{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:15:13Z","timestamp":1760238913822,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,11]],"date-time":"2020-09-11T00:00:00Z","timestamp":1599782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["20614","16722"],"award-info":[{"award-number":["20614","16722"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Milano","award":["Linea 2B - 2017"],"award-info":[{"award-number":["Linea 2B - 2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1\u20132 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines\u2019 ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients\u2019 BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.<\/jats:p>","DOI":"10.3390\/cancers12092600","type":"journal-article","created":{"date-parts":[[2020,9,11]],"date-time":"2020-09-11T09:05:16Z","timestamp":1599815116000},"page":"2600","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0867-9527","authenticated-orcid":false,"given":"Maria Teresa","family":"Palano","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"given":"Domenica","family":"Giannandrea","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"given":"Natalia","family":"Platonova","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"given":"Germano","family":"Gaudenzi","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Laboratory of Geriatric and Oncologic Neuroendocrinology Research, 20095 Cusano Milanino, Italy"}]},{"given":"Monica","family":"Falleni","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6130-2665","authenticated-orcid":false,"given":"Delfina","family":"Tosi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9096-713X","authenticated-orcid":false,"given":"Elena","family":"Lesma","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0289-404X","authenticated-orcid":false,"given":"Valentina","family":"Citro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2252-1424","authenticated-orcid":false,"given":"Michela","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7639-518X","authenticated-orcid":false,"given":"Ilaria","family":"Saltarella","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1515-0090","authenticated-orcid":false,"given":"Roberto","family":"Ria","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124 Bari, Italy"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4940-1318","authenticated-orcid":false,"given":"Elisa","family":"Taiana","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milano. Hematology, Fondazione Ca\u2019 Granda IRCCS Policlinico, 20122 Milano, Italy"}]},{"given":"Antonino","family":"Neri","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milano. Hematology, Fondazione Ca\u2019 Granda IRCCS Policlinico, 20122 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2478-683X","authenticated-orcid":false,"given":"Giovanni","family":"Vitale","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Laboratory of Geriatric and Oncologic Neuroendocrinology Research, 20095 Cusano Milanino, Italy"},{"name":"Department of Clinical Sciences and Community Health (DISCCO), University of Milan, 20122 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1078-1704","authenticated-orcid":false,"given":"Raffaella","family":"Chiaramonte","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milano, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-3-319-40320-5_5","article-title":"Role of Endothelial Cells and Fibroblasts in Multiple Myeloma Angiogenic Switch","volume":"169","author":"Ribatti","year":"2016","journal-title":"Cancer Treat. 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PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182640"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/9\/2600\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:08Z","timestamp":1760177348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/9\/2600"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,11]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["cancers12092600"],"URL":"https:\/\/doi.org\/10.3390\/cancers12092600","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2020,9,11]]}}}