{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:18:05Z","timestamp":1789409885653,"version":"build-2803163510"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005711","name":"Universit\u00e4t Hamburg","doi-asserted-by":"publisher","award":["LFF\u2010FV 45"],"award-info":[{"award-number":["LFF\u2010FV 45"]}],"id":[{"id":"10.13039\/501100005711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022790","name":"Hector Stiftung II","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Low\u2010dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low\u2010dose anti\u2010VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti\u2010VEGFR2 therapy alone. Short\u2010term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting.<\/jats:p>","DOI":"10.1002\/ijc.35132","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T03:39:47Z","timestamp":1724384387000},"page":"186-200","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prolonged inhibition of intratumoral mast cells enhances efficacy of low\u2010dose antiangiogenic therapy"],"prefix":"10.1002","volume":"156","author":[{"given":"Nikolaus","family":"Berenbrok","sequence":"first","affiliation":[{"name":"Division of Personalized Medical Oncology (A420) German Cancer Research Center (DKFZ), German Center for Lung Research (DZL)  Heidelberg Germany"},{"name":"DKFZ\u2010Hector Cancer Institute at the University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg  Mannheim Germany"},{"name":"Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim University of Heidelberg  Mannheim Germany"},{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Vargas\u2010Delgado","sequence":"additional","affiliation":[{"name":"Division of Personalized Medical Oncology (A420) German Cancer Research Center (DKFZ), German Center for Lung Research (DZL)  Heidelberg Germany"},{"name":"DKFZ\u2010Hector Cancer Institute at the University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg  Mannheim Germany"},{"name":"Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim University of Heidelberg  Mannheim Germany"},{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Beitzen\u2010Heineke","sequence":"additional","affiliation":[{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Light Microscopy Facility (W210) German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Gensch","sequence":"additional","affiliation":[{"name":"Division of Personalized Medical Oncology (A420) German Cancer Research Center (DKFZ), German Center for Lung Research (DZL)  Heidelberg Germany"},{"name":"DKFZ\u2010Hector Cancer Institute at the University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg  Mannheim Germany"},{"name":"Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim University of Heidelberg  Mannheim Germany"},{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Loges","sequence":"additional","affiliation":[{"name":"Division of Personalized Medical Oncology (A420) German Cancer Research Center (DKFZ), German Center for Lung Research (DZL)  Heidelberg Germany"},{"name":"DKFZ\u2010Hector Cancer Institute at the University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg  Mannheim Germany"},{"name":"Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim University of Heidelberg  Mannheim Germany"},{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5036-1769","authenticated-orcid":false,"given":"Isabel","family":"Ben\u2010Batalla","sequence":"additional","affiliation":[{"name":"Division of Personalized Medical Oncology (A420) German Cancer Research Center (DKFZ), German Center for Lung Research (DZL)  Heidelberg Germany"},{"name":"DKFZ\u2010Hector Cancer Institute at the University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg  Mannheim Germany"},{"name":"Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim University of Heidelberg  Mannheim Germany"},{"name":"Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum University Comprehensive Cancer Center  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00221"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24631-6"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/15680096113139990004"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02842-y"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.613114"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01330-z"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1533033820980116"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.3653"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00211"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174444"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00622-y"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119458"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01445"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00327-8"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4220-1"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/15330338221106530"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0530-3"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.14881"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3074"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002088"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0546(08)75222-4"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.038"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.020"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.13"},{"key":"e_1_2_11_26_1","first-page":"2714","article-title":"Anti\u2010vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production","volume":"8","author":"Sweeney P","year":"2002","journal-title":"Clin Cancer Res"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.2147\/HP.S93413"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1919764117"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.689132"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.06.035"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1366-x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6918"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.iac.2014.01.002"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-498105"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-016-0408-8"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0771"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djj498"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-024-05741-2"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/1533033820926591"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101029"},{"key":"e_1_2_11_41_1","first-page":"315","article-title":"Principal long\u2010term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase","volume":"4","author":"Mughal TI","year":"2010","journal-title":"Biol Theory"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/2047-783X-16-5-206"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.4103\/0976-500X.149141"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000004934"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20600-7"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1138"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9124050"},{"key":"e_1_2_11_48_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0268244","article-title":"Treatment with a VEGFR\u20102 antibody results in intra\u2010tumor immune modulation and enhances anti\u2010tumor efficacy of PD\u2010L1 blockade in syngeneic murine tumor models","volume":"17","author":"Li Y","year":"2022","journal-title":"PLoS One"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215397109"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111607"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-bioeng-071813-105259"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-07-2527"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.10.6955"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.12608"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24066"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.144535"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2015-0108"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.553"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.35132","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T12:20:29Z","timestamp":1731500429000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.35132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,22]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/ijc.35132"],"URL":"https:\/\/doi.org\/10.1002\/ijc.35132","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,22]]},"assertion":[{"value":"2024-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}