Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.
Neovascularization is essential for growth and spread of primary and metastatic tumors. We have identified a novel cytokine, endothelial-monocyte activating polypeptide (EMAP) II, that potently inhibits tumor growth, and appears to have antiangiogenic activity. Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001). Neovascularization of the mouse cornea was similarly prevented by EMAP II (P < 0.003). Intraperitoneally administered EMAP II suppressed the growth of primary Lewis lung carcinomas, with a reduction in tumor volume of 65% versus controls (P < 0.003). Tumors from human breast carcinoma-derived MDA-MB 468 cells were suppressed by >80% in EMAP II-treated animals (P < 0.005). In a lung metastasis model, EMAP II blocked outgrowth of Lewis lung carcinoma macrometastases; total surface metastases were diminished by 65%, and of the 35% metastases present, approximately 80% were inhibited with maximum diameter <2 mm (P < 0.002 vs. controls). In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner, whereas other cell types were unaffected. These data suggest that EMAP II is a tumor-suppressive mediator with antiangiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature.
Schwarz
M A
MA
Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York 10032, USA. mschwarz@chla.usc.edu
Kandel
J
J
Brett
J
J
Li
J
J
Hayward
J
J
Schwarz
R E
RE
Chappey
O
O
Wautier
J L
JL
Chabot
J
J
Lo Gerfo
P
P
Stern
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018827:Carcinoma, Lewis Lung; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006131:Growth Inhibitors / Q000097:blood / Q000235:genetics / Q000493:pharmacokinetics / Q000502:physiology*; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000493:pharmacokinetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D016601:RNA-Binding Proteins / Q000097:blood / Q000235:genetics / Q000493:pharmacokinetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology*
D016207:Cytokines; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C077219:small inducible cytokine subfamily E, member 1; D016222:Fibroblast Growth Factor 2