A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation.
Angiomatous lesions are common in infants and children. Hemangioendotheliomas (HE) represent one type of these lesions. Endothelial cell proliferation and the development of vascular/blood cell-filled spaces are inherent in the growth of HE. Therefore, understanding mechanisms that regulate the proliferation of these lesions should provide key insight into mechanisms regulating angiogenesis. A murine model was used to test the significance of monocyte chemoattractant protein (MCP)-1 in HE proliferation. EOMA cells, a cell line derived from a spontaneously arising murine HE, generate these lesions with 100% efficiency when injected subcutaneously into syngeneic mice. MCP-1 produced by EOMA cells recruit macrophages, which were shown to induce angiogenic behavior in EOMA cells by stimulating transwell migration and inducing sprout formation on type I collagen gels. When EOMA cells were injected into MCP-1(-/-) mice, only 50% of the mice developed tumors, presumably because the low levels of MCP-1 expressed by the injected EOMA cells were enough to overcome any host deficits of this chemokine. When EOMA cells were coinjected with a neutralizing antibody to MCP-1, tumors failed to develop in any of the treated mice, including syngeneic 129P3, C57Bl/6 (wild type), and MCP-1(-/-). These results present the first evidence that MCP-1 is required for HE proliferation and may promote the growth of these lesions by stimulating angiogenic behavior of endothelial cells. This study has produced the first in vivo evidence of a complete response for any neoplasm, specifically a vascular proliferative lesion, to anti-MCP-1 therapy in animals with intact immune systems.
Gordillo
Gayle M
GM
Division of Plastic Surgery, The Ohio State University Medical Center, 410 W. 10th Ave., Columbus, OH 43210, USA. gordillo-1@medctr.osu.edu
Onat
Duygu
D
Stockinger
Michael
M
Roy
Sashwati
S
Atalay
Mustafa
M
Beck
F Michael
FM
Sen
Chandan K
CK
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000502:physiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006390:Hemangioendothelioma / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*
D018932:Chemokine CCL2