{"doi":"10.3390/cells13221835","title":"Modeling Lymphoma Angiogenesis, Lymphangiogenesis, and Vessel Co-Option, and the Effects of Inhibition of Lymphoma–Vessel Interactions with an αCD20-EndoP125A Antibody Fusion Protein","abstract":"Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma-vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma-vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine-chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination.","journal":"Cells","year":2024,"id":482103,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1322418,"name":"Yu Zhang","orcid":"0000-0003-1375-1594","position":1,"is_corresponding":false},{"id":1322419,"name":"Seung-Uon Shin","orcid":"0009-0000-3458-4380","position":2,"is_corresponding":false},{"id":1322420,"name":"Hyun‐Mi Cho","orcid":"0000-0001-7307-7963","position":3,"is_corresponding":false},{"id":313792,"name":"Sundaram Ramakrishnan","orcid":"0000-0002-3102-9231","position":4,"is_corresponding":false},{"id":1322421,"name":"Ankita P. Sankar","orcid":"0009-0005-0344-8008","position":5,"is_corresponding":false},{"id":355509,"name":"Jennifer R. Chapman","orcid":"0000-0002-6214-4152","position":6,"is_corresponding":false},{"id":675334,"name":"Daniel Bilbao","orcid":"0000-0003-1630-8811","position":7,"is_corresponding":false},{"id":1322422,"name":"Rathin Das","orcid":"0009-0008-6109-7914","position":8,"is_corresponding":false},{"id":758351,"name":"Hava Gil-Henn","orcid":"0000-0003-4064-0478","position":9,"is_corresponding":false},{"id":35668,"name":"Izidore S. Lossos","orcid":"0000-0002-9346-9013","position":10,"is_corresponding":false},{"id":799041,"name":"Joseph D. Rosenblatt","orcid":"0000-0003-0798-0403","position":11,"is_corresponding":false},{"id":1322417,"name":"Christian Elledge","orcid":"0009-0007-1725-0662","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:07:14.349221Z","pmid":"39594584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}