{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T20:39:57Z","timestamp":1764103197573,"version":"3.41.2"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cachexia is defined as an involuntary decrease in body weight, which can increase the risk of death in cancer patients and reduce the quality of life. Cachexia-inducing factors (CIFs) have been reported in colorectal cancer and pancreatic adenocarcinoma, but their value in diffuse large B-cell lymphoma (DLBCL) requires further genetic research.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used gene expression data from Gene Expression Omnibus to evaluate the expression landscape of 25 known CIFs in DLBCL patients and compared them with normal lymphoma tissues from two cohorts [GSE56315 (<jats:italic>n<\/jats:italic> = 88) and GSE12195 (<jats:italic>n<\/jats:italic> = 136)]. The mutational status of CIFs were also evaluated in The Cancer Genome Atlas database. Based on the expression profiles of 25 CIFs, a single exploratory dataset which was merged by the datasets of GSE10846 (<jats:italic>n<\/jats:italic> = 420) and GSE31312 (<jats:italic>n<\/jats:italic> = 498) were divided into two molecular subtypes by using the method of consensus clustering. Immune microenvironment between different subtypes were assessed <jats:italic>via<\/jats:italic> single-sample gene set enrichment analysis and the CIBERSORT algorithm. The treatment response of commonly used chemotherapeutic drugs was predicted and gene set variation analysis was utilized to reveal the divergence in activated pathways for distinct subtypes. A risk signature was derived by univariate Cox regression and LASSO regression in the merged dataset (<jats:italic>n<\/jats:italic> = 882), and two independent cohorts [GSE87371 (<jats:italic>n<\/jats:italic> = 221) and GSE32918 (<jats:italic>n<\/jats:italic> = 244)] were used for validation, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Clustering analysis with CIFs further divided the cases into two molecular subtypes (cluster A and cluster B) associated with distinct prognosis, immunological landscape, chemosensitivity, and biological process. A risk-prognostic signature based on CCL2, CSF2, IL15, IL17A, IL4, TGFA, and TNFSF10 for DLBCL was developed, and significant differences in overall survival analysis were found between the low- and high-risk groups in the training dataset and another two independent validation datasets. Multivariate regression showed that the risk signature was an independently prognostic factor in contrast to other clinical characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrated that CIFs further contribute to the observed heterogeneity of DLBCL, and molecular classification and a risk signature based on CIFs are both promising tools for prognostic stratification, which may provide important clues for precision medicine and tumor-targeted therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2021.648856","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T15:27:06Z","timestamp":1621265226000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Comprehensive Characterization of Cachexia-Inducing Factors in Diffuse Large B-Cell Lymphoma Reveals a Molecular Subtype and a Prognosis-Related Signature"],"prefix":"10.3389","volume":"9","author":[{"given":"Zhixing","family":"Kuang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongqiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaoxing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiannan","family":"Tu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123603","article-title":"Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma.","volume":"12","author":"Agrusa","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2662","DOI":"10.1038\/s41375-019-0509-6","article-title":"Distinct subtypes of diffuse large B-cell lymphoma defined by hypermutated genes.","volume":"33","author":"Alkodsi","year":"2019","journal-title":"Leukemia"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.3324\/haematol.2019.243626","article-title":"Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma.","volume":"105","author":"Autio","year":"2020","journal-title":"Haematologica"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-020-00389-w","article-title":"Genetic and epigenetic determinants of diffuse large B-cell lymphoma.","volume":"10","author":"Bakhshi","year":"2020","journal-title":"Blood Cancer J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.blre.2016.06.003","article-title":"Clinical approach to diffuse large B cell lymphoma.","volume":"30","author":"Caimi","year":"2016","journal-title":"Blood Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3818","DOI":"10.1182\/blood-2008-02-138933","article-title":"IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma.","volume":"112","author":"Calvo","year":"2008","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/sj.cr.2007.90","article-title":"IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase\/AKT pathway.","volume":"17","author":"Carey","year":"2007","journal-title":"Cell Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/s41591-018-0016-8","article-title":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.","volume":"24","author":"Chapuy","year":"2018","journal-title":"Nat Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1200\/JCO.2014.57.7080","article-title":"Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis.","volume":"33","author":"Dybkaer","year":"2015","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2422","DOI":"10.1038\/s41379-020-0616-y","article-title":"Evolving insights into the genomic complexity and immune landscape of diffuse large B-cell lymphoma: opportunities for novel biomarkers.","volume":"33","author":"El Hussein","year":"2020","journal-title":"Mod Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1158\/2159-8290.CD-20-0174","article-title":"Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma.","volume":"10","author":"Ennishi","year":"2020","journal-title":"Cancer Discov"},{"key":"B14","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","article-title":"Cancer cachexia: mediators, signaling, and metabolic pathways.","volume":"16","author":"Fearon","year":"2012","journal-title":"Cell Metab"},{"key":"B15","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1002\/jcsm.12565","article-title":"The expression landscape of cachexia-inducing factors in human cancers.","volume":"11","author":"Freire","year":"2020","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107468","article-title":"pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels.","volume":"9","author":"Geeleher","year":"2014","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-06921-2","article-title":"Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma.","volume":"20","author":"Go","year":"2020","journal-title":"BMC Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1002\/jcsm.12115","article-title":"Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.","volume":"7","author":"Go","year":"2016","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"B19","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1080\/01635581.2013.741760","article-title":"Body mass index, weight change, and survival in non-Hodgkin lymphoma patients in Connecticut women.","volume":"65","author":"Han","year":"2013","journal-title":"Nutr Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5118","DOI":"10.1158\/0008-5472.can-16-0342","article-title":"CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity.","volume":"77","author":"Herrmann","year":"2017","journal-title":"Cancer research"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.21037\/atm-20-5363","article-title":"Genomic analysis of the prognostic value of colony-stimulating factors (CSFs) and colony-stimulating factor receptors (CSFRs) across 24 solid cancer types.","volume":"8","author":"Huang","year":"2020","journal-title":"Ann Transl Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3707","DOI":"10.1182\/blood-2004-08-3216","article-title":"Hodgkin lymphoma therapy with interleukin-4 receptor-directed cytotoxin in an infiltrating animal model.","volume":"105","author":"Kawakami","year":"2005","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1182\/blood.2019000847","article-title":"The immune landscape and response to immune checkpoint blockade therapy in lymphoma.","volume":"135","author":"Kline","year":"2020","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1158\/2326-6066.CIR-15-0154","article-title":"IL17A-Mediated Endothelial Breach Promotes Metastasis Formation.","volume":"4","author":"Kulig","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1001\/jamaoncol.2017.1609","article-title":"Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer.","volume":"3","author":"Li","year":"2017","journal-title":"JAMA Oncol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"55","DOI":"10.14740\/jh536","article-title":"C-Reactive Protein Level: A Key Predictive Marker of Cachexia in Lymphoma and Myeloma Patients.","volume":"8","author":"Mallard","year":"2019","journal-title":"J Hematol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1182\/blood-2016-02-698027","article-title":"IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells.","volume":"128","author":"Mao","year":"2016","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1038\/s41571-019-0225-1","article-title":"Genetic alterations and their clinical implications in DLBCL.","volume":"16","author":"Miao","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1158\/1078-0432.CCR-12-3603","article-title":"Molecular pathways: interleukin-15 signaling in health and in cancer.","volume":"20","author":"Mishra","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1200\/JCO.2016.71.7603","article-title":"Clinical Applications of the Genomic Landscape of Aggressive Non-Hodgkin Lymphoma.","volume":"35","author":"Moffitt","year":"2017","journal-title":"J Clin Oncol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1182\/blood-2010-11-321554","article-title":"miRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy.","volume":"118","author":"Montes-Moreno","year":"2011","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1182\/blood-2004-07-2947","article-title":"Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.","volume":"105","author":"Monti","year":"2005","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"313","DOI":"10.3109\/10428194.2015.1056183","article-title":"Short- and Long-term weight changes among United States veterans with diffuse large B-cell lymphoma treated with CHOP chemotherapy.","volume":"57","author":"O\u2019Brian","year":"2016","journal-title":"Leuk Lymphoma"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1182\/blood-2017-11-764332","article-title":"Genetics of diffuse large B-cell lymphoma.","volume":"131","author":"Pasqualucci","year":"2018","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/jcsm.12489","article-title":"Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia.","volume":"11","author":"Pettersen","year":"2020","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"B36","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s00262-018-2273-2","article-title":"Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly.","volume":"68","author":"Poles","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-10-121","article-title":"A MCP1 fusokine with CCR2-specific tumoricidal activity.","volume":"10","author":"Rafei","year":"2011","journal-title":"Molecular cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"238","DOI":"10.3324\/haematol.2014.113472","article-title":"Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial.","volume":"100","author":"Riihijarvi","year":"2015","journal-title":"Haematologica"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1182\/blood.2019002414","article-title":"Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent.","volume":"135","author":"Risue\u00f1o","year":"2020","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e555","DOI":"10.1016\/s1470-2045(15)00005-4","article-title":"Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas.","volume":"16","author":"Sarkozy","year":"2015","journal-title":"The Lancet Oncology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.","volume":"378","author":"Schmitz","year":"2018","journal-title":"N Engl J Med"},{"key":"B42","doi-asserted-by":"publisher","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":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071869","article-title":"New Insights into Diffuse Large B-Cell Lymphoma Pathobiology.","volume":"12","author":"Solimando","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01300","article-title":"A Prognostic Nomogram Combining Immune-Related Gene Signature and Clinical Factors Predicts Survival in Patients With Lung Adenocarcinoma.","volume":"10","author":"Song","year":"2020","journal-title":"Front Oncol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082418","article-title":"Inflammatory Cells in Diffuse Large B Cell Lymphoma.","volume":"9","author":"Tamma","year":"2020","journal-title":"J Clin Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/s1470-2045(18)30080-9","article-title":"Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.","volume":"19","author":"Tang","year":"2018","journal-title":"The Lancet Oncology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1182\/blood-2017-07-796342","article-title":"Immune evasion via PD-1\/PD-L1 on NK cells and monocyte\/macrophages is more prominent in Hodgkin lymphoma than DLBCL.","volume":"131","author":"Vari","year":"2018","journal-title":"Blood"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030601","article-title":"FDG-PET Imaging for Hodgkin and Diffuse Large B-Cell Lymphoma-An Updated Overview.","volume":"12","author":"Voltin","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1093\/annonc\/mdy505","article-title":"Intratumoral IL17-producing cells infiltration correlate with antitumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer.","volume":"30","author":"Wang","year":"2019","journal-title":"Ann Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-01011-z","article-title":"New agents and regimens for diffuse large B cell lymphoma.","volume":"13","author":"Wang","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1747332","article-title":"Tumor-infiltrating IL-17A(+) cells determine favorable prognosis and adjuvant chemotherapeutic response in muscle-invasive bladder cancer.","volume":"9","author":"Wang","year":"2020","journal-title":"Oncoimmunology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.blre.2018.03.005","article-title":"Prognostication of diffuse large B-cell lymphoma in the molecular era: moving beyond the IPI.","volume":"32","author":"Wight","year":"2018","journal-title":"Blood Rev"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking.","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"B54","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.ccell.2020.03.015","article-title":"A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications.","volume":"37","author":"Wright","year":"2020","journal-title":"Cancer Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1093\/carcin\/bgw038","article-title":"MiR-374a suppresses lung adenocarcinoma cell proliferation and invasion by targeting TGFA gene expression.","volume":"37","author":"Wu","year":"2016","journal-title":"Carcinogenesis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1080\/10428194.2016.1217526","article-title":"Weight change trends and overall survival in United States veterans with follicular lymphoma treated with chemotherapy.","volume":"58","author":"Xiao","year":"2017","journal-title":"Leuk Lymphoma"},{"key":"B57","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1182\/blood-2017-07-740993","article-title":"PD-1 expression and clinical PD-1 blockade in B-cell lymphomas.","volume":"131","author":"Xu-Monette","year":"2018","journal-title":"Blood"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1016\/s1470-2045(13)70491-1","article-title":"Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis.","volume":"14","author":"Zhang","year":"2013","journal-title":"The Lancet Oncology"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.648856\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T15:27:12Z","timestamp":1621265232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.648856\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":57,"alternative-id":["10.3389\/fcell.2021.648856"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.648856","relation":{},"ISSN":["2296-634X"],"issn-type":[{"type":"electronic","value":"2296-634X"}],"subject":[],"published":{"date-parts":[[2021,5,17]]},"article-number":"648856"}}