Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model.
Host antiangiogenesis factors defend against tumor growth. The matricellular protein, thrombospondin-2 (TSP-2), has been shown to act as an antiangiogenesis factor in a carcinogen-induced model of skin cancer. Here, using an in vivo malignant glioma model in which the characteristics of the tumors formed after intracerebral implantation of GL261 mouse glioma cells are assessed, we found that tumor growth and microvessel density were significantly enhanced in tumors propagated in TSP-2(-/-) mice. Mechanistically, matrix metalloproteinase (MMP)-2 has been associated with neoangiogenesis and it has been proposed that the levels of available MMP-2 may be down-regulated by formation of a complex with TSP-2 that is internalized by low-density lipoprotein receptor-related protein 1 (LRP1). We found elevated expression of MMP-2 and MMP-9 in tumors propagated in TSP-2(-/-) mice, with a preferential localization in the microvasculature. In wild-type mice, MMP-2 was coexpressed with TSP-2 in the tumor microvasculature. In vitro, addition of recombinant (rec) TSP-2 to mouse brain microvessel endothelial cells reduced MMP-2 levels and invasion through mechanisms that could be inhibited by a competitive inhibitor of ligand binding to LRP1 or by siLRP1. Thus, the antiangiogenic activity of TSP-2 is capable of inhibiting the growth of gliomas in part by reducing the levels of MMP-2 in the tumor microvasculature. This mechanism is mediated by LRP1.
Fears
Constance Y
CY
Departments of Pathology and Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Grammer
J Robert
JR
Stewart
Jerry E
JE
Annis
Douglas S
DS
Mosher
Deane F
DF
Bornstein
Paul
P
Gladson
Candece L
CL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D019699:Thrombospondins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099262:Thrombospondin 2
D017077:Culture Media, Conditioned; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D011973:Receptors, LDL; D019699:Thrombospondins; D025521:Tumor Suppressor Proteins; D000099262:Thrombospondin 2; C486645:Lrp1 protein, mouse