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Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.

Schwarz MA, Kandel J, Brett J, Li J, Hayward J, Schwarz RE, Chappey O, Wautier JL, Chabot J, Lo Gerfo P, Stern D - J. Exp. Med. (1999)

Bottom Line: Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York 10032, USA. mschwarz@chla.usc.edu

ABSTRACT
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.

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Corneal neoangiogenesis model: effect of rEMAP II on bFGF-induced neovascularization. Hydron pellets containing bFGF (≈90 ng) were implanted in corneal pockets. Mice were then treated with EMAP II (2 μg i.p. every 24 h for 5 d; B) or vehicle (A), and the corneal neovascular response was assessed. The total number of neovessels originating in the limbus was counted (C; *P < 0.003), and the area of neovascularization was calculated (D; *P < 0.002). Data shown are the results of 16 observations in 8 animals in each of the experimental groups, for a total of 32 observations in 16 animals. The experiment was repeated twice.
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Figure 3: Corneal neoangiogenesis model: effect of rEMAP II on bFGF-induced neovascularization. Hydron pellets containing bFGF (≈90 ng) were implanted in corneal pockets. Mice were then treated with EMAP II (2 μg i.p. every 24 h for 5 d; B) or vehicle (A), and the corneal neovascular response was assessed. The total number of neovessels originating in the limbus was counted (C; *P < 0.003), and the area of neovascularization was calculated (D; *P < 0.002). Data shown are the results of 16 observations in 8 animals in each of the experimental groups, for a total of 32 observations in 16 animals. The experiment was repeated twice.

Mentions: In view of our previous in vitro studies with EMAP II 56, in which it initially appeared to have properties of an inflammatory mediator, the results of these experiments in the Matrigel model were unexpected. This led us to confirm these observations in another neovascularization model, namely that using the mouse cornea 16. For these studies, bFGF was incorporated into slow-release polymer pellets (Hydron) which were implanted into corneal pockets of mice. Animals then received rEMAP II (2 μg/d every 24 h) or vehicle alone intraperitoneally for 5 d. Corneal neovascularization was evident in animals receiving vehicle (Fig. 3 A), and was markedly suppressed by treatment with rEMAP II (Fig. 3 B). This initial impression was confirmed by counting the number of neovessels originating in the limbus (Fig. 3 C) and by determining the area of corneal neovascularization (Fig. 3 D); in each case, ≈60% suppression of vessel ingrowth was observed. Taken together, these data in the Matrigel implant and corneal neovascularization models suggested that rEMAP II had the capacity to suppress neovessel formation in response to bFGF.


Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.

Schwarz MA, Kandel J, Brett J, Li J, Hayward J, Schwarz RE, Chappey O, Wautier JL, Chabot J, Lo Gerfo P, Stern D - J. Exp. Med. (1999)

Corneal neoangiogenesis model: effect of rEMAP II on bFGF-induced neovascularization. Hydron pellets containing bFGF (≈90 ng) were implanted in corneal pockets. Mice were then treated with EMAP II (2 μg i.p. every 24 h for 5 d; B) or vehicle (A), and the corneal neovascular response was assessed. The total number of neovessels originating in the limbus was counted (C; *P < 0.003), and the area of neovascularization was calculated (D; *P < 0.002). Data shown are the results of 16 observations in 8 animals in each of the experimental groups, for a total of 32 observations in 16 animals. The experiment was repeated twice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195582&req=5

Figure 3: Corneal neoangiogenesis model: effect of rEMAP II on bFGF-induced neovascularization. Hydron pellets containing bFGF (≈90 ng) were implanted in corneal pockets. Mice were then treated with EMAP II (2 μg i.p. every 24 h for 5 d; B) or vehicle (A), and the corneal neovascular response was assessed. The total number of neovessels originating in the limbus was counted (C; *P < 0.003), and the area of neovascularization was calculated (D; *P < 0.002). Data shown are the results of 16 observations in 8 animals in each of the experimental groups, for a total of 32 observations in 16 animals. The experiment was repeated twice.
Mentions: In view of our previous in vitro studies with EMAP II 56, in which it initially appeared to have properties of an inflammatory mediator, the results of these experiments in the Matrigel model were unexpected. This led us to confirm these observations in another neovascularization model, namely that using the mouse cornea 16. For these studies, bFGF was incorporated into slow-release polymer pellets (Hydron) which were implanted into corneal pockets of mice. Animals then received rEMAP II (2 μg/d every 24 h) or vehicle alone intraperitoneally for 5 d. Corneal neovascularization was evident in animals receiving vehicle (Fig. 3 A), and was markedly suppressed by treatment with rEMAP II (Fig. 3 B). This initial impression was confirmed by counting the number of neovessels originating in the limbus (Fig. 3 C) and by determining the area of corneal neovascularization (Fig. 3 D); in each case, ≈60% suppression of vessel ingrowth was observed. Taken together, these data in the Matrigel implant and corneal neovascularization models suggested that rEMAP II had the capacity to suppress neovessel formation in response to bFGF.

Bottom Line: Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York 10032, USA. mschwarz@chla.usc.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus