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.

• Authors: S Dias, K Hattori, B Heissig, Z Zhu, Y Wu, L Witte, D J Hicklin, M Tateno, P Bohlen, M A Moore, S Rafii
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 19 Pg. 10857-62 (Sep 11 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11553814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endothelial Growth Factors
• Lymphokines
• Receptors, Growth Factor
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Receptor Protein-Tyrosine Kinases
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Autocrine Communication
• Cell Division
• Cells, Cultured
• Coculture Techniques
• Endothelial Growth Factors (metabolism)
• Endothelium, Vascular (cytology, metabolism)
• HL-60 Cells
• Humans
• Leukemia, Promyelocytic, Acute (metabolism, physiopathology)
• Lymphokines (metabolism)
• Mice
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Neoplasms, Experimental (metabolism, physiopathology)
• Neovascularization, Pathologic (physiopathology)
• Paracrine Communication
• Receptor Protein-Tyrosine Kinases (metabolism)
• Receptors, Growth Factor (metabolism)
• Receptors, Vascular Endothelial Growth Factor
• Signal Transduction
• Time Factors
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors