{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T10:27:29Z","timestamp":1792319249610,"version":"4.4.0"},"reference-count":107,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian Pancreatic Cancer Foundation","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches.<\/jats:p>","DOI":"10.3390\/biom12020320","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T20:24:26Z","timestamp":1645129466000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting the Endocannabinoidome in Pancreatic Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Valerio","family":"Falasca","sequence":"first","affiliation":[{"name":"School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-7235","authenticated-orcid":false,"given":"Marco","family":"Falasca","sequence":"additional","affiliation":[{"name":"Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ren, M., Tang, Z., Wu, X., Spengler, R., Jiang, H., Yang, Y., and Boivin, N. (2019). The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs. Sci. Adv., 5.","DOI":"10.1126\/sciadv.aaw1391"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.jep.2006.05.034","article-title":"A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China","volume":"108","author":"Jiang","year":"2006","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","unstructured":"World Health Organization (2022, February 01). Management of Substance Abuse: Cannabis. Available online: http:\/\/www.who.int\/substance_abuse\/facts\/cannabis\/en\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1039\/p19840002881","article-title":"Base-catalysed double-bond isomerizations of cannabinoids: Structural and stereochemical aspects","volume":"1","author":"Srebnik","year":"1984","journal-title":"J. Chem. Soc. Perkin Trans."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0009-3084(00)00184-5","article-title":"A historical overview of chemical research on cannabinoids","volume":"108","author":"Mechoulam","year":"2000","journal-title":"Chem. Phys. Lipids"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1021\/acs.jafc.0c07472","article-title":"Cannabis and Cannabis Edibles: A Review","volume":"69","author":"Peng","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0166-2236(98)01283-1","article-title":"Endocannabinoids: Endogenous cannabinoid receptor ligands with neuromodulatory action","volume":"21","author":"Melck","year":"1998","journal-title":"Trends Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1080\/10408444.2020.1762539","article-title":"The synthetic cannabinoids phenomenon: From structure to toxicological properties. A review","volume":"50","author":"Alves","year":"2020","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.tips.2015.02.008","article-title":"Endocannabinoid signaling at the periphery: 50 years after THC","volume":"36","author":"Maccarrone","year":"2015","journal-title":"Trends Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1042\/bst0260267","article-title":"Pharmacological, physiological and clinical implications of the discovery of cannabinoid receptors","volume":"26","author":"Pertwee","year":"1998","journal-title":"Biochem. Soc. Trans."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0165-6147(97)01161-9","article-title":"Endocannabinoids: A new class of vasoactive substances","volume":"19","author":"Randall","year":"1998","journal-title":"Trends Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1006\/nbdi.1998.0214","article-title":"Biochemistry of the endogenous ligands of cannabinoid receptors","volume":"5","author":"Deutsch","year":"1998","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S87","DOI":"10.1016\/j.pain.2013.03.023","article-title":"Endocannabinoids: A unique opportunity to develop multitarget analgesics","volume":"154","author":"Maione","year":"2013","journal-title":"Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/pancan.2018.0019","article-title":"Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer","volume":"5","author":"Sharafi","year":"2019","journal-title":"J. Pancreat Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_16","unstructured":"MacDonald, E., and Farrah, K. (2019). CADTH Rapid Response Reports, Medical Cannabis Use in Palliative Care: Review of Clinical Effectiveness and Guidelines\u2014An Update."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Malhotra, P., Casari, I., and Falasca, M. (2021). Therapeutic potential of cannabinoids in combination cancer therapy. Adv. Biol. Regul., 79.","DOI":"10.1016\/j.jbior.2020.100774"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-2999(98)00649-9","article-title":"Endocannabinoids","volume":"359","author":"Mechoulam","year":"1998","journal-title":"Eur. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.1470919","article-title":"Isolation and structure of a brain constituent that binds to the cannabinoid receptor","volume":"258","author":"Devane","year":"1992","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.2174\/138955706776073466","article-title":"New insights into endocannabinoid degradation and its therapeutic potential","volume":"6","author":"Bari","year":"2006","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1083\/jcb.200305129","article-title":"Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain","volume":"163","author":"Bisogno","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.1074\/jbc.M306642200","article-title":"Molecular Characterization of a Phospholipase D Generating Anandamide and Its Congeners","volume":"279","author":"Okamoto","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/384083a0","article-title":"Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides","volume":"384","author":"Cravatt","year":"1996","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10819","DOI":"10.1073\/pnas.152334899","article-title":"Brain monoglyceride lipase participating in endocannabinoid inactivation","volume":"99","author":"Dinh","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1152\/physrev.00002.2016","article-title":"From phytocannabinoids to cannabinoid receptors and endocannabinoids: Pleiotropic physiological and pathological roles through complex pharmacology","volume":"96","author":"Ligresti","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plipres.2018.05.002","article-title":"2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain","volume":"71","author":"Baggelaar","year":"2018","journal-title":"Prog. Lipid Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11481-009-9177-z","article-title":"Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: Focus on G-protein-coupled receptors and transient receptor potential channels","volume":"5","year":"2010","journal-title":"J. Neuroimmune Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrd.2018.115","article-title":"New approaches and challenges to targeting the endocannabinoid system","volume":"17","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Munawar, N., Oriowo, M.A., and Masocha, W. (2017). Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Front. Pharm., 8.","DOI":"10.3389\/fphar.2017.00136"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s11745-008-3182-5","article-title":"Monoacylglycerols activate capsaicin receptor, TRPV1","volume":"43","author":"Iwasaki","year":"2008","journal-title":"Lipids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.ejphar.2005.05.032","article-title":"Anandamide induced PPAR\u03b3 transcriptional activation and 3T3-L1 preadipocyte differentiation","volume":"517","author":"Bouaboula","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jbior.2015.10.003","article-title":"Role of the lysophosphatidylinositol\/GPR55 axis in cancer","volume":"60","author":"Falasca","year":"2016","journal-title":"Adv. Biol. Regul."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R191","DOI":"10.1530\/JME-16-0253","article-title":"GPR55: A new promising target for metabolism?","volume":"58","author":"Imbernon","year":"2017","journal-title":"J. Mol. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41574-020-00459-w","article-title":"Targeting lipid GPCRs to treat type 2 diabetes mellitus\u2014Progress and challenges","volume":"17","author":"Ghislain","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14216","DOI":"10.1021\/acs.jmedchem.0c00926","article-title":"Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?","volume":"63","author":"Morales","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.neuron.2012.12.016","article-title":"TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids","volume":"77","author":"Cao","year":"2013","journal-title":"Neuron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1096\/fj.14-268300","article-title":"Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance","volume":"29","author":"Lee","year":"2015","journal-title":"Faseb J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wagner, N., and Wagner, K.D. (2020). The Role of PPARs in Disease. Cells, 9.","DOI":"10.3390\/cells9112367"},{"key":"ref_39","first-page":"694","article-title":"Lysophosphatidylinositol signalling: New wine from an old bottle","volume":"1821","author":"Falasca","year":"2012","journal-title":"Biochim. et Biophys. Acta (BBA)-Mol. Cell Biol. Lipids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.plipres.2010.02.003","article-title":"N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA)","volume":"49","author":"Ueda","year":"2010","journal-title":"Prog. Lipid Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bhandari, S., Bisht, K.S., and Merkler, D.J. (2021). The Biosynthesis and Metabolism of the N-Acylated Aromatic Amino Acids: N-Acylphenylalanine, N-Acyltyrosine, N-Acyltryptophan, and N-Acylhistidine. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.801749"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Di Marzo, V., and Wang, J. (2014). The Endocannabinoidome: The World of Endocannabinoids and Related Mediators, Academic Press.","DOI":"10.1016\/B978-0-12-420126-2.00018-3"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2014.04.001","article-title":"New players in the fatty acyl ethanolamide metabolism","volume":"86","author":"Rahman","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.plefa.2013.06.002","article-title":"Analysis of the \u201cendocannabinoidome\u201d in peripheral tissues of obese Zucker rats","volume":"89","author":"Iannotti","year":"2013","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lian, J., Casari, I., and Falasca, M. (2021). Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract. Pharmacol. Res., 175.","DOI":"10.1016\/j.phrs.2021.106025"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3322\/caac.21637","article-title":"Cancer statistics for adolescents and young adults, 2020","volume":"70","author":"Miller","year":"2020","journal-title":"CA A Cancer J. Clin."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Rawla, P., Sunkara, T., and Gaduputi, V. (2019). Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World J. Oncol., 10.","DOI":"10.14740\/wjon1166"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1072-7515(99)00075-7","article-title":"Pancreatic cancer: A report of treatment and survival trends for 100,313 patients diagnosed from 1985\u20131995, using the National Cancer Database","volume":"189","author":"Sener","year":"1999","journal-title":"J. Am. Coll. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1002\/ijc.23114","article-title":"Cannabinoids in pancreatic cancer: Correlation with survival and pain","volume":"122","author":"Michalski","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1001\/jama.2020.21717","article-title":"Looking to Long-term Survivors for Improved Pancreatic Cancer Treatment","volume":"324","author":"Kuehn","year":"2020","journal-title":"JAMA"},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"11216","DOI":"10.3748\/wjg.v20.i32.11216","article-title":"Pancreatic cancer and its stroma: A conspiracy theory","volume":"20","author":"Xu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1200\/JCO.1997.15.6.2403","article-title":"Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial","volume":"15","author":"Burris","year":"1997","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1056\/NEJMoa1809775","article-title":"FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer","volume":"379","author":"Conroy","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.3748\/wjg.v18.i14.1565","article-title":"Adjuvant and neoadjuvant treatment in pancreatic cancer","volume":"18","author":"Hijona","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41575-018-0005-x","article-title":"Therapeutic developments in pancreatic cancer: Current and future perspectives","volume":"15","author":"Neoptolemos","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jbior.2017.11.007","article-title":"Molecular and cellular mechanisms of chemoresistance in pancreatic cancer","volume":"68","author":"Adamska","year":"2018","journal-title":"Adv. Biol. Regul."},{"key":"ref_59","unstructured":"National Academies of Sciences, Engineering, and Medicine (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, The National Academies Press."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6368","DOI":"10.1038\/s41388-018-0390-1","article-title":"GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine","volume":"37","author":"Ferro","year":"2018","journal-title":"Oncogene"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.tips.2018.02.011","article-title":"Lysophosphatidylinositols, from Cell Membrane Constituents to GPR55 Ligands","volume":"39","author":"Alhouayek","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Moreno, E., Cavic, M., Krivokuca, A., and Canela, E.I. (2020). The Interplay between Cancer Biology and the Endocannabinoid System-Significance for Cancer Risk, Prognosis and Response to Treatment. Cancers, 12.","DOI":"10.3390\/cancers12113275"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1136\/gut.2005.073205","article-title":"Vanilloids in pancreatic cancer: Potential for chemotherapy and pain management","volume":"55","author":"Hartel","year":"2006","journal-title":"Gut"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/cbf.3483","article-title":"Transient receptor potential vanilloid 1 promotes EGFR ubiquitination and modulates EGFR\/MAPK signalling in pancreatic cancer cells","volume":"38","author":"Huang","year":"2020","journal-title":"Cell Biochem. Funct."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1002\/mc.23208","article-title":"Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer","volume":"59","author":"Liu","year":"2020","journal-title":"Mol. Carcinog."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Sailler, S., Schmitz, K., J\u00e4ger, E., Ferreiros, N., Wicker, S., Zschiebsch, K., Pickert, G., Geisslinger, G., Walter, C., and Tegeder, I. (2014). Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans. Oncoscience, 1.","DOI":"10.18632\/oncoscience.33"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.prostaglandins.2010.12.002","article-title":"Anti-proliferative effect of a putative endocannabinoid, 2-arachidonylglyceryl ether in prostate carcinoma cells","volume":"94","author":"Nithipatikom","year":"2011","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1124\/jpet.114.220368","article-title":"Protective role of cannabinoid receptor 2 activation in galactosamine\/lipopolysaccharide-induced acute liver failure through regulation of macrophage polarization and microRNAs","volume":"353","author":"Tomar","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Glogauer, J., and Blay, J. (2021). Cannabinoids, their cellular receptors, and effects on the invasive phenotype of carcinoma and metastasis. Cancer Rep.","DOI":"10.1002\/cnr2.1475"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrc1188","article-title":"Cannabinoids: Potential anticancer agents","volume":"3","author":"Guzman","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1172\/JCI200316116","article-title":"Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors","volume":"111","author":"Casanova","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/73171","article-title":"Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation","volume":"6","author":"Izquierdo","year":"2000","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6748","DOI":"10.1158\/0008-5472.CAN-06-0169","article-title":"Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes","volume":"66","author":"Carracedo","year":"2006","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1002\/elps.201200402","article-title":"Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists","volume":"34","author":"Brandi","year":"2013","journal-title":"Electrophoresis"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Donadelli, M., Dando, I., Zaniboni, T., Costanzo, C., Dalla Pozza, E., Scupoli, M.T., Scarpa, A., Zappavigna, S., Marra, M., and Abbruzzese, A. (2011). Gemcitabine\/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis., 2.","DOI":"10.1038\/cddis.2011.36"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Laezza, C., Pagano, C., Navarra, G., Pastorino, O., Proto, M.C., Fiore, D., Piscopo, C., Gazzerro, P., and Bifulco, M. (2020). The endocannabinoid system: A target for cancer treatment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030747"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D\u2019Alessandro, A., Zolla, L., and Palmieri, M. (2013). Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis., 4.","DOI":"10.1038\/cddis.2013.151"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Michalski, C.W., Maier, M., Erkan, M., Sauliunaite, D., Bergmann, F., Pacher, P., Batkai, S., Giese, N.A., Giese, T., and Friess, H. (2008). Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001701"},{"key":"ref_79","first-page":"925s","article-title":"Systemic and local immunosuppression in pancreatic cancer patients","volume":"7","author":"Voss","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Timmer, F.E.F., Geboers, B., Nieuwenhuizen, S., Dijkstra, M., Schouten, E.A.C., Puijk, R.S., de Vries, J.J.J., van den Tol, M.P., Bruynzeel, A.M.E., and Streppel, M.M. (2021). Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers, 13.","DOI":"10.3390\/cancers13164138"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Iozzo, M., Sgrignani, G., Comito, G., Chiarugi, P., and Giannoni, E. (2021). Endocannabinoid System and Tumour Microenvironment: New Intertwined Connections for Anticancer Approaches. Cells, 10.","DOI":"10.3390\/cells10123396"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Kienzl, M., Kargl, J., and Schicho, R. (2020). The Immune Endocannabinoid System of the Tumor Microenvironment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21238929"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/apha.12474","article-title":"Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells","volume":"214","author":"Braitch","year":"2015","journal-title":"Acta Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Qiu, C., Yang, L., Wang, B., Cui, L., Li, C., Zhuo, Y., Zhang, L., Zhang, S., Zhang, Q., and Wang, X. (2019). The role of 2-arachidonoylglycerol in the regulation of the tumor-immune microenvironment in murine models of pancreatic cancer. Biomed. Pharm., 115.","DOI":"10.1016\/j.biopha.2019.108952"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ijc.31030","article-title":"G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1","volume":"142","author":"Hasenoehrl","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.tips.2007.11.001","article-title":"Allosteric modulation of heterodimeric G-protein-coupled receptors","volume":"28","author":"Milligan","year":"2007","journal-title":"Trends Pharm. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"44234","DOI":"10.1074\/jbc.M112.364109","article-title":"The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55","volume":"287","author":"Kargl","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1242\/jcs.020958","article-title":"Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression","volume":"121","author":"Zoratti","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/cr.2011.60","article-title":"GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils","volume":"21","author":"Balenga","year":"2011","journal-title":"Cell Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Adamska, A., Domenichini, A., Capone, E., Damiani, V., Akkaya, B.G., Linton, K.J., Di Sebastiano, P., Chen, X., Keeton, A.B., and Ramirez-Alcantara, V. (2019). Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer. J. Exp. Clin. Cancer Res., 38.","DOI":"10.1186\/s13046-019-1308-7"},{"key":"ref_91","first-page":"612","article-title":"Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke","volume":"13","author":"Sacks","year":"2018","journal-title":"Int. J. Stroke"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1073\/pnas.1815034116","article-title":"Therapeutic targeting of HER2\u2013CB2R heteromers in HER2-positive breast cancer","volume":"116","author":"Moreno","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-G\u00f3mez, E., Andradas, C., Blasco-Benito, S., Caffarel, M.M., Garc\u00eda-Taboada, E., Villa-Morales, M., Moreno, E., Hamann, S., Mart\u00edn-Villar, E., and Flores, J.M. (2015). Role of Cannabinoid Receptor CB2 in HER2 Pro-oncogenic Signaling in Breast Cancer. JNCI J. Natl. Cancer Inst., 107.","DOI":"10.1093\/jnci\/djv077"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5387","DOI":"10.1111\/bph.12850","article-title":"Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling","volume":"171","author":"Balenga","year":"2014","journal-title":"Br. J. Pharm."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1074\/jbc.M115.712661","article-title":"Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression","volume":"291","author":"Coke","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1053\/j.gastro.2005.06.056","article-title":"CXCR4 Expression Increases Liver and Lung Metastasis in a Mouse Model of Pancreatic Cancer","volume":"129","author":"Saur","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jbior.2019.02.001","article-title":"Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential","volume":"72","author":"Domenichini","year":"2019","journal-title":"Adv. Biol. Regul."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"35448","DOI":"10.18632\/oncotarget.26234","article-title":"Naturally occurring compounds as pancreatic cancer therapeutics","volume":"9","author":"Lohse","year":"2018","journal-title":"Oncotarget"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Su, T.-F., Zhang, L.-H., Peng, M., Wu, C.-H., Pan, W., Tian, B., Shi, J., Pan, H.-L., and Li, M. (2011). Cannabinoid CB2 Receptors Contribute to Upregulation of \u03b2-endorphin in Inflamed Skin Tissues by Electroacupuncture. Mol. Pain, 7.","DOI":"10.1186\/1744-8069-7-98"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.brainresbull.2016.07.009","article-title":"Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia","volume":"125","author":"Auh","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.phrs.2016.07.013","article-title":"Selective GPR55 antagonism reduces chemoresistance in cancer cells","volume":"111","author":"Singh","year":"2016","journal-title":"Pharm. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1111\/bph.14440","article-title":"Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors","volume":"176","author":"Tham","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_103","first-page":"1","article-title":"Cannabidiol Possibly Improves Survival of Patients with Pancreatic Cancer: A Case Series","volume":"3","author":"Nahler","year":"2020","journal-title":"Clin. Oncol. Res."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Yasmin-Karim, S., Moreau, M., Mueller, R., Sinha, N., Dabney, R., Herman, A., and Ngwa, W. (2018). Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00114"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.4049\/jimmunol.174.6.3281","article-title":"Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response","volume":"174","author":"McKallip","year":"2005","journal-title":"J. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Yang, Y., Huynh, N., Dumesny, C., Wang, K., He, H., and Nikfarjam, M. (2020). Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218035"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Ramer, R., Wittig, F., and Hinz, B. (2021). The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies. Cancers, 13.","DOI":"10.3390\/cancers13225701"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:21:30Z","timestamp":1760134890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,17]]},"references-count":107,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["biom12020320"],"URL":"https:\/\/doi.org\/10.3390\/biom12020320","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,17]]}}}