Targeted disruption of heparan sulfate interaction with hepatocyte and vascular endothelial growth factors blocks normal and oncogenic signaling.
Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) regulate normal development and homeostasis and drive disease progression in many forms of cancer. Both proteins signal by binding to receptor tyrosine kinases and heparan sulfate (HS) proteoglycans on target cell surfaces. Basic residues comprising the primary HS binding sites on HGF and VEGF provide similar surface charge distributions without underlying structural similarity. Combining three acidic amino acid substitutions in these sites in the HGF isoform NK1 or the VEGF isoform VEGF165 transformed each into potent, selective competitive antagonists of their respective normal and oncogenic signaling pathways. Our findings illustrate the importance of HS in growth factor driven cancer progression and reveal an efficient strategy for therapeutic antagonist development.
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1501, USA.
Fabiola
F
Cecchi
Deborah
D
Pajalunga
C Andrew
CA
Fowler
Aykut
A
Uren
Daniel C
DC
Rabe
Benedetta
B
Peruzzi
Nicholas J
NJ
Macdonald
Davida K
DK
Blackman
Stephen J
SJ
Stahl
R Andrew
RA
Byrd
Donald P
DP
Bottaro
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D018390:Gene Targeting; D006497:Heparan Sulfate / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D018952:Antigens, CD34; D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D020033:Protein Isoforms; D019859:Proto-Oncogene Proteins c-met; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human