{"doi":"10.1073/pnas.191117498","title":"Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias","abstract":"<jats:p>\n            Antiangiogenic agents block the effects of tumor-derived angiogenic factors (paracrine factors), such as vascular endothelial growth factor (VEGF), on endothelial cells (EC), inhibiting the growth of solid tumors. However, whether inhibition of angiogenesis also may play a role in liquid tumors is not well established. We recently have shown that certain leukemias not only produce VEGF but also selectively express functional VEGF receptors (VEGFRs), such as VEGFR-2 (Flk-1, KDR) and VEGFR1 (Flt1), resulting in the generation of an autocrine loop. Here, we examined the relative contribution of paracrine (EC-dependent) and autocrine (EC-independent) VEGF/VEGFR signaling pathways, by using a human leukemia model, where autocrine and paracrine VEGF/VEGFR loops could be selectively inhibited by neutralizing mAbs specific for murine EC (paracrine pathway) or human tumor (autocrine) VEGFRs. Blocking either the paracrine or the autocrine VEGF/VEGFR-2 pathway delayed leukemic growth and engraftment\n            <jats:italic>in vivo</jats:italic>\n            , but failed to cure inoculated mice. Long-term remission with no evidence of disease was achieved only if mice were treated with mAbs against both murine and human VEGFR-2, whereas mAbs against human or murine VEGFR-1 had no effect on mice survival. Therefore, effective antiangiogenic therapies to treat VEGF-producing, VEGFR-expressing leukemias may require blocking both paracrine and autocrine VEGF/VEGFR-2 angiogenic loops to achieve remission and long-term cure.\n          </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2001,"id":16323,"datarank":12.960761362942057,"base_score":5.598421958998375,"endowment":5.598421958998375,"self_citation_contribution":0.8397632938497563,"citation_network_contribution":12.1209980690923,"self_endowment_contribution":0.8397632938497563,"citer_contribution":12.1209980690923,"corpus_percentile":null,"corpus_rank":null,"citation_count":269,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":120897,"name":"Koichi Hattori","orcid":null,"position":1,"is_corresponding":false},{"id":120898,"name":"Beate Heissig","orcid":null,"position":2,"is_corresponding":false},{"id":120899,"name":"Zhenping Zhu","orcid":null,"position":3,"is_corresponding":false},{"id":58894,"name":"Yan Wu","orcid":"0000-0002-8874-8886","position":4,"is_corresponding":false},{"id":120900,"name":"Larry Witte","orcid":null,"position":5,"is_corresponding":false},{"id":120901,"name":"Daniel J. Hicklin","orcid":null,"position":6,"is_corresponding":false},{"id":120902,"name":"Masatoshi Tateno","orcid":null,"position":7,"is_corresponding":false},{"id":120903,"name":"Peter Bohlen","orcid":null,"position":8,"is_corresponding":false},{"id":120905,"name":"Malcolm A. S. Moore","orcid":null,"position":9,"is_corresponding":false},{"id":120906,"name":"Shahin Rafii","orcid":null,"position":10,"is_corresponding":false},{"id":120896,"name":"Sergio Dias","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.598421958998375,"endowment":5.598421958998375,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"11553814","pmcid":"PMC58564","openalex_id":"https://openalex.org/W2015867957","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL-61401","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL-61849","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL061849","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL-58707","title":null}],"total_grants":4,"fwci":6.167,"citation_percentile":0.97231035,"influential_citations":3,"citation_trend":[{"year":2012,"count":8},{"year":2013,"count":10},{"year":2014,"count":5},{"year":2015,"count":11},{"year":2016,"count":12},{"year":2017,"count":5},{"year":2018,"count":4},{"year":2019,"count":3},{"year":2020,"count":8},{"year":2021,"count":5},{"year":2022,"count":6},{"year":2023,"count":7},{"year":2024,"count":5},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/58564","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc58564?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/58564","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.191117498","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.191117498","host_type":"journal"}],"fields_of_study":["Angiogenesis and VEGF in Cancer","Cancer, Hypoxia, and Metabolism","PI3K/AKT/mTOR signaling in cancer","Biology","Medicine","Animals","Autocrine Communication","Cell Division","Cells, Cultured","Coculture Techniques","Endothelial Growth Factors","Endothelium, Vascular","HL-60 Cells","Humans","Leukemia, Promyelocytic, Acute","Lymphokines","Mice","Neoplasm Invasiveness","Neoplasm Transplantation","Neoplasms, Experimental","Neovascularization, Pathologic","Paracrine Communication","Receptor Protein-Tyrosine Kinases","Receptors, Growth Factor","Receptors, Vascular Endothelial Growth Factor","Signal Transduction","Time Factors","Transplantation, Heterologous","Vascular Endothelial Growth Factor A","Vascular Endothelial Growth Factors"],"mesh_terms":["Endothelium, Vascular","Cells, Cultured","HL-60 Cells","Animals","Humans","Mice","Leukemia, Promyelocytic, Acute","Neoplasms, Experimental","Neoplasm Invasiveness","Neovascularization, Pathologic","Receptor Protein-Tyrosine Kinases","Receptors, Vascular Endothelial Growth Factor","Vascular Endothelial Growth Factors","Vascular Endothelial Growth Factor A","Endothelial Growth Factors","Receptors, Growth Factor","Lymphokines","Transplantation, Heterologous","Coculture Techniques","Neoplasm Transplantation","Autocrine Communication","Paracrine Communication","Signal Transduction","Cell Division","Time Factors"],"keywords":["Autocrine signalling","Paracrine signalling","Cancer research","Angiogenesis","Vascular endothelial growth factor","Kinase insert domain receptor","Vascular endothelial growth factor A","Biology","Internal medicine","Receptor","Medicine","VEGF receptors"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-01T21:27:25.289404Z","pmid":null,"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,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}