Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias Journal Article
| Authors: | Dias, S.; Hattori, K.; Heissig, B.; Zhu, Z.; Wu, Y.; Witte, L.; Hicklin, D. J.; Tateno, M.; Bohlen, P.; Moore, M. A. S.; Rafii, S. |
| Article Title: | Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias |
| Abstract: | 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 in vivo, 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. |
| Keywords: | signal transduction; vasculotropin; cancer survival; controlled study; treatment outcome; vascular endothelial growth factor a; leukemia; unclassified drug; cancer growth; nonhuman; receptors, vascular endothelial growth factor; mouse; animals; mice; animal tissue; cells, cultured; cell division; vasculotropin receptor; animal experiment; animal model; in vivo study; tumor xenograft; vasculotropin receptor 2; angiogenesis; neovascularization, pathologic; time factors; leukemia, promyelocytic, acute; cancer regression; endothelium, vascular; neoplasms, experimental; transplantation, heterologous; autocrine effect; paracrine signaling; autocrine communication; neoplasm invasiveness; receptor protein-tyrosine kinases; neoplasm transplantation; vasculotropin antibody; receptors, growth factor; coculture techniques; paracrine communication; monoclonal antibody dc101; receptor antibody; vascular endothelial growth factors; endothelial growth factors; hl-60 cells; humans; male; female; priority journal; article; lymphokines; monoclonal antibody imc 1c11 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 98 |
| Issue: | 19 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2001-09-11 |
| Start Page: | 10857 |
| End Page: | 10862 |
| Language: | English |
| DOI: | 10.1073/pnas.191117498 |
| PUBMED: | 11553814 |
| PROVIDER: | scopus |
| PMCID: | PMC58564 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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