Identification of a novel membrane protein, HP59, with therapeutic potential as a target of tumor angiogenesis.
CM101, a polysaccharide isolated from the culture medium of Group B streptococcus, a neonatal pathogen, targets pathological angiogenesis and inhibits tumor growth in mice and humans. CM101 also targets neonatal lung and adult sheep lung endothelial cells. A gene encoding a transmembrane protein that interacts with CM101 was isolated from a sheep lung endothelial cell cDNA library. The gene, termed sp55, encodes a 495-amino acid polypeptide. COS-7 cells transfected with a vector containing sp55 express the SP55 protein-bound CM101 in a concentration-dependent manner. Stably transfected CHO cells also bound CM101. The corresponding human gene, hp59, was isolated from a human fetal lung cDNA library and had a predicted identity to SP55 of 86% over 495 amino acids. HP59 protein was shown by immunohistochemistry to be present in the pathological tumor vasculature of the lung, breast, colon, and ovary, but not in the normal vasculature, suggesting that the protein may be critical to pathological angiogenesis. The hp59 gene and/or the HP59 protein was not expressed in a variety of normal tissues, but was significantly expressed in human fetal lung, consistent with the pathophysiology of Group B streptococcus infections in neonates. Mice immunized with HP59 and SP55 peptides showed significant attenuation of tumor growth. Immunization effectively inhibited both the tumor angiogenesis and vasculogenesis processes, as evidenced by lack of both HP59- and CD34-positive vessels. These results and the immunohistochemistry data suggest a therapeutic potential for the CM101 target protein HP59 both as a drug target and as a vaccine against pathoangiogenesis.
Fu
C
C
Department of Biochemistry, Vanderbilt University, 23rd at Pierce, Nashville, TN 37232, USA.
Bardhan
S
S
Cetateanu
N D
ND
Wamil
B D
BD
Wang
Y
Y
Yan
H P
HP
Shi
E
E
Carter
C
C
Venkov
C
C
Yakes
F M
FM
Page
D L
DL
Lloyd
R S
RS
Mernaugh
R L
RL
Hellerqvist
C G
CG
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D019921:Biotinylation; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D004730:Endothelium, Vascular; D015723:Gene Library; D015698:Genomic Library; D006801:Humans; D008168:Lung; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000032:analysis* / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D027361:Organic Anion Transporters; D011135:Polysaccharides, Bacterial / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011652:Pulmonary Circulation / Q000502:physiology*; D015183:Restriction Mapping; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012756:Sheep; D027981:Symporters; D014162:Transfection; D014841:von Willebrand Factor / Q000032:analysis
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D027361:Organic Anion Transporters; D011135:Polysaccharides, Bacterial; D027981:Symporters; C421224:sialic acid transport proteins; C032263:streptococcal polysaccharide type III group B; D014841:von Willebrand Factor