{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:58:52Z","timestamp":1792166332275,"version":"4.4.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,19]],"date-time":"2016-08-19T00:00:00Z","timestamp":1471564800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,19]],"date-time":"2016-08-19T00:00:00Z","timestamp":1471564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. The effects depend on the chemoattractant chemerin, which is released by the tumour endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response, as well as an important inhibitor of cancer cachexia. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome.<\/jats:p>","DOI":"10.1038\/ncomms12528","type":"journal-article","created":{"date-parts":[[2016,8,19]],"date-time":"2016-08-19T11:22:00Z","timestamp":1471605720000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia"],"prefix":"10.1038","volume":"7","author":[{"given":"Ralph","family":"Klose","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Krzywinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Castells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Gotthardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva Maria","family":"Putz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chahrazade","family":"Kantari-Mimoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naima","family":"Chikdene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Katharina","family":"Meinecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Schr\u00f6dter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Helfrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Fandrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Sexl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stockmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,19]]},"reference":[{"key":"BFncomms12528_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/nrclinonc.2010.223","volume":"8","author":"L Zitvogel","year":"2011","unstructured":"Zitvogel, L., Kepp, O. & Kroemer, G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin. Oncol. 8, 151\u2013160 (2011).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"BFncomms12528_CR2","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrd3455","volume":"10","author":"P Carmeliet","year":"2011","unstructured":"Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417\u2013427 (2011).","journal-title":"Nat. Rev. Drug Discov."},{"key":"BFncomms12528_CR3","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1038\/nature07445","volume":"456","author":"C Stockmann","year":"2008","unstructured":"Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814\u2013818 (2008).","journal-title":"Nature"},{"key":"BFncomms12528_CR4","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0167-5273(02)00235-8","volume":"85","author":"KC Fearon","year":"2002","unstructured":"Fearon, K. C. & Moses, A. G. Cancer cachexia. Int. J. Cardiol. 85, 73\u201381 (2002).","journal-title":"Int. J. Cardiol."},{"key":"BFncomms12528_CR5","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1001\/jama.1980.03310040056033","volume":"244","author":"WD DeWys","year":"1980","unstructured":"DeWys, W. D. Nutritional care of the cancer patient. JAMA 244, 374\u2013376 (1980).","journal-title":"JAMA"},{"key":"BFncomms12528_CR6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1097\/01.mco.0000165004.93707.88","volume":"8","author":"C Deans","year":"2005","unstructured":"Deans, C. & Wigmore, S. J. Systemic inflammation, cachexia and prognosis in patients with cancer. Curr. Opin. Clin. Nutr. Metab. Care 8, 265\u2013269 (2005).","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"BFncomms12528_CR7","doi-asserted-by":"publisher","first-page":"8E","DOI":"10.1016\/j.amjcard.2008.02.065","volume":"101","author":"M Lainscak","year":"2008","unstructured":"Lainscak, M., Filippatos, G. S., Gheorghiade, M., Fonarow, G. C. & Anker, S. D. Cachexia: common, deadly, with an urgent need for precise definition and new therapies. Am. J. Cardiol. 101, 8E\u201310E (2008).","journal-title":"Am. J. Cardiol."},{"key":"BFncomms12528_CR8","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1126\/science.1198973","volume":"333","author":"SK Das","year":"2011","unstructured":"Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233\u2013238 (2011).","journal-title":"Science"},{"key":"BFncomms12528_CR9","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1073\/pnas.0308647100","volume":"101","author":"C Bing","year":"2004","unstructured":"Bing, C. et al. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc. Natl Acad. Sci. USA 101, 2500\u20132505 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12528_CR10","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1097\/SPC.0b013e3283311d09","volume":"3","author":"JM Argiles","year":"2009","unstructured":"Argiles, J. M., Busquets, S., Toledo, M. & Lopez-Soriano, F. J. The role of cytokines in cancer cachexia. Curr. Opin. Support. Palliat. Care 3, 263\u2013268 (2009).","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"BFncomms12528_CR11","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","volume":"16","author":"KC Fearon","year":"2012","unstructured":"Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153\u2013166 (2012).","journal-title":"Cell Metab."},{"key":"BFncomms12528_CR12","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nrclinonc.2012.209","volume":"10","author":"K Fearon","year":"2013","unstructured":"Fearon, K., Arends, J. & Baracos, V. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10, 90\u201399 (2013).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"BFncomms12528_CR13","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.bbrc.2007.08.104","volume":"362","author":"SG Roh","year":"2007","unstructured":"Roh, S. G. et al. Chemerin--a new adipokine that modulates adipogenesis via its own receptor. Biochem. Biophys. Res. Commun. 362, 1013\u20131018 (2007).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFncomms12528_CR14","doi-asserted-by":"publisher","first-page":"244","DOI":"10.4049\/jimmunol.174.1.244","volume":"174","author":"BA Zabel","year":"2005","unstructured":"Zabel, B. A., Silverio, A. M. & Butcher, E. C. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J. Immunol. 174, 244\u2013251 (2005).","journal-title":"J. Immunol."},{"key":"BFncomms12528_CR15","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1084\/jem.20030382","volume":"198","author":"V Wittamer","year":"2003","unstructured":"Wittamer, V. et al. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 198, 977\u2013985 (2003).","journal-title":"J. Exp. Med."},{"key":"BFncomms12528_CR16","doi-asserted-by":"publisher","first-page":"3625","DOI":"10.1182\/blood-2006-08-038844","volume":"109","author":"S Parolini","year":"2007","unstructured":"Parolini, S. et al. The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues. Blood 109, 3625\u20133632 (2007).","journal-title":"Blood"},{"key":"BFncomms12528_CR17","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/nri1936","volume":"6","author":"L Zitvogel","year":"2006","unstructured":"Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715\u2013727 (2006).","journal-title":"Nat. Rev. Immunol."},{"key":"BFncomms12528_CR18","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.celrep.2013.07.012","volume":"4","author":"EM Putz","year":"2013","unstructured":"Putz, E. M. et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 4, 437\u2013444 (2013).","journal-title":"Cell Rep."},{"key":"BFncomms12528_CR19","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1084\/jem.20112124","volume":"209","author":"RK Pachynski","year":"2012","unstructured":"Pachynski, R. K. et al. The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses. J. Exp. Med. 209, 1427\u20131435 (2012).","journal-title":"J. Exp. Med."},{"key":"BFncomms12528_CR20","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/nrc1369","volume":"4","author":"RS Kerbel","year":"2004","unstructured":"Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer 4, 423\u2013436 (2004).","journal-title":"Nat. Rev. Cancer"},{"key":"BFncomms12528_CR21","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/S0092-8674(02)00734-1","volume":"109","author":"CA Schmitt","year":"2002","unstructured":"Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335\u2013346 (2002).","journal-title":"Cell"},{"key":"BFncomms12528_CR22","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1016\/j.biocel.2004.10.013","volume":"37","author":"I Ben-Porath","year":"2005","unstructured":"Ben-Porath, I. & Weinberg, R. A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961\u2013976 (2005).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"BFncomms12528_CR23","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1101\/gad.17276711","volume":"25","author":"Y Chien","year":"2011","unstructured":"Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125\u20132136 (2011).","journal-title":"Genes Dev."},{"key":"BFncomms12528_CR24","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nature05529","volume":"445","author":"W Xue","year":"2007","unstructured":"Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656\u2013660 (2007).","journal-title":"Nature"},{"key":"BFncomms12528_CR25","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cell.2008.06.049","volume":"134","author":"V Krizhanovsky","year":"2008","unstructured":"Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657\u2013667 (2008).","journal-title":"Cell"},{"key":"BFncomms12528_CR26","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/j.cell.2008.03.038","volume":"133","author":"JC Acosta","year":"2008","unstructured":"Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006\u20131018 (2008).","journal-title":"Cell"},{"key":"BFncomms12528_CR27","doi-asserted-by":"publisher","first-page":"e24850","DOI":"10.4161\/onci.24850","volume":"2","author":"E Vacchelli","year":"2013","unstructured":"Vacchelli, E. et al. Trial Watch: Immunostimulatory cytokines. Oncoimmunology 2, e24850 (2013).","journal-title":"Oncoimmunology"},{"key":"BFncomms12528_CR28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrc1252","volume":"4","author":"G Dranoff","year":"2004","unstructured":"Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11\u201322 (2004).","journal-title":"Nat. Rev. Cancer"},{"key":"BFncomms12528_CR29","doi-asserted-by":"publisher","first-page":"23982","DOI":"10.1074\/jbc.M111.220491","volume":"286","author":"S Muruganandan","year":"2011","unstructured":"Muruganandan, S. et al. Chemerin, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) target gene that promotes mesenchymal stem cell adipogenesis. J. Biol. Chem. 286, 23982\u201323995 (2011).","journal-title":"J. Biol. Chem."},{"key":"BFncomms12528_CR30","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1016\/j.peptides.2009.05.030","volume":"30","author":"K Shimamura","year":"2009","unstructured":"Shimamura, K. et al. Identification of a stable chemerin analog with potent activity toward ChemR23. Peptides 30, 1529\u20131538 (2009).","journal-title":"Peptides"},{"key":"BFncomms12528_CR31","doi-asserted-by":"publisher","first-page":"C1621","DOI":"10.1152\/ajpcell.00187.2011","volume":"302","author":"ME Issa","year":"2012","unstructured":"Issa, M. E. et al. Chemokine-like receptor 1 regulates skeletal muscle cell myogenesis. Am. J. Physiol. Cell Physiol. 302, C1621\u2013C1631 (2012).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"BFncomms12528_CR32","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1111\/jcmm.12487","volume":"19","author":"Q Xie","year":"2015","unstructured":"Xie, Q. et al. Chemerin-induced mitochondrial dysfunction in skeletal muscle. J. Cell. Mol. Med. 19, 986\u2013995 (2015).","journal-title":"J. Cell. Mol. Med."},{"key":"BFncomms12528_CR33","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1158\/1541-7786.MCR-11-0065","volume":"9","author":"SM Welford","year":"2011","unstructured":"Welford, S. M. & Giaccia, A. J. Hypoxia and senescence: the impact of oxygenation on tumor suppression. Mol. Cancer Res. 9, 538\u2013544 (2011).","journal-title":"Mol. Cancer Res."},{"key":"BFncomms12528_CR34","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/nri2607","volume":"9","author":"V Nizet","year":"2009","unstructured":"Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9, 609\u2013617 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"BFncomms12528_CR35","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s10555-011-9281-4","volume":"30","author":"E Tartour","year":"2011","unstructured":"Tartour, E. et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 30, 83\u201395 (2011).","journal-title":"Cancer Metastasis Rev."},{"key":"BFncomms12528_CR36","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1182\/blood-2005-11-026823","volume":"109","author":"D Cervi","year":"2007","unstructured":"Cervi, D. et al. Enhanced natural-killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia. Blood 109, 2139\u20132146 (2007).","journal-title":"Blood"},{"key":"BFncomms12528_CR37","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1593\/neo.121758","volume":"15","author":"A Bruno","year":"2013","unstructured":"Bruno, A. et al. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia 15, 133\u2013142 (2013).","journal-title":"Neoplasia"},{"key":"BFncomms12528_CR38","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1084\/jem.20111497","volume":"209","author":"W Hansen","year":"2012","unstructured":"Hansen, W. et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med. 209, 2001\u20132016 (2012).","journal-title":"J. Exp. Med."},{"key":"BFncomms12528_CR39","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/nm1523","volume":"13","author":"M Obeid","year":"2007","unstructured":"Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54\u201361 (2007).","journal-title":"Nat. Med."},{"key":"BFncomms12528_CR40","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1242\/dev.126.6.1149","volume":"126","author":"HP Gerber","year":"1999","unstructured":"Gerber, H. P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149\u20131159 (1999).","journal-title":"Development"},{"key":"BFncomms12528_CR41","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1023\/A:1008942828960","volume":"8","author":"BE Clausen","year":"1999","unstructured":"Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265\u2013277 (1999).","journal-title":"Transgenic Res."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms12528.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12528","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12528.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T10:31:59Z","timestamp":1672828319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms12528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,19]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,25]]}},"alternative-id":["BFncomms12528"],"URL":"https:\/\/doi.org\/10.1038\/ncomms12528","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,19]]},"assertion":[{"value":"22 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12528"}}