{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T17:31:50Z","timestamp":1769016710860,"version":"3.49.0"},"reference-count":115,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Opioids are a challenging class of drugs due to their dual role. They alleviate pain, but also pose a risk of dependency, or trigger constipation, particularly in cancer patients, who require the more potent painkillers in more advanced stages of the disease, closely linked to pain resulting from general inflammation, bone metastases, and primary or secondary tumour outgrowth-related nerve damage. Clinicians\u2019 vigilance considering treatment with opioids is necessary, bearing in mind extensive data accumulated over decades that have reported the contribution of opioids to immunosuppression, tumour progression, or impaired tissue regeneration, either following opioid use during surgical tumour resection and post-surgical pain treatment, or as a result of other diseases like diabetes, where chronic wounds healing constitutes a challenge. During last few years, an increasing trend for seeking relationships between opioids and epithelial\u2013mesenchymal transition (EMT) in cancer research can be observed. Transiently lasting EMT is desirable during wound healing, but in cancer, or vital organ fibrogenesis, EMT appears to be an obstacle to overcome, forcing to adjust treatment strategies that would reduce the risk for worsening of the disease outcome and patient prognosis. The same opioid may demonstrate promoting or inhibitory effect on EMT, dependently on various conditions in particular clinical cases. We have summarized current findings on this issue to uncover some rules that govern opioid-mediated EMT induction or repression; however, many aspects still remain to be elucidated.<\/jats:p>","DOI":"10.3390\/ph18010120","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T10:27:58Z","timestamp":1737109678000},"page":"120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Opioid System and Epithelial\u2013Mesenchymal Transition"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1938-8143","authenticated-orcid":false,"given":"Marzena","family":"\u0141azarczyk","sequence":"first","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5910-2955","authenticated-orcid":false,"given":"Dominik","family":"Skiba","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4186-4900","authenticated-orcid":false,"given":"Michel-Edwar","family":"Mickael","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinga","family":"Jasku\u0142a","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-6194","authenticated-orcid":false,"given":"Agata","family":"Nawrocka","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Religa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institute, 171 77 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Sacharczuk","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, 05-552 Jastrzebiec, Poland"},{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Garcia, M.A., Nelson, W.J., and Chavez, N. (2018). Cell-Cell Junctions Organize Structural and Signaling Networks. Cold Spring Harb. Perspect. Biol., 10.","DOI":"10.1101\/cshperspect.a029181"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1056\/NEJM197203092861006","article-title":"Current concepts. cell junctions","volume":"286","author":"Weinstein","year":"1972","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/(SICI)1521-1878(199806)20:6<488::AID-BIES7>3.0.CO;2-I","article-title":"Structure and assembly of hemidesmosomes","volume":"20","author":"Jones","year":"1998","journal-title":"Bioessays"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1096\/fasebj.10.8.8666164","article-title":"Desmosomes and hemidesmosomes: Structure and function of molecular components","volume":"10","author":"Green","year":"1996","journal-title":"FASEB J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0092-8674(82)90400-7","article-title":"The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells","volume":"31","author":"Moll","year":"1982","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1083\/jcb.200603161","article-title":"New consensus nomenclature for mammalian keratins","volume":"174","author":"Schweizer","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gr\u00f6ger, C.J., Grubinger, M., Waldh\u00f6r, T., Vierlinger, K., and Mikulits, W. (2012). Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051136"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"\u0141azarczyk, M., Mickael, M.E., Skiba, D., Kurzejamska, E., \u0141awi\u0144ski, M., Horba\u0144czuk, J.O., Radziszewski, J., Fraczek, K., Wolinska, R., and Paszkiewicz, J. (2023). The Journey of Cancer Cells to the Brain: Challenges and Opportunities. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043854"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.4049\/jimmunol.155.3.1450","article-title":"Characterization of latent TGF-beta activation by murine peritoneal macrophages","volume":"155","author":"Nunes","year":"1995","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","article-title":"TGF-\u03b2 signaling in health, disease, and therapeutics","volume":"9","author":"Deng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.1038\/onc.2009.180","article-title":"Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells","volume":"28","author":"Sullivan","year":"2009","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1073\/pnas.1820459116","article-title":"Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma","volume":"116","author":"Ebbing","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jhep.2014.03.033","article-title":"EGF\/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition","volume":"61","author":"Mergey","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1093\/carcin\/bgy018","article-title":"FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase\/MMP1 signal","volume":"39","author":"Schelch","year":"2018","journal-title":"Carcinogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jprot.2016.06.009","article-title":"Proteomic analysis of ovarian cancer cells during epithelial-mesenchymal transition (EMT) induced by epidermal growth factor (EGF) reveals mechanisms of cell cycle control","volume":"151","author":"Grassi","year":"2017","journal-title":"J. Proteomics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/jcb.21667","article-title":"Modulation of several waves of gene expression during FGF-1 induced epithelial-mesenchymal transition of carcinoma cells","volume":"104","author":"Billottet","year":"2008","journal-title":"J. Cell Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/1479-5876-10-213","article-title":"A new mechanism of action of sulodexide in diabetic nephropathy: Inhibits heparanase-1 and prevents FGF-2-induced renal epithelial-mesenchymal transition","volume":"10","author":"Masola","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117503","DOI":"10.1016\/j.lfs.2020.117503","article-title":"IGF-1 promotes multiple myeloma progression through PI3K\/Akt-mediated epithelial-mesenchymal transition","volume":"249","author":"Peng","year":"2020","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for epithelial-mesenchymal transitions","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12967-018-1539-y","article-title":"Upregulation of the EMT marker vimentin is associated with poor clinical outcome in acute myeloid leukemia","volume":"16","author":"Wu","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nojszewska, N., Idilli, O., Sarkar, D., Ahouiyek, Z., Arroyo-Berdugo, Y., Sandoval, C., Amin-Anjum, M.S., Bowers, S., Greaves, D., and Saeed, L. (2023). Bone marrow mesenchymal\/fibroblastic stromal cells induce a distinctive EMT-like phenotype in AML cells. Eur. J. Cell Biol., 102.","DOI":"10.1016\/j.ejcb.2023.151334"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1182\/blood.2019002548","article-title":"The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1","volume":"136","author":"Carmichael","year":"2020","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1158\/0008-5472.CAN-17-0032","article-title":"Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas?","volume":"77","author":"Sannino","year":"2017","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1158\/0008-5472.CAN-19-2373","article-title":"The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype","volume":"80","author":"Vandamme","year":"2020","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/S0002-9440(10)62370-X","article-title":"Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion","volume":"166","author":"Smalley","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/(SICI)1096-9896(200001)190:1<15::AID-PATH489>3.0.CO;2-L","article-title":"Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments]","volume":"190","author":"Bukholm","year":"2000","journal-title":"J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/sj.onc.1209808","article-title":"NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of ZEB-1 and ZEB-2","volume":"26","author":"Chua","year":"2007","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.canlet.2010.09.007","article-title":"ZEB1-responsive genes in non-small cell lung cancer","volume":"300","author":"Gemmill","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1053\/j.gastro.2011.08.038","article-title":"Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells","volume":"141","author":"Singh","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/35000034","article-title":"The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells","volume":"2","author":"Batlle","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1242\/jcs.00224","article-title":"The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: A comparison with Snail and E47 repressors","volume":"116","author":"Peinado","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.abb.2008.11.016","article-title":"Tumor-induced upregulation of Twist, Snail, and Slug represses the activity of the human VE-cadherin promoter","volume":"482","author":"Lopez","year":"2009","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41580-020-0237-9","article-title":"Guidelines and definitions for research on epithelial-mesenchymal transition","volume":"21","author":"Yang","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41419-024-06694-7","article-title":"Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer","volume":"15","author":"Metge","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.trecan.2020.06.005","article-title":"Targeting EMT in Cancer with Repurposed Metabolic Inhibitors","volume":"6","author":"Ramesh","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1038\/s41467-021-24545-3","article-title":"Morphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition","volume":"12","author":"Zhao","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer","volume":"20","author":"Dongre","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41416-020-01178-9","article-title":"EMTome: A resource for pan-cancer analysis of epithelial-mesenchymal transition genes and signatures","volume":"124","author":"Vasaikar","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"i103","DOI":"10.1093\/bja\/aeu165","article-title":"Increased \u03bc-opioid receptor expression in metastatic lung cancer","volume":"113","author":"Singleton","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lennon, F.E., Mirzapoiazova, T., Mambetsariev, B., Poroyko, V.A., Salgia, R., Moss, J., and Singleton, P.A. (2014). The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091577"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1080\/21655979.2022.2066045","article-title":"Sufentanil inhibits the proliferation and epithelial mesenchymal transition of lung cancer cells through Wnt\/beta-catenin signaling pathway","volume":"13","author":"Guan","year":"2022","journal-title":"Bioengineered"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0165-0173(01)00160-6","article-title":"The biology of the opioid growth factor receptor (OGFr)","volume":"38","author":"Zagon","year":"2002","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000092107","article-title":"Signal transduction induced by opioids in immune cells: A review","volume":"13","author":"Balog","year":"2006","journal-title":"Neuroimmunomodulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110064","DOI":"10.1016\/j.intimp.2023.110064","article-title":"Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition","volume":"118","author":"Zhang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhang, Q., and Sioud, M. (2023). Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087493"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107999","DOI":"10.1016\/j.intimp.2021.107999","article-title":"A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment","volume":"99","author":"Zhang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Gu, F., Zhou, Y., Tian, L., Chen, J., Zhang, C., Huang, Z., Yu, W., and Xie, K. (2024). Morphine promotes non-small cell lung cancer progression by downregulating E-cadherin via the PI3K\/AKT\/mTOR pathway. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-72198-1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1002\/ijc.25788","article-title":"Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors","volume":"129","author":"Trujillo","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_50","first-page":"9","article-title":"Direct effects of delta opioid receptor agonists on invasion-associated activities of HCT-8\/E11 colon cancer cells","volume":"30","author":"Debruyne","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.neo.2020.12.011","article-title":"Opioids drive breast cancer metastasis through the \u03b4-opioid receptor and oncogenic STAT3","volume":"23","author":"Tripolt","year":"2021","journal-title":"Neoplasia"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Gyamfi, J., Lee, Y.H., Eom, M., and Choi, J. (2018). Interleukin-6\/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-27184-9"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1083\/jcb.147.7.1561","article-title":"Bifurcation of cell migratory and proliferative signaling by the adaptor protein Shc","volume":"147","author":"Collins","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"303","DOI":"10.32604\/biocell.2005.29.303","article-title":"TNFalpha increases in vitro migration of human HPV18-positive SW756 cervical carcinoma cells","volume":"29","author":"Hidalgo","year":"2005","journal-title":"Biocell"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Huang, Y.H., Sue, S.H., Wu, Z.S., Huang, S.M., Lee, S.Y., and Wu, Z.F. (2022). Antitumorigenic Effect of Tramadol and Synergistic Effect With Doxorubicin in Human Breast Cancer Cells. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.811716"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6282","DOI":"10.1158\/0008-5472.CAN-11-1610","article-title":"Transplantation of \u03b2-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma","volume":"71","author":"Sarkar","year":"2011","journal-title":"Cancer Res."},{"key":"ref_57","first-page":"391","article-title":"Nalbuphine: An autoradiographic opioid receptor binding profile in the central nervous system of an agonist\/antagonist analgesic","volume":"244","author":"Schmidt","year":"1988","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s13046-019-1184-1","article-title":"Nalbuphine suppresses breast cancer stem-like properties and epithelial-mesenchymal transition via the AKT-NF\u03baB signaling pathway","volume":"38","author":"Yu","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1080\/08923973.2023.2228476","article-title":"Sufentanil inhibits the metastasis and immune response of breast cancer via mediating the NF-\u03baB pathway","volume":"45","author":"Li","year":"2023","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10585-023-10199-6","article-title":"Sufentanil combined with parecoxib sodium inhibits proliferation and metastasis of HER2-positive breast cancer cells and regulates epithelial-mesenchymal transition","volume":"40","author":"Xu","year":"2023","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Murugan, S., Rousseau, B., and Sarkar, D.K. (2021). Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer. Cancers, 13.","DOI":"10.3390\/cancers13194858"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.bbrc.2017.09.146","article-title":"Adrenaline promotes epithelial-to-mesenchymal transition via HuR-TGF\u03b2 regulatory axis in pancreatic cancer cells and the implication in cancer prognosis","volume":"493","author":"Pu","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"100458","DOI":"10.1016\/j.clinsp.2024.100458","article-title":"Oxycodone enhances antitumor effect of paclitaxel on human breast cancer SKBR3 cells in vitro","volume":"79","author":"Liu","year":"2024","journal-title":"Clinics"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Li, H., Ma, Z., and Lei, Y. (2021). The expression of kappa-opioid receptor promotes the migration of breast cancer cells in vitro. BMC Anesthesiol., 21.","DOI":"10.1186\/s12871-021-01429-z"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2100300","DOI":"10.1002\/minf.202100300","article-title":"Multi-targeted Drug Repurposing Approach for Breast Cancer via Integrated Functional Network Analysis","volume":"41","author":"Kandasamy","year":"2022","journal-title":"Mol. Inform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4206","DOI":"10.1200\/JCO.24.00381","article-title":"Naldemedine for Opioid-Induced Constipation in Patients with Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial","volume":"42","author":"Hamano","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1038\/s41416-022-01928-x","article-title":"Possible mechanism for improving the endogenous immune system through the blockade of peripheral \u03bc-opioid receptors by treatment with naldemedine","volume":"127","author":"Gondoh","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_68","first-page":"72","article-title":"MOR promotes epithelial-mesenchymal transition and proliferation via PI3K\/AKT signaling pathway in human colorectal cancer","volume":"55","author":"Gao","year":"2022","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.omtm.2022.03.005","article-title":"A repositioning screen using an FGFR2 splicing reporter reveals compounds that regulate epithelial-mesenchymal transitions and inhibit growth of prostate cancer xenografts","volume":"25","author":"Li","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1016\/j.bja.2018.09.030","article-title":"The mu-opioid receptor is a molecular marker for poor prognosis in hepatocellular carcinoma and represents a potential therapeutic target","volume":"122","author":"Chen","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"106718","DOI":"10.1016\/j.intimp.2020.106718","article-title":"Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo","volume":"86","author":"Liu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/abbs\/gmaa169","article-title":"Successive treatment with naltrexone induces epithelial-mesenchymal transition and facilitates the malignant biological behaviors of bladder cancer cells","volume":"53","author":"Wang","year":"2021","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/cac2.12408","article-title":"\u03bc-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR\/AKT\/Slug pathway: A comprehensive study including randomized controlled trial","volume":"43","author":"Wang","year":"2023","journal-title":"Cancer Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1016\/j.clinthera.2019.10.002","article-title":"Perioperative Opioid-sparing Strategies: Utility of Conventional NSAIDs in Adults","volume":"41","author":"Martinez","year":"2019","journal-title":"Clin. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e242","DOI":"10.1016\/j.bja.2021.12.034","article-title":"Opioid-sparing strategies and their link to postoperative morphine and antiemetic administration: A retrospective study","volume":"128","author":"Coeckelenbergh","year":"2022","journal-title":"Br. J. Anaesth."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Liu, W., Ou, C., Xue, R., Yang, X., Ye, Y., Wang, X., and Xie, J. (2024). Opioid-free anesthesia attenuates perioperative immunosuppression by regulating macrophages polarization in gastric cancer patients treated with neoadjuvant PD-1 inhibitor. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1438859"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7586100","DOI":"10.1155\/2021\/7586100","article-title":"Sufentanil Inhibits the Proliferation and Metastasis of Esophageal Cancer by Inhibiting the NF-\u03baB and Snail Signaling Pathways","volume":"2021","author":"Tang","year":"2021","journal-title":"J. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1248\/bpb.b19-00779","article-title":"Morphine Stimulates Migration and Growth and Alleviates the Effects of Chemo Drugs via AMPK-Dependent Induction of Epithelial-Mesenchymal Transition in Esophageal Carcinoma Cells","volume":"43","author":"Zhang","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Charbaji, N., Sch\u00e4fer-Korting, M., and K\u00fcchler, S. (2012). Morphine stimulates cell migration of oral epithelial cells by delta-opioid receptor activation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042616"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1002\/jcp.30161","article-title":"Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer","volume":"236","author":"Lu","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tips.2009.08.002","article-title":"The \u201ctoll\u201d of opioid-induced glial activation: Improving the clinical efficacy of opioids by targeting glia","volume":"30","author":"Watkins","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1091\/mbc.e16-06-0427","article-title":"Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer","volume":"27","author":"Jorand","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_83","first-page":"17684","article-title":"Fentanyl inhibits cell viability in human pancreatic cancer cell line and tumor growth in pancreatic cancer cell-transplanted mice","volume":"8","author":"Miao","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Xiao, K., Zheng, Q., and Bao, L. (2022). Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR. BMC Anesthesiol., 22.","DOI":"10.1186\/s12871-022-01812-4"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s41415-022-5166-x","article-title":"Reviewing the epidemiology of head and neck cancer: Definitions, trends and risk factors","volume":"233","author":"Gormley","year":"2022","journal-title":"Br. Dent. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7698","DOI":"10.1002\/jcp.30421","article-title":"Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu-opioid receptor","volume":"236","author":"Gorur","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Yang, H.F., Yu, M., Jin, H.D., Yao, J.Q., Lu, Z.L., Yabasin, I.B., Yan, Q., and Wen, Q.P. (2017). Fentanyl Promotes Breast Cancer Cell Stemness and Epithelial-Mesenchymal Transition by Upregulating \u03b11, 6-Fucosylation via Wnt\/\u03b2-Catenin Signaling Pathway. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00510"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.ajpath.2022.12.016","article-title":"Inflammation-Associated Lung Tissue Remodeling and Fibrosis in Morphine-Dependent SIV-Infected Macaques","volume":"193","author":"Chemparathy","year":"2023","journal-title":"Am. J. Pathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.peptides.2015.04.002","article-title":"Beta-casomorphin-7 prevents epithelial-mesenchymal transdifferentiation of NRK-52E cells at high glucose level: Involvement of AngII-TGF-\u03b21 pathway","volume":"70","author":"Zhang","year":"2015","journal-title":"Peptides"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1111\/febs.15459","article-title":"Alleviation of TGF-\u03b21 induced tubular epithelial-mesenchymal transition via the \u03b4-opioid receptor","volume":"288","author":"Luo","year":"2021","journal-title":"FEBS J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/wrr.12496","article-title":"Relationship between opioid treatment and rate of healing in chronic wounds","volume":"25","author":"Shanmugam","year":"2017","journal-title":"Wound Repair. Regen."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1432-0436.2006.00065.x","article-title":"Deletion of delta-opioid receptor in mice alters skin differentiation and delays wound healing","volume":"74","author":"Zhou","year":"2006","journal-title":"Differentiation"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/bph.12687","article-title":"Activation of the \u03b4-opioid receptor promotes cutaneous wound healing by affecting keratinocyte intercellular adhesion and migration","volume":"172","author":"Bigliardi","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.2337\/diabetes.51.10.3055","article-title":"Naltrexone, an opioid antagonist, facilitates reepithelialization of the cornea in diabetic rat","volume":"51","author":"Zagon","year":"2002","journal-title":"Diabetes"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1258\/ebm.2011.011163","article-title":"Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats","volume":"236","author":"McLaughlin","year":"2011","journal-title":"Exp. Biol. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1097\/ANA.0000000000000778","article-title":"Brain Cancer Progression: A Retrospective Multicenter Comparison of Awake Craniotomy Versus General Anesthesia in High-grade Glioma Resection","volume":"34","author":"Chowdhury","year":"2022","journal-title":"J. Neurosurg. Anesthesiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e19099","DOI":"10.1200\/JCO.2020.38.15_suppl.e19099","article-title":"The effect of regional anesthesia on cancer related outcomes after oncological surgeries: A systematic review","volume":"38","author":"Lin","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Zhu, Q., Li, K., Li, H., Han, F., Tang, Z., and Wang, Z. (2021). Ketamine Induced Bladder Fibrosis Through MTDH\/P38 MAPK\/EMT Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.743682"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"118154","DOI":"10.1016\/j.lfs.2020.118154","article-title":"Isoflurane promotes epithelial-to-mesenchymal transition and metastasis of bladder cancer cells through HIF-1\u03b1-\u03b2-catenin\/Notch1 pathways","volume":"258","author":"Lu","year":"2020","journal-title":"Life Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"346","DOI":"10.3892\/ol.2023.13932","article-title":"Lidocaine induces epithelial-mesenchymal transition and aggravates cancer behaviors in non-small cell lung cancer A549 cells","volume":"26","author":"Hsieh","year":"2023","journal-title":"Oncol. Lett."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.12659\/MSM.899955","article-title":"Ketamine Inhalation Ameliorates Ovalbumin-Induced Murine Asthma by Suppressing the Epithelial-Mesenchymal Transition","volume":"22","author":"Song","year":"2016","journal-title":"Med. Sci. Monit."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Lu, H.L., Wu, K.C., Chen, C.W., Weng, H.K., Huang, B.M., Lin, T.Y., Liu, M.H., So, E.C., Lin, R.M., and Wang, Y.K. (2021). Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition. Life, 11.","DOI":"10.3390\/life11121396"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/cam4.3621","article-title":"Lidocaine inhibits the metastatic potential of ovarian cancer by blocking Na(V) 1.5-mediated EMT and FAK\/Paxillin signaling pathway","volume":"10","author":"Liu","year":"2021","journal-title":"Cancer Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"417","DOI":"10.5055\/jom.2021.0675","article-title":"Multimodal opioid sparing onco-anesthesia: A consensus practice guideline from Society of Onco-Anesthesia and Perioperative Care (SOAPC)","volume":"17","author":"Solanki","year":"2021","journal-title":"J. Opioid Manag."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1007\/s00268-022-06473-5","article-title":"Comparison of the Analgesic Efficacy of Opioid-Sparing Multimodal Analgesia and Morphine-Based Patient-Controlled Analgesia in Minimally Invasive Surgery for Colorectal Cancer","volume":"46","author":"Yeo","year":"2022","journal-title":"World J. Surg."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.anclin.2021.11.001","article-title":"Opioid-Sparing Perioperative Analgesia Within Enhanced Recovery Programs","volume":"40","author":"McEvoy","year":"2022","journal-title":"Anesthesiol. Clin."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e638","DOI":"10.1016\/j.jpainsymman.2023.06.022","article-title":"Should Buprenorphine Be Considered a First-Line Opioid for the Treatment of Moderate to Severe Cancer Pain?","volume":"66","author":"Chwistek","year":"2023","journal-title":"J. Pain Symptom Manag."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1001\/jamaoncol.2022.2191","article-title":"Consensus-Based Guidance on Opioid Management in Individuals with Advanced Cancer-Related Pain and Opioid Misuse or Use Disorder","volume":"8","author":"Khodyakov","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/pm\/pnz356","article-title":"Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion","volume":"21","author":"Webster","year":"2020","journal-title":"Pain Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.bja.2017.11.086","article-title":"Efficacy and adverse effects of buprenorphine in acute pain management: Systematic review and meta-analysis of randomised controlled trials","volume":"120","author":"White","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_111","first-page":"CD002068","article-title":"Bisphosphonates for the relief of pain secondary to bone metastases","volume":"2002","author":"Wong","year":"2002","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1158\/1535-7163.MCT-12-0304","article-title":"Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-\u03baB","volume":"12","author":"Schech","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1007\/s00210-021-02164-5","article-title":"Zoledronic acid-loaded lipidic nanoparticles enhance apoptosis and attenuate invasiveness by inhibiting epithelial to mesenchymal transition (EMT) in HepG(2) cancer cells","volume":"394","author":"Sabzichi","year":"2021","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"117925","DOI":"10.1016\/j.lfs.2020.117925","article-title":"Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt\/\u03b2-catenin pathway","volume":"256","author":"Lv","year":"2020","journal-title":"Life Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e287","DOI":"10.1136\/bmjspcare-2021-003293","article-title":"Peripheral nerve blocks in advanced cancer pain: Retrospective case series","volume":"13","author":"Rouhento","year":"2023","journal-title":"BMJ Support. Palliat. 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