{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:02:01Z","timestamp":1791234121707,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20\u201325 kg\/m2), overweight (25\u201330 kg\/m2), or obese (30\u201335 kg\/m2) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and\/or disease progression.<\/jats:p>","DOI":"10.3390\/cancers15174347","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T11:41:18Z","timestamp":1693482078000},"page":"4347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response"],"prefix":"10.3390","volume":"15","author":[{"given":"Maria","family":"Ochiai","sequence":"first","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3192-6530","authenticated-orcid":false,"given":"Sara","family":"Fierstein","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farouq","family":"XsSali","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"DeVito","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura R.","family":"Purkey","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"May","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Correa-Medina","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Kelley","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Page","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-5609","authenticated-orcid":false,"given":"Kathleen","family":"DeCicco-Skinner","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, 4400 Massachusetts Ave, NW, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ajh.25791","article-title":"Multiple myeloma: 2020 update on diagnosis, risk-stratification and management","volume":"95","author":"Rajkumar","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0140-6736(16)31594-X","article-title":"Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial","volume":"389","author":"Durie","year":"2017","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1093\/ije\/dyz273","article-title":"Has the prevalence of overweight, obesity and central obesity levelled off in the United States? Trends, patterns, disparities, and future projections for the obesity epidemic","volume":"49","author":"Wang","year":"2020","journal-title":"Int. J. Epidemiol."},{"key":"ref_5","unstructured":"Fryar, C.D., Carroll, M.D., and Ogden, C.L. (2020). Prevalence of Overweight, Obesity, and Severe Obesity among Adults Aged 20 and Over: United States, 1960\u20131962 through 2017\u20132018, National Center for Health Statistics."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1056\/NEJMsr1606602","article-title":"Body Fatness and Cancer\u2014Viewpoint of the IARC Working Group","volume":"375","author":"Scoccianti","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1111\/bjh.12935","article-title":"Body size and multiple myeloma mortality: A pooled analysis of 20 prospective studies","volume":"166","author":"Teras","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1182\/bloodadvances.2017007609","article-title":"Obesity and risk of monoclonal gammopathy of undetermined significance and progression to multiple myeloma: A population-based study","volume":"1","author":"Thordardottir","year":"2017","journal-title":"Blood Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.ejca.2011.01.020","article-title":"Body mass index and risk of multiple myeloma: A meta-analysis of prospective studies","volume":"47","author":"Wallin","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"Pawlyn","year":"2021","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41568-020-0245-2","article-title":"Bone marrow niches in haematological malignancies","volume":"20","author":"Bonnet","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.3324\/haematol.2014.113852","article-title":"A hostel for the hostile: The bone marrow niche in hematologic neoplasms","volume":"100","author":"Krause","year":"2015","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3389\/fendo.2016.00067","article-title":"Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells","volume":"7","author":"Falank","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fendo.2016.00085","article-title":"Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?","volume":"7","author":"Hardouin","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_15","first-page":"121","article-title":"Clinical implications of bone marrow adiposity","volume":"283","author":"Rosen","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S395","DOI":"10.1194\/jlr.R800057-JLR200","article-title":"Adipocyte metabolism and obesity","volume":"50","author":"Attie","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10555-022-10063-1","article-title":"The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer","volume":"41","author":"Bunnell","year":"2022","journal-title":"Cancer Metastasis Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.canlet.2016.06.010","article-title":"Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling","volume":"380","author":"Bullwinkle","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1158\/0008-5472.CAN-20-1088","article-title":"Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype","volume":"81","author":"Fairfield","year":"2021","journal-title":"Cancer Res"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1002\/jbmr.3951","article-title":"Myeloma Cells Down-Regulate Adiponectin in Bone Marrow Adipocytes Via TNF-Alpha","volume":"35","author":"Morris","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1016\/j.ajpath.2016.07.012","article-title":"Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone","volume":"186","author":"Trotter","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1182\/blood-2007-10-116129","article-title":"Improved survival in multiple myeloma and the impact of novel therapies","volume":"111","author":"Kumar","year":"2008","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/leu.2008.402","article-title":"Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): An analysis of the Greek Myeloma Study Group (GMSG)","volume":"23","author":"Kastritis","year":"2009","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bobin, A., Liuu, E., Moya, N., Gruchet, C., Sabirou, F., L\u00e9vy, A., Gardeney, H., Nsiala, L., Cailly, L., and Guidez, S. (2020). Multiple Myeloma: An Overview of the Current and Novel Therapeutic Approaches in 2020. Cancers, 12.","DOI":"10.3390\/cancers12102885"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.18632\/oncotarget.1497","article-title":"Drug resistance in multiple myeloma: Latest findings and new concepts on molecular mechanisms","volume":"4","author":"Abdi","year":"2013","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pinto, V., Bergantim, R., Caires, H.R., Seca, H., Guimar\u00e3es, J.E., and Vasconcelos, M.H. (2020). Multiple Myeloma: Available Therapies and Causes of Drug Resistance. Cancers, 12.","DOI":"10.3390\/cancers12020407"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/leu.2011.196","article-title":"Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study","volume":"26","author":"Kumar","year":"2012","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"973836","DOI":"10.3389\/fonc.2022.973836","article-title":"Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche","volume":"12","author":"Solimando","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"341430","DOI":"10.1155\/2015\/341430","article-title":"Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma","volume":"2015","author":"Yang","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.5732\/cjc.011.10329","article-title":"Multidrug resistance associated proteins in multidrug resistance","volume":"31","author":"Sodani","year":"2012","journal-title":"Chin. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood.V93.5.1658","article-title":"Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines","volume":"93","author":"Damiano","year":"1999","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1038\/sj.onc.1206315","article-title":"Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB\/p50) in myeloma cells","volume":"22","author":"Landowski","year":"2003","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4319","DOI":"10.1038\/sj.onc.1203782","article-title":"Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR)","volume":"19","author":"Hazlehurst","year":"2000","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1182\/blood.V73.3.747.747","article-title":"Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: Association with level of drug resistance and drug accumulation","volume":"73","author":"Dalton","year":"1989","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/10428194.2014.907890","article-title":"The role of P-glycoprotein in drug resistance in multiple myeloma","volume":"56","author":"Abraham","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1182\/blood.V81.2.490.490","article-title":"P-glycoprotein expression in human plasma cell myeloma: Correlation with prior chemotherapy","volume":"81","author":"Grogan","year":"1993","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/bjc.1992.95","article-title":"Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma","volume":"65","author":"Linsenmeyer","year":"1992","journal-title":"Br. J. Cancer"},{"key":"ref_38","first-page":"e51312","article-title":"Endothelial cell tube formation assay for the in vitro study of angiogenesis","volume":"91","author":"Henry","year":"2014","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-1-0716-2217-9_12","article-title":"Endothelial Cell Tube Formation Assay: An In Vitro Model for Angiogenesis","volume":"2475","author":"Kelley","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.18632\/oncotarget.109","article-title":"A critical role for the NFkB pathway in multiple myeloma","volume":"1","author":"Demchenko","year":"2010","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Morales-Mart\u00ednez, M., and Vega, M.I. (2022). Roles and Regulation of BCL-xL in Hematological Malignancies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042193"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"861709","DOI":"10.3389\/fonc.2022.861709","article-title":"Caspase-8: Friend or Foe in Bortezomib\/Lenalidomide-Based Therapy for Myeloma","volume":"12","author":"Zhou","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.3390\/cancers2041952","article-title":"The Enigmatic Roles of Caspases in Tumor Development","volume":"2","author":"Zwacka","year":"2010","journal-title":"Cancers"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"701301","DOI":"10.3389\/fphar.2021.701301","article-title":"Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease","volume":"12","author":"Avrutsky","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0093-7754(01)90022-3","article-title":"Bone marrow angiogenesis in patients with active multiple myeloma","volume":"28","author":"Vacca","year":"2001","journal-title":"Semin. Oncol."},{"key":"ref_46","unstructured":"Itoh, T., Tanioka, M., Yoshida, H., Yoshioka, T., Nishimoto, H., and Itohara, S. (1998). Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res., 58."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1172\/JCI6870","article-title":"Matrix metalloproteinases in angiogenesis: A moving target for therapeutic intervention","volume":"103","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Neumeister, P., Schulz, E., Pansy, K., Szmyra, M., and Deutsch, A.J. (2022). Targeting the Microenvironment for Treating Multiple Myeloma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147627"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1182\/blood.2021013832","article-title":"Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins","volume":"139","author":"Panaroni","year":"2022","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1038\/sj.leu.2404658","article-title":"Neighboring adipocytes participate in the bone marrow microenvironment of multiple myeloma cells","volume":"21","author":"Caers","year":"2007","journal-title":"Leukemia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1172\/JCI127201","article-title":"Adipocyte and lipid metabolism in cancer drug resistance","volume":"129","author":"Cao","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"34329","DOI":"10.18632\/oncotarget.6020","article-title":"Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-021-02209-w","article-title":"Induction of m6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance","volume":"41","author":"Wang","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_54","first-page":"271","article-title":"Cancer drug resistance in multiple myeloma","volume":"5","author":"Uckun","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Zhang, X., Xiao, W., Wang, L., Tian, Z., and Zhang, J. (2011). Deactivation of Signal Transducer and Activator of Transcription 3 Reverses Chemotherapeutics Resistance of Leukemia Cells via Down-Regulating P-gp. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020965"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13558","DOI":"10.1038\/srep13558","article-title":"Chronic inflammation up-regulates P-gp in peripheral mononuclear blood cells via the STAT3\/Nf-\u03bab pathway in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice","volume":"5","author":"Liu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8529","DOI":"10.3390\/curroncol29110672","article-title":"Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma","volume":"29","author":"Suzuki","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Huang, Y., Wang, Y., Tang, J., Qin, S., Shen, X., He, S., and Ju, S. (2021). CAM-DR: Mechanisms, Roles and Clinical Application in Tumors. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.698047"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Roy, P., Sarkar, U.A., and Basak, S. (2018). The NF-\u03baB Activating Pathways in Multiple Myeloma. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020059"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"118688","DOI":"10.1016\/j.bbamcr.2020.118688","article-title":"Targeting apoptotic caspases in cancer","volume":"1867","author":"Boice","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s10555-018-9736-y","article-title":"Novel roles of apoptotic caspases in tumor repopulation, epigenetic reprogramming, carcinogenesis, and beyond","volume":"37","author":"Zhao","year":"2018","journal-title":"Cancer Metastasis Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ccr.2005.10.013","article-title":"A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib","volume":"8","author":"Chauhan","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1182\/blood-2009-03-213009","article-title":"Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma","volume":"115","author":"Chauhan","year":"2010","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e22593","DOI":"10.7554\/eLife.22593","article-title":"Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma","volume":"6","author":"Fianco","year":"2017","journal-title":"eLife"},{"key":"ref_66","first-page":"303","article-title":"Caspase-8 Regulates the Antimyeloma Activity of Bortezomib and Lenalidomide","volume":"379","author":"Zhou","year":"2021","journal-title":"Experiment"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1016\/j.jcjd.2016.08.166","article-title":"Caspase 8 Plays a Pivotal Role in Adipose Tissue Inflammatory Signalling and Glucose HomeostasisImage 9","volume":"40","author":"Luk","year":"2016","journal-title":"Can. J. Diabetes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1182\/blood-2003-08-2946","article-title":"Angiogenic switch during 5T2MM murine myeloma tumorigenesis: Role of CD45 heterogeneity","volume":"103","author":"Asosingh","year":"2004","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1158\/1541-7786.MCR-21-0941","article-title":"A Hyaluronan and Proteoglycan Link Protein 1 Matrikine: Role of Matrix Metalloproteinase 2 in Multiple Myeloma NF-\u03baB Activation and Drug Resistance","volume":"20","author":"Mark","year":"2022","journal-title":"Mol. Cancer Res. MCR"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3550","DOI":"10.1038\/sj.onc.1207383","article-title":"Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis","volume":"23","author":"Xie","year":"2004","journal-title":"Oncogene"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:43:44Z","timestamp":1760129024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,31]]},"references-count":70,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cancers15174347"],"URL":"https:\/\/doi.org\/10.3390\/cancers15174347","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,31]]}}}