cancer cells by inducing G0\/G1 cell cycle arrest","volume":"103","author":"Usugi","year":"2019","journal-title":"Pharmacology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1124\/jpet.103.053322","article-title":"Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats","volume":"307","author":"Yamada","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.1200\/jco.2011.29.15_suppl.4114","article-title":"The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer","volume":"29","author":"Stephenson","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/MPA.0000000000000458","article-title":"A phase I study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma","volume":"45","author":"Ko","year":"2016","journal-title":"Pancreas"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.1200\/JCO.2015.62.8719","article-title":"Randomized phase Ib\/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer","volume":"33","author":"Catenacci","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.3892\/ol.2016.4930","article-title":"Antitumor effects of the hyaluronan inhibitor 4-methylumbelliferone on pancreatic cancer","volume":"12","author":"Yoshida","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Lin, Z., Zheng, L.-C., Zhang, H.-J., Tsang, S.W., and Bian, Z.-X. (2015). Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0789-y"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00280-010-1470-2","article-title":"A phase I\/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer","volume":"68","author":"Kanai","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1111\/1750-3841.13793","article-title":"Multifunctional curcumin mediate multitherapeutic effects","volume":"82","author":"Shehzad","year":"2017","journal-title":"J. Food Sci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.bcp.2007.08.016","article-title":"Curcumin as \u201cCurecumin\u201d: From kitchen to clinic","volume":"75","author":"Goel","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_125","first-page":"391","article-title":"Antiproliferative effects of curcumin analog L49H37 in pancreatic stellate cells: A comparative study","volume":"28","author":"Gundewar","year":"2015","journal-title":"Ann. Gastroenterol. Q. Publ. Hell. Soc. Gastroenterol."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Tsang, S.W., Zhang, H., Lin, C., Xiao, H., Wong, M., Shang, H., Yang, Z.-J., Lu, A., Yung, K.K.-L., and Bian, Z. (2013). Rhein, a natural anthraquinone derivative, attenuates the activation of pancreatic stellate cells and ameliorates pancreatic fibrosis in mice with experimental chronic pancreatitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082201"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/ptr.5266","article-title":"Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells","volume":"29","author":"Tsang","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Yan, B., Cheng, L., Jiang, Z., Chen, K., Zhou, C., Sun, L., Cao, J., Qian, W., Li, J., and Shan, T. (2018). Resveratrol inhibits ROS-promoted activation and glycolysis of pancreatic stellate cells via suppression of miR-21. Oxid. Med. Cell. Longev.","DOI":"10.1155\/2018\/1346958"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.3892\/or.2013.2741","article-title":"The distinct mechanisms of the antitumor activity of emodin in different types of cancer","volume":"30","author":"Wei","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/mc.22084","article-title":"Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth","volume":"54","author":"Cha","year":"2015","journal-title":"Mol. Carcinog."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.4314\/tjpr.v14i8.15","article-title":"Synergistic cancer growth-inhibitory effect of emodin and low-dose cisplatin on gastric cancer cells in vitro","volume":"14","author":"Huang","year":"2015","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10549-014-3164-7","article-title":"Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs","volume":"148","author":"Jia","year":"2014","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.bcp.2005.06.008","article-title":"Ellagic acid blocks activation of pancreatic stellate cells","volume":"70","author":"Masamune","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1164\/rccm.200404-531OC","article-title":"Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice","volume":"171","author":"Aono","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1158\/1541-7786.MCR-07-0355","article-title":"Imatinib mesylate inhibits proliferation and exerts an antifibrotic effect in human breast stroma fibroblasts","volume":"6","author":"Gioni","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1111\/1440-1681.12286","article-title":"Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: A n insight","volume":"41","author":"Shiha","year":"2014","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"G907","DOI":"10.1152\/ajpgi.00420.2004","article-title":"Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats","volume":"288","author":"Yoshiji","year":"2005","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1748-717X-4-66","article-title":"Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model","volume":"4","author":"Li","year":"2009","journal-title":"Radiat. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1124\/jpet.106.113407","article-title":"Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial\/mesenchymal phenotypes: Implications for treatment of fibrotic diseases","volume":"321","author":"Vittal","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_140","first-page":"77","article-title":"A multi-institutional phase 2 study of imatinib mesylate and gemcitabine for first-line treatment of advanced pancreatic cancer","volume":"5","author":"Moss","year":"2012","journal-title":"Gastrointest. Cancer Res. GCR"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/MPA.0b013e31815d50f9","article-title":"A phase II trial of imatinib mesylate in patients with metastatic pancreatic cancer","volume":"36","author":"Gharibo","year":"2008","journal-title":"Pancreas"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.canlet.2016.10.019","article-title":"Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression","volume":"385","author":"Duan","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.lfs.2018.07.046","article-title":"Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer","volume":"208","author":"Qian","year":"2018","journal-title":"Life Sci."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1158\/0008-5472.CAN-18-1334","article-title":"Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma","volume":"79","author":"Carlson","year":"2019","journal-title":"Cancer Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11912-017-0608-3","article-title":"Targeting the tumor stroma: The biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20)","volume":"19","author":"Wong","year":"2017","journal-title":"Curr. Oncol. Rep."},{"key":"ref_146","unstructured":"Vennin, C., Chin, V.T., Warren, S.C., Lucas, M.C., Herrmann, D., Magenau, A., Melenec, P., Walters, S.N., del Monte-Nieto, G., and Conway, J.R. (2017). Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl. Med."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Whatcott, C.J., Ng, S., Barrett, M.T., Hostetter, G., Von Hoff, D.D., and Han, H. (2017). Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183871"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/21541248.2017.1345712","article-title":"Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy","volume":"11","author":"Vennin","year":"2020","journal-title":"Small GTPases"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"6311","DOI":"10.21873\/anticanres.11227","article-title":"Rho-associated protein kinase (ROCK) inhibitors inhibit survivin expression and sensitize pancreatic cancer stem cells to gemcitabine","volume":"36","author":"Takeda","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1158\/0008-5472.CAN-17-1339","article-title":"Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarcinoma invasion and tumor growth","volume":"78","author":"Rath","year":"2018","journal-title":"Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s12325-017-0547-2","article-title":"Repurposing pentoxifylline for the treatment of fibrosis: An overview","volume":"34","author":"Wen","year":"2017","journal-title":"Adv. Ther."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"S80","DOI":"10.1097\/00005344-199500252-00017","article-title":"Production of proinflammatory cytokines and cytokines involved in the TH1\/TH2 balance is modulated by pentoxifylline","volume":"25","author":"Bienvenu","year":"1995","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S1043-6618(03)00002-1","article-title":"The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat","volume":"47","author":"Baiuomy","year":"2003","journal-title":"Pharmacol. Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"104357","DOI":"10.1016\/j.phrs.2019.104357","article-title":"Dasatinib ameliorates chronic pancreatitis induced by caerulein via anti-fibrotic and anti-inflammatory mechanism","volume":"147","author":"Zeng","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41571-020-0363-5","article-title":"The tumour microenvironment in pancreatic cancer\u2014Clinical challenges and opportunities","volume":"17","author":"Ho","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"370","DOI":"10.3389\/fphys.2013.00370","article-title":"pH sensing and regulation in cancer","volume":"4","author":"Damaghi","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"779","DOI":"10.2217\/14796694.1.6.779","article-title":"Tumor acidity, chemoresistance and proton pump inhibitors","volume":"1","author":"Fais","year":"2005","journal-title":"Future Oncol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nrc2468","article-title":"Hypoxia, HIF1 and glucose metabolism in the solid tumour","volume":"8","author":"Denko","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1158\/jcr.1925.148","article-title":"The metabolism of carcinoma cells","volume":"9","author":"Warburg","year":"1925","journal-title":"J. Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Strapcova, S., Takacova, M., Csaderova, L., Martinelli, P., Lukacikova, L., Gal, V., Kopacek, J., and Svastova, E. (2020). Clinical and pre-clinical evidence of carbonic anhydrase ix in pancreatic cancer and its high expression in pre-cancerous lesions. Cancers, 12.","DOI":"10.3390\/cancers12082005"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s13277-013-0679-1","article-title":"Lactate dehydrogenase A is overexpressed in pancreatic cancer and promotes the growth of pancreatic cancer cells","volume":"34","author":"Rong","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1139\/bcb-2014-0078","article-title":"Acid-base transport in pancreatic cancer: Molecular mechanisms and clinical potential","volume":"92","author":"Kong","year":"2014","journal-title":"Biochem. Cell Biol."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Stock, C., and Pedersen, S.F. (2017). Roles of pH and the Na+\/H+ exchanger NHE1 in cancer: From cell biology and animal models to an emerging translational perspective. Seminars in Cancer Biology, Academic Press.","DOI":"10.1016\/j.semcancer.2016.12.001"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nrc3110","article-title":"Dysregulated pH: A perfect storm for cancer progression","volume":"11","author":"Webb","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1096\/fj.00-0029com","article-title":"Na+\/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes","volume":"14","author":"Reshkin","year":"2000","journal-title":"FASEB J."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-physiol-021119-034627","article-title":"The acidic tumor microenvironment as a driver of cancer","volume":"82","author":"Boedtkjer","year":"2020","journal-title":"Annu. Rev. Physiol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/BF00132746","article-title":"The role of proteolytic enzymes in cancer invasion and metastasis","volume":"10","author":"Duffy","year":"1992","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tips.2007.10.011","article-title":"Cysteine cathepsin proteases as pharmacological targets in cancer","volume":"29","author":"Palermo","year":"2008","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_169","first-page":"2127","article-title":"Proton transport inhibitors as potentially selective anticancer drugs","volume":"29","author":"Harguindey","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrc1713","article-title":"The role of disturbed pH dynamics and the Na+\/H+ exchanger in metastasis","volume":"5","author":"Cardone","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Weniger, M., Honselmann, K.C., and Liss, A.S. (2018). The extracellular matrix and pancreatic cancer: A complex relationship. Cancers, 10.","DOI":"10.3390\/cancers10090316"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.bbrc.2020.02.018","article-title":"Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility","volume":"525","author":"Shin","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.2174\/138161212799504902","article-title":"Multiple biological activities of lactic acid in cancer: Influences on tumor growth, angiogenesis and metastasis","volume":"18","author":"Dhup","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/path.4218","article-title":"Cancer-generated lactic acid: A regulatory, immunosuppressive metabolite?","volume":"230","author":"Choi","year":"2013","journal-title":"J. Pathol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.drup.2012.07.002","article-title":"Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance","volume":"15","author":"Gonen","year":"2012","journal-title":"Drug Resist. Updates"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S1028-4559(09)60296-5","article-title":"Mechanisms of chemotherapeutic drug resistance in cancer therapy\u2014A quick review","volume":"48","author":"Liu","year":"2009","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.med.53.082901.103929","article-title":"Mechanisms of cancer drug resistance","volume":"53","author":"Gottesman","year":"2002","journal-title":"Annu. Rev. Med."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/B978-0-12-397927-8.00004-X","article-title":"Targeting the metabolic microenvironment of tumors","volume":"65","author":"Bailey","year":"2012","journal-title":"Adv. Pharmacol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1517\/14656566.6.7.1049","article-title":"Proton pump inhibitors may reduce tumour resistance","volume":"6","author":"Fais","year":"2005","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0034-5687(78)90080-4","article-title":"Weak acids, weak bases, and intracellular pH","volume":"33","author":"Roos","year":"1978","journal-title":"Respir. Physiol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/jcp.1041000103","article-title":"Intracellular pH changes during the cell cycle in Tetrahymena","volume":"100","author":"Gillies","year":"1979","journal-title":"J. Cell. Physiol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/S0006-2952(03)00467-2","article-title":"Tumor acidity, ion trapping and chemotherapeutics: I. Acid pH affects the distribution of chemotherapeutic agents in vitro","volume":"66","author":"Mahoney","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/(SICI)1097-0215(19990331)81:1<81::AID-IJC15>3.0.CO;2-P","article-title":"Characterization of intracellular pH gradients in human multidrug-resistant tumor cells by means of scanning microspectrofluorometry and dual-emission-ratio probes","volume":"81","author":"Belhoussine","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/bjc.1992.262","article-title":"Effects of agents which inhibit the regulation of intracellular pH on murine solid tumours","volume":"66","author":"Newell","year":"1992","journal-title":"Br. J. Cancer"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/S0360-3016(00)01590-X","article-title":"Acidic environment modifies heat-or radiation-induced apoptosis in human maxillary cancer cells","volume":"49","author":"Ohtsubo","year":"2001","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.drup.2015.08.004","article-title":"Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach","volume":"23","author":"Taylor","year":"2015","journal-title":"Drug Resist. Updates"},{"key":"ref_187","first-page":"641","article-title":"P-glycoprotein\u2013actin association through ERM family proteins: A role in P-glycoprotein function in human cells of lymphoid origin","volume":"99","author":"Luciani","year":"2002","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1002\/ijc.26285","article-title":"P-glycoprotein binds to ezrin at amino acid residues 149\u2013242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma","volume":"130","author":"Brambilla","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1093\/jnci\/djh305","article-title":"Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs","volume":"96","author":"Luciani","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0360-3016(00)00803-8","article-title":"Pancreatic tumors show high levels of hypoxia","volume":"48","author":"Koong","year":"2000","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.ijrobp.2014.11.004","article-title":"High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma","volume":"91","author":"Colbert","year":"2015","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_192","first-page":"5447","article-title":"A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation","volume":"12","author":"Semenza","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1074\/jbc.270.3.1230","article-title":"Purification and Characterization of Hypoxia-inducible Factor 1 (\u2217)","volume":"270","author":"Wang","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1152\/physiol.00045.2008","article-title":"Regulation of oxygen homeostasis by hypoxia-inducible factor 1","volume":"24","author":"Semenza","year":"2009","journal-title":"Physiology"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1124\/mol.106.027029","article-title":"Hypoxia-inducible factor-1 (HIF-1)","volume":"70","author":"Ke","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00018-019-03444-3","article-title":"Hypoxia: A barricade to conquer the pancreatic cancer","volume":"77","author":"Tan","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"32253","DOI":"10.1074\/jbc.271.50.32253","article-title":"Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its \u03b1 subunit","volume":"271","author":"Huang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_198","first-page":"609","article-title":"Oxygen (es) and the hypoxia-inducible factor-1","volume":"378","author":"Wenger","year":"1997","journal-title":"Biol. Chem."},{"key":"ref_199","doi-asserted-by":"crossref","unstructured":"Semenza, G.L. (2000). HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol.","DOI":"10.1152\/jappl.2000.88.4.1474"},{"key":"ref_200","first-page":"1309","article-title":"Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression","volume":"3","author":"Itakura","year":"1997","journal-title":"Clin. Cancer Res."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1593\/neo.81618","article-title":"Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma","volume":"11","author":"Erkan","year":"2009","journal-title":"Neoplasia"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/BF03401559","article-title":"Angiogenesis inhibitors generated by tumors","volume":"1","author":"Folkman","year":"1995","journal-title":"Mol. Med."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1054\/bjoc.2001.2018","article-title":"Relation of hypoxia inducible factor 1 \u03b1 and 2 \u03b1 in operable non-small cell lung cancer to angiogenic\/molecular profile of tumours and survival","volume":"85","author":"Giatromanolaki","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature04871","article-title":"Hypoxia signalling in cancer and approaches to enforce tumour regression","volume":"441","author":"Dayan","year":"2006","journal-title":"Nature"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.tips.2017.05.002","article-title":"Reprogramming of the Tumor in the Hypoxic Niche: The Emerging Concept and Associated Therapeutic Strategies","volume":"38","author":"Qiu","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_206","first-page":"4721","article-title":"Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer","volume":"23","author":"Shibaji","year":"2003","journal-title":"Anticancer Res."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/j.1365-2559.2005.02160.x","article-title":"Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas","volume":"46","author":"Couvelard","year":"2005","journal-title":"Histopathology"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1083\/jcb.201209151","article-title":"Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia","volume":"201","author":"Yuen","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_209","doi-asserted-by":"crossref","unstructured":"Lucien, F., Brochu-Gaudreau, K., Arsenault, D., Harper, K., and Dubois, C.M. (2011). Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028851"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1172\/JCI66715","article-title":"HIF1\u03b1 and HIF2\u03b1 independently activate SRC to promote melanoma metastases","volume":"123","author":"Hanna","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"2646148","DOI":"10.1155\/2017\/2646148","article-title":"Epithelial-mesenchymal transition in pancreatic cancer: A review","volume":"2017","author":"Wang","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","article-title":"EMT and dissemination precede pancreatic tumor formation","volume":"148","author":"Rhim","year":"2012","journal-title":"Cell"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.trecan.2016.01.001","article-title":"Probing the fifty shades of EMT in metastasis","volume":"2","author":"Li","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/0955-0674(92)90103-J","article-title":"Membrane proteases: Roles in tissue remodeling and tumour invasion","volume":"4","author":"Chen","year":"1992","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1158\/0008-5472.CAN-08-2819","article-title":"Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer","volume":"69","author":"Arumugam","year":"2009","journal-title":"Cancer Res."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1245\/s10434-007-9435-3","article-title":"The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor\/c-Met signaling","volume":"14","author":"Ide","year":"2007","journal-title":"Ann. Surg. Oncol."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1158\/0008-5472.CAN-11-1433","article-title":"Hypoxia triggers hedgehog-mediated tumor\u2013stromal interactions in pancreatic cancer","volume":"73","author":"Hostetter","year":"2013","journal-title":"Cancer Res."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"G709","DOI":"10.1152\/ajpgi.90356.2008","article-title":"Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer","volume":"295","author":"Masamune","year":"2008","journal-title":"Am. J. Physiol.\u2014Gastrointest. Liver Physiol."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/jcp.10374","article-title":"How to overcome (and exploit) tumor hypoxia for targeted gene therapy","volume":"197","author":"Greco","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1357-4310(00)01677-4","article-title":"Exploiting the hypoxic cancer cell: Mechanisms and therapeutic strategies","volume":"6","author":"Brown","year":"2000","journal-title":"Mol. Med. Today"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1158\/0008-5472.CAN-04-3395","article-title":"Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment","volume":"65","author":"Papandreou","year":"2005","journal-title":"Cancer Res."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/1097-0215(200002)9999:9999<::AID-IJC1064>3.0.CO;2-P","article-title":"Cancer cells surviving hypoxia obtain hypoxia resistance and maintain anti-apoptotic potential under reoxygenation","volume":"91","author":"Kinoshita","year":"2001","journal-title":"Int. J. Cancer"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1128\/MCB.24.7.2875-2889.2004","article-title":"Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and-independent mechanisms and contributes to drug resistance","volume":"24","author":"Erler","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1080\/07853890410018231","article-title":"Hypoxia-inducible factors and hypoxic cell death in tumour physiology","volume":"36","author":"Bacon","year":"2004","journal-title":"Ann. Med."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1158\/1078-0432.CCR-03-0488","article-title":"Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine","volume":"10","author":"Yokoi","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S0306-3623(96)00081-X","article-title":"The P-glycoprotein multidrug transporter","volume":"27","author":"Fardel","year":"1996","journal-title":"Gen. Pharmacol. Vasc. Syst."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0076-6879(04)81025-5","article-title":"Assessing oxygen sensitivity of the multidrug resistance (MDR) gene","volume":"381","author":"Comerford","year":"2004","journal-title":"Methods Enzymol."},{"key":"ref_228","first-page":"4470","article-title":"ENO1 silencing impaires hypoxia-induced gemcitabine chemoresistance associated with redox modulation in pancreatic cancer cells","volume":"11","author":"Wang","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1086\/423488","article-title":"Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein","volume":"190","author":"Abdalla","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"13673","DOI":"10.1039\/C8NR03297A","article-title":"A novel \u03b1-enolase-targeted drug delivery system for high efficacy prostate cancer therapy","volume":"10","author":"Wang","year":"2018","journal-title":"Nanoscale"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1016\/j.cgh.2009.07.039","article-title":"Desmoplasia of pancreatic ductal adenocarcinoma","volume":"7","author":"Pandol","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1200\/jco.2015.33.3_suppl.359","article-title":"Final results of a phase Ib study of gemcitabine plus PEGPH20 in patients with stage IV previously untreated pancreatic cancer","volume":"33","author":"Hingorani","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"4508","DOI":"10.3892\/mmr.2015.3960","article-title":"Triptolide suppresses proliferation, hypoxia-inducible factor-1\u03b1 and c-Myc expression in pancreatic cancer cells","volume":"12","author":"Ding","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1002\/ijc.28583","article-title":"Triptolide reverses hypoxia-induced epithelial\u2013mesenchymal transition and stem-like features in pancreatic cancer by NF-\u03baB downregulation","volume":"134","author":"Liu","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_235","unstructured":"ClinicalTrials.gov Identifier: NCT01927965 (2021, September 23). Study of Minnelide\u2122 in Patients With Advanced GI Tumors, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01927965."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"10892","DOI":"10.1074\/jbc.M800102200","article-title":"Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia","volume":"283","author":"Zhang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.canlet.2016.05.016","article-title":"Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma","volume":"378","author":"Lang","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_238","doi-asserted-by":"crossref","unstructured":"Abraham, R. (2004). mTOR as a positive regulator of tumor cell responses to hypoxia. TOR, Springer.","DOI":"10.1007\/978-3-642-18930-2_18"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1200\/JCO.2008.18.9514","article-title":"Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer","volume":"27","author":"Wolpin","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s00280-015-2730-y","article-title":"Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer","volume":"75","author":"Kordes","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s10585-012-9519-8","article-title":"Attenuation of reactive oxygen species by antioxidants suppresses hypoxia-induced epithelial-mesenchymal transition and metastasis of pancreatic cancer cells","volume":"30","author":"Shimojo","year":"2013","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.freeradbiomed.2014.02.002","article-title":"Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1\u03b1 in pancreatic cancer","volume":"69","author":"Sibenaller","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-017-0664-4","article-title":"The role of cellular reactive oxygen species in cancer chemotherapy","volume":"37","author":"Yang","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1038\/emm.2013.85","article-title":"Cancer cell metabolism: Implications for therapeutic targets","volume":"45","author":"Jang","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.cell.2008.08.021","article-title":"Cancer cell metabolism: Warburg and beyond","volume":"134","author":"Hsu","year":"2008","journal-title":"Cell"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/bjc.2016.412","article-title":"Tumour microenvironment factors shaping the cancer metabolism landscape","volume":"116","author":"Anastasiou","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg effect: How does it benefit cancer cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tibs.2014.06.005","article-title":"The pentose phosphate pathway and cancer","volume":"39","author":"Patra","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.molcel.2015.10.018","article-title":"Cancer\u2019s fuel choice: New flavors for a picky eater","volume":"60","author":"DeNicola","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1158\/0008-5472.CAN-14-2211","article-title":"Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein","volume":"75","author":"Kamphorst","year":"2015","journal-title":"Cancer Res."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41568-018-0048-x","article-title":"Nutrient scavenging in cancer","volume":"18","author":"Finicle","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.bbcan.2018.04.011","article-title":"The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance","volume":"1870","author":"Biancur","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Rev. Cancer"},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nrm4024","article-title":"Autophagy at the crossroads of catabolism and anabolism","volume":"16","author":"Kaur","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1101\/gad.2016111","article-title":"Pancreatic cancers require autophagy for tumor growth","volume":"25","author":"Yang","year":"2011","journal-title":"Genes Dev."},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1158\/2159-8290.CD-14-0362","article-title":"Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations","volume":"4","author":"Yang","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1600-0854.2009.00878.x","article-title":"Defining macropinocytosis","volume":"10","author":"Kerr","year":"2009","journal-title":"Traffic"},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature12138","article-title":"Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells","volume":"497","author":"Commisso","year":"2013","journal-title":"Nature"},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nm.4256","article-title":"Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors","volume":"23","author":"Davidson","year":"2017","journal-title":"Nat. Med."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms16031","article-title":"Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions","volume":"8","author":"Olivares","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: The metabolic requirements of cell proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.yexmp.2010.08.006","article-title":"Cancer metabolism: The Warburg effect today","volume":"89","author":"Ferreira","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.4161\/cc.8.23.10238","article-title":"The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma","volume":"8","author":"Pavlides","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.cmet.2015.08.015","article-title":"MYC\/PGC-1\u03b1 balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells","volume":"22","author":"Sancho","year":"2015","journal-title":"Cell Metab."},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"332","DOI":"10.15698\/cst2018.12.166","article-title":"The role of metabolic adaptation to nutrient stress in pancreatic cancer","volume":"2","author":"Derle","year":"2018","journal-title":"Cell Stress"},{"key":"ref_269","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1101\/gad.1415606","article-title":"Genetics and biology of pancreatic ductal adenocarcinoma","volume":"20","author":"Hezel","year":"2006","journal-title":"Genes Dev."},{"key":"ref_270","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2007.10.002","article-title":"The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation","volume":"7","author":"DeBerardinis","year":"2008","journal-title":"Cell Metab."},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","article-title":"Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism","volume":"149","author":"Ying","year":"2012","journal-title":"Cell"},{"key":"ref_272","doi-asserted-by":"crossref","first-page":"e18126","DOI":"10.7554\/eLife.18126","article-title":"In vivo genetic dissection of tumor growth and the Warburg effect","volume":"5","author":"Wang","year":"2016","journal-title":"eLife"},{"key":"ref_273","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/s42255-020-00315-1","article-title":"KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth","volume":"2","author":"Raho","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_274","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nrc2715","article-title":"p53 and metabolism","volume":"9","author":"Vousden","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_275","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cmet.2015.05.023","article-title":"NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus","volume":"22","author":"Canto","year":"2015","journal-title":"Cell Metab."},{"key":"ref_276","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.cmet.2017.11.005","article-title":"Waste not, want not: Lactate oxidation fuels the TCA cycle","volume":"26","author":"Chandel","year":"2017","journal-title":"Cell Metab."},{"key":"ref_277","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1073\/pnas.1219555110","article-title":"Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma","volume":"110","author":"Guillaumond","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.radonc.2009.06.025","article-title":"Pyruvate into lactate and back: From the Warburg effect to symbiotic energy fuel exchange in cancer cells","volume":"92","author":"Feron","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_279","doi-asserted-by":"crossref","first-page":"777","DOI":"10.18632\/oncoscience.109","article-title":"Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question","volume":"1","author":"Alfarouk","year":"2014","journal-title":"Oncoscience"},{"key":"ref_280","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tibs.2010.05.003","article-title":"Glutamine addiction: A new therapeutic target in cancer","volume":"35","author":"Wise","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_281","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.15252\/embj.201696151","article-title":"Cancer cell metabolism: The essential role of the nonessential amino acid, glutamine","volume":"36","author":"Zhang","year":"2017","journal-title":"EMBO J."},{"key":"ref_282","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.critrevonc.2017.03.026","article-title":"Drug resistance in pancreatic cancer: Impact of altered energy metabolism","volume":"114","author":"Grasso","year":"2017","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_283","doi-asserted-by":"crossref","unstructured":"Guo, Y., Deng, Y., Li, X., Ning, Y., Lin, X., Guo, S., Chen, M., and Han, M. (2016). Glutaminolysis was induced by TGF-\u03b21 through PP2Ac regulated Raf-MEK-ERK signaling in endothelial cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162658"},{"key":"ref_284","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature12040","article-title":"Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway","volume":"496","author":"Son","year":"2013","journal-title":"Nature"},{"key":"ref_285","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.canlet.2017.04.029","article-title":"GOT1-mediated anaplerotic glutamine metabolism regulates chronic acidosis stress in pancreatic cancer cells","volume":"400","author":"Abrego","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_286","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1038\/nm.3686","article-title":"Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development","volume":"20","author":"Mayers","year":"2014","journal-title":"Nat. Med."},{"key":"ref_287","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.21873\/anticanres.13314","article-title":"Towards a personalized approach in pancreatic cancer diagnostics through plasma amino acid analysis","volume":"39","author":"Tumas","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_288","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nature19084","article-title":"Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion","volume":"536","author":"Sousa","year":"2016","journal-title":"Nature"},{"key":"ref_289","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1158\/2159-8290.CD-19-0959","article-title":"Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer","volume":"10","author":"Parker","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_290","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/s42255-020-0226-5","article-title":"Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours","volume":"2","author":"Zhu","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_291","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00280-017-3477-4","article-title":"Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma","volume":"81","author":"Altan","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_292","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1158\/0008-5472.CAN-18-3855","article-title":"Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses","volume":"79","author":"Daher","year":"2019","journal-title":"Cancer Res."},{"key":"ref_293","first-page":"932","article-title":"CYP2J2-produced epoxyeicosatrienoic acids contribute to the ferroptosis resistance of pancreatic ductal adenocarcinoma in a PPAR \u03b3-dependent manner","volume":"46","author":"Tao","year":"2021","journal-title":"Zhong Nan Da Xue Xue Bao Yi Xue Ban."},{"key":"ref_294","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1080\/15548627.2020.1714209","article-title":"Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein","volume":"16","author":"Dai","year":"2020","journal-title":"Autophagy"},{"key":"ref_295","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-20154-8","article-title":"Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173\/STING-dependent DNA sensor pathway","volume":"11","author":"Dai","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_296","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1158\/0008-5472.CAN-16-1979","article-title":"HSPA5 regulates ferroptotic cell death in cancer cells","volume":"77","author":"Zhu","year":"2017","journal-title":"Cancer Res."},{"key":"ref_297","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1053\/j.gastro.2017.07.036","article-title":"Inhibition of Aurora kinase A induces necroptosis in pancreatic carcinoma","volume":"153","author":"Xie","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_298","doi-asserted-by":"crossref","first-page":"517","DOI":"10.18632\/oncoscience.160","article-title":"Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells","volume":"2","author":"Eling","year":"2015","journal-title":"Oncoscience"},{"key":"ref_299","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1080\/15548627.2020.1739447","article-title":"Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death","volume":"17","author":"Li","year":"2021","journal-title":"Autophagy"},{"key":"ref_300","doi-asserted-by":"crossref","unstructured":"Tang, R., Wu, Z., Rong, Z., Xu, J., Wang, W., Zhang, B., Yu, X., and Shi, S. (2021). Ferroptosis-related lncRNA pairs to predict the clinical outcome and molecular characteristics of pancreatic ductal adenocarcinoma. Brief. Bioinform.","DOI":"10.1093\/bib\/bbab388"},{"key":"ref_301","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41420-021-00662-2","article-title":"NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner","volume":"7","author":"Huang","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_302","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.chembiol.2021.01.006","article-title":"MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells","volume":"28","author":"Kuang","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_303","doi-asserted-by":"crossref","first-page":"1868691","DOI":"10.1080\/2162402X.2020.1868691","article-title":"The dark side of ferroptosis in pancreatic cancer","volume":"10","author":"Liu","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_304","doi-asserted-by":"crossref","unstructured":"Chen, X., Kang, R., Kroemer, G., and Tang, D. (2021). Targeting ferroptosis in pancreatic cancer: A double-edged sword. Trends Cancer.","DOI":"10.1016\/j.trecan.2021.04.005"},{"key":"ref_305","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.plipres.2013.08.005","article-title":"Lipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids","volume":"52","author":"Zaidi","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"ref_306","doi-asserted-by":"crossref","first-page":"e189","DOI":"10.1038\/oncsis.2015.49","article-title":"Lipid metabolic reprogramming in cancer cells","volume":"5","author":"Vasseur","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_307","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/sj.pcan.4500879","article-title":"Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer","volume":"9","author":"Liu","year":"2006","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_308","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.canlet.2018.08.006","article-title":"Fatty acid oxidation: An emerging facet of metabolic transformation in cancer","volume":"435","author":"Ma","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_309","doi-asserted-by":"crossref","unstructured":"Reyes-Castellanos, G., Masoud, R., and Carrier, A. (2020). Mitochondrial metabolism in PDAC: From better knowledge to new targeting strategies. Biomedicines, 8.","DOI":"10.3390\/biomedicines8080270"},{"key":"ref_310","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1097\/RCT.0b013e318227a545","article-title":"The metabolic features of normal pancreas and pancreatic adenocarcinoma: Preliminary result of in vivo proton magnetic resonance spectroscopy at 3.0 T","volume":"35","author":"Ma","year":"2011","journal-title":"J. Comput. Assist. Tomogr."},{"key":"ref_311","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1073\/pnas.1421601112","article-title":"Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma","volume":"112","author":"Guillaumond","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_312","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1053\/j.gastro.2013.08.018","article-title":"A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice","volume":"145","author":"Philip","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_313","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.metabol.2009.03.027","article-title":"Increased lipid metabolism and cell turnover of MiaPaCa2 cells induced by high-fat diet in an orthotopic system","volume":"58","author":"Wang","year":"2009","journal-title":"Metabolism"},{"key":"ref_314","doi-asserted-by":"crossref","first-page":"8882","DOI":"10.1073\/pnas.1307237110","article-title":"Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids","volume":"110","author":"Kamphorst","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_315","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.bbrc.2015.05.108","article-title":"Up-regulation of fatty acid synthase induced by EGFR\/ERK activation promotes tumor growth in pancreatic cancer","volume":"463","author":"Bian","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_316","doi-asserted-by":"crossref","unstructured":"Sunami, Y., Rebelo, A., and Kleeff, J. (2018). Lipid metabolism and lipid droplets in pancreatic cancer and stellate cells. Cancers, 10.","DOI":"10.3390\/cancers10010003"},{"key":"ref_317","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ccell.2014.12.002","article-title":"Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress","volume":"27","author":"Schug","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_318","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bbcan.2011.10.007","article-title":"Understanding the central role of citrate in the metabolism of cancer cells","volume":"1825","author":"Icard","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Rev. Cancer"},{"key":"ref_319","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/nrc.2016.87","article-title":"The metabolic fate of acetate in cancer","volume":"16","author":"Schug","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_320","first-page":"71","article-title":"Regulation of acetate utilization by monocarboxylate transporter 1 (MCT1) in hepatocellular carcinoma (HCC)","volume":"26","author":"Jeon","year":"2018","journal-title":"Oncol. Res. Featur. Preclin. Clin. Cancer Ther."},{"key":"ref_321","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrc3579","article-title":"Disrupting proton dynamics and energy metabolism for cancer therapy","volume":"13","author":"Parks","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_322","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.celrep.2016.12.055","article-title":"Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation","volume":"18","author":"Bulusu","year":"2017","journal-title":"Cell Rep."},{"key":"ref_323","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.21873\/anticanres.11016","article-title":"Inhibition of fatty acid synthesis induces apoptosis of human pancreatic cancer cells","volume":"36","author":"Nishi","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_324","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/mc.20778","article-title":"Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms","volume":"51","author":"Bracci","year":"2012","journal-title":"Mol. Carcinog."},{"key":"ref_325","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1593\/neo.121508","article-title":"Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48Cre\/+-LSL-KrasG12D\/+ mice","volume":"14","author":"Mohammed","year":"2012","journal-title":"Neoplasia"},{"key":"ref_326","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4103\/1477-3163.115422","article-title":"Mapping cancer cell metabolism with13C flux analysis: Recent progress and future challenges","volume":"12","author":"Duckwall","year":"2013","journal-title":"J. Carcinog."},{"key":"ref_327","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/nrc.2016.82","article-title":"Metabolic control of epigenetics in cancer","volume":"16","author":"Kinnaird","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_328","doi-asserted-by":"crossref","first-page":"16875","DOI":"10.18632\/oncotarget.15171","article-title":"Glucose transporter GLUT1 expression and clinical outcome in solid tumors: A systematic review and meta-analysis","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_329","doi-asserted-by":"crossref","first-page":"19760","DOI":"10.18632\/oncotarget.15035","article-title":"Prognostic value of GLUT-1 expression in pancreatic cancer: Results from 538 patients","volume":"8","author":"Sharen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_330","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3892\/ol.2016.4586","article-title":"Expression and clinical significance of glucose transporter-1 in pancreatic cancer","volume":"12","author":"Lu","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_331","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1097\/MPA.0000000000000580","article-title":"Increased Expression of the GLUT-1 Gene is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma","volume":"45","author":"Abbott","year":"2016","journal-title":"Pancreas"},{"key":"ref_332","doi-asserted-by":"crossref","first-page":"13206","DOI":"10.18632\/oncotarget.14570","article-title":"Predictive value of glucose transporter-1 and glucose transporter-3 for survival of cancer patients: A meta-analysis","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_333","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.canlet.2017.10.041","article-title":"Apigenin: A dietary flavonoid with diverse anticancer properties","volume":"413","author":"Gajski","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_334","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jss.2010.10.041","article-title":"Apigenin down-regulates the hypoxia response genes: HIF-1\u03b1, GLUT-1, and VEGF in human pancreatic cancer cells","volume":"167","author":"Melstrom","year":"2011","journal-title":"J. Surg. Res."},{"key":"ref_335","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1097\/MPA.0b013e3181735ccb","article-title":"Apigenin inhibits the GLUT-1 glucose transporter and the phosphoinositide 3-kinase\/Akt pathway in human pancreatic cancer cells","volume":"37","author":"Melstrom","year":"2008","journal-title":"Pancreas"},{"key":"ref_336","doi-asserted-by":"crossref","unstructured":"Ashrafizadeh, M., Bakhoda, M.R., Bahmanpour, Z., Ilkhani, K., Zarrabi, A., Makvandi, P., Khan, H., Mazaheri, S., Darvish, M., and Mirzaei, H. (2020). Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms with Emphasis on Pancreatic Cancer. Front. Chem., 8.","DOI":"10.3389\/fchem.2020.00829"},{"key":"ref_337","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00018-019-03278-z","article-title":"The enhancement of glycolysis regulates pancreatic cancer metastasis","volume":"77","author":"Yang","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_338","doi-asserted-by":"crossref","first-page":"56081","DOI":"10.18632\/oncotarget.9760","article-title":"Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer","volume":"8","author":"Anderson","year":"2017","journal-title":"Oncotarget"},{"key":"ref_339","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.bbrc.2013.09.041","article-title":"INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells","volume":"440","author":"Min","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_340","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.biocel.2007.03.021","article-title":"Glycolysis in cancer: A potential target for therapy","volume":"39","author":"Gatenby","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_341","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1002\/path.4159","article-title":"Differential regulation of HIF-mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts","volume":"229","author":"Morten","year":"2013","journal-title":"J. Pathol."},{"key":"ref_342","doi-asserted-by":"crossref","first-page":"5177","DOI":"10.18632\/oncotarget.2120","article-title":"Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine","volume":"5","author":"Isayev","year":"2014","journal-title":"Oncotarget"},{"key":"ref_343","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s11523-013-0273-x","article-title":"Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer","volume":"8","author":"Ota","year":"2013","journal-title":"Target. Oncol."},{"key":"ref_344","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.3748\/wjg.v22.i12.3471","article-title":"Glucose metabolic phenotype of pancreatic cancer","volume":"22","author":"Chan","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_345","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s10059-009-0151-7","article-title":"Glyceraldehyde-3-phosphate, a glycolytic intermediate, plays a key role in controlling cell fate via inhibition of caspase activity","volume":"28","author":"Jang","year":"2009","journal-title":"Mol. Cells"},{"key":"ref_346","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.1007\/s10620-019-05642-2","article-title":"Fructose-bisphosphate aldolase a regulates hypoxic adaptation in hepatocellular carcinoma and involved with tumor malignancy","volume":"64","author":"Li","year":"2019","journal-title":"Dig. Dis. Sci."},{"key":"ref_347","first-page":"1","article-title":"Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy","volume":"7","author":"Yu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_348","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2014.12.035","article-title":"Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer","volume":"358","author":"Augoff","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_349","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1245\/s10434-008-9955-5","article-title":"Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: Association with hypoxia-inducible factor (HIF-1\u03b1) pathway, angiogenic factors production and poor prognosis","volume":"15","author":"Kolev","year":"2008","journal-title":"Ann. Surg. Oncol."},{"key":"ref_350","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/bjc.2013.681","article-title":"Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia","volume":"110","author":"Maftouh","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_351","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1073\/pnas.0914433107","article-title":"Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression","volume":"107","author":"Le","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_352","doi-asserted-by":"crossref","unstructured":"Mohammad, G.H., Vassileva, V., Acedo, P., Olde Damink, S.W., Malago, M., Dhar, D.K., and Pereira, S.P. (2019). Targeting pyruvate kinase M2 and lactate dehydrogenase a is an effective combination strategy for the treatment of pancreatic cancer. Cancers, 11.","DOI":"10.3390\/cancers11091372"},{"key":"ref_353","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.semcdb.2015.08.004","article-title":"Pyruvate kinase: Function, regulation and role in cancer","volume":"43","author":"Israelsen","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_354","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1002\/pro.505","article-title":"Human pyruvate kinase M2: A multifunctional protein","volume":"19","author":"Gupta","year":"2010","journal-title":"Protein Sci."},{"key":"ref_355","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s10620-015-3931-2","article-title":"PKM2 promotes cell survival and invasion under metabolic stress by enhancing Warburg effect in pancreatic ductal adenocarcinoma","volume":"61","author":"Li","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_356","first-page":"881","article-title":"Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species","volume":"52","author":"Yokoyama","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_357","first-page":"2211","article-title":"Upregulation of pyruvate kinase M2 expression by fatty acid synthase contributes to gemcitabine resistance in pancreatic cancer","volume":"15","author":"Tian","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_358","first-page":"4681","article-title":"Isozymes of pyruvate kinase from human brain, meningiomas, and malignant gliomas","volume":"38","author":"Verbiest","year":"1978","journal-title":"Cancer Res."},{"key":"ref_359","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.yexcr.2015.05.017","article-title":"Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells","volume":"336","author":"Kim","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_360","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.cell.2015.03.011","article-title":"A lactate-induced response to hypoxia","volume":"161","author":"Lee","year":"2015","journal-title":"Cell"},{"key":"ref_361","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory effect of tumor cell\u2013derived lactic acid on human T cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"ref_362","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/j.celrep.2014.11.025","article-title":"MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies","volume":"9","author":"Baek","year":"2014","journal-title":"Cell Rep."},{"key":"ref_363","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fphar.2011.00049","article-title":"Anticancer targets in the glycolytic metabolism of tumors: A comprehensive review","volume":"2","author":"Porporato","year":"2011","journal-title":"Front. Pharmacol."},{"key":"ref_364","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1093\/carcin\/bgu124","article-title":"Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells","volume":"35","author":"Lai","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_365","doi-asserted-by":"crossref","first-page":"472","DOI":"10.2337\/diabetes.54.2.472","article-title":"Fatty acid translocase (FAT\/CD36) is localized on insulin-containing granules in human pancreatic \u03b2-cells and mediates fatty acid effects on insulin secretion","volume":"54","author":"Noushmehr","year":"2005","journal-title":"Diabetes"},{"key":"ref_366","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1245\/s10434-019-07927-2","article-title":"Impact of CD36 on chemoresistance in pancreatic ductal adenocarcinoma","volume":"27","author":"Kubo","year":"2020","journal-title":"Ann. Surg. Oncol."},{"key":"ref_367","first-page":"2523","article-title":"Immnunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma","volume":"27","author":"Alo","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_368","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1158\/1055-9965.EPI-09-0144","article-title":"Serum fatty acid synthase as a marker of pancreatic neoplasia","volume":"18","author":"Walter","year":"2009","journal-title":"Cancer Epidemiol. Prev. Biomark."},{"key":"ref_369","first-page":"89","article-title":"Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers","volume":"2","author":"Yang","year":"2011","journal-title":"Int. J. Biochem. Mol. Biol."},{"key":"ref_370","doi-asserted-by":"crossref","first-page":"e532","DOI":"10.1038\/cddis.2013.60","article-title":"Targeting cellular metabolism to improve cancer therapeutics","volume":"4","author":"Zhao","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_371","doi-asserted-by":"crossref","first-page":"15795","DOI":"10.1007\/s13277-016-5382-6","article-title":"An indispensable role of CPT-1a to survive cancer cells during energy stress through rewiring cancer metabolism","volume":"37","author":"Luo","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_372","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1158\/0008-5472.CAN-12-3009","article-title":"Stalling the engine of resistance: Targeting cancer metabolism to overcome therapeutic resistance","volume":"73","author":"Butler","year":"2013","journal-title":"Cancer Res."},{"key":"ref_373","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1615\/CritRevOncog.v18.i1-2.80","article-title":"Tumor-stromal interactions in pancreatic cancer","volume":"18","author":"Whatcott","year":"2013","journal-title":"Crit. Rev. Oncog."},{"key":"ref_374","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1158\/1078-0432.CCR-15-1155","article-title":"Impaired synthesis of stromal components in response to minnelide improves vascular function, drug delivery, and survival in pancreatic cancer","volume":"22","author":"Banerjee","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_375","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1470-2045(15)00027-3","article-title":"Metformin in patients with advanced pancreatic cancer: A double-blind, randomised, placebo-controlled phase 2 trial","volume":"16","author":"Kordes","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_376","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/S1470-2045(17)30314-5","article-title":"Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: A single-centre, open-label, dose-escalation, phase 1 trial","volume":"18","author":"Alistar","year":"2017","journal-title":"Lancet Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/23\/6135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:40:05Z","timestamp":1760168405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/23\/6135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":376,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cancers13236135"],"URL":"https:\/\/doi.org\/10.3390\/cancers13236135","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,6]]}}}