Endothelial-monocyte activating polypeptide II, a novel anti-tumor 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. From murine methylcholanthrene A-induced fibrosarcomas, well-known for their spontaneous vascular insufficiency, we have identified and purified a novel cytokine, Endothelial-Monocyte Activating Polypeptide (EMAP) II, that potently inhibits tumor growth in vivo, and appears to have anti-angiogenic activity in vivo and in vitro. Mice implanted with a matrix containing basic fibroblast growth factor showed an intense local angiogenic response which EMAP II blocked by 76% (p<0.001). Intraperitoneally administered recombinant EMAP II suppressed the primary Lewis Lung Carcinomas, with a reduction in tumor volume of 65% compared with controls (p<0.003 by Mann-Whitney). In a lung metastasis model, EMAP II blocked outgrowth of Lewis Lung carcinoma macrometastases; total surface metastases were suppressed by 65%, and of the 35% metastases present, about 80% of these were inhibited with maximum diameter <2mm (p<0.002 compared with controls). In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner; an effect enhanced by concomitant hypoxia, whereas other cell types, such as Lewis Lung carcinoma cells, were unaffected. These data suggest that EMAP II is a tumor-suppressive mediator with anti-angiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature.