Inhibition of angiogenesis and tumor metastasis by targeting a matrix immobilized cryptic extracellular matrix epitope in laminin.
Angiogenesis and tumor metastasis depend on extracellular matrix (ECM) remodeling and subsequent cellular interactions with these modified proteins. An in-depth understanding of how both endothelial and tumor cells use matrix-immobilized cryptic ECM epitopes to regulate invasive cell behavior may lead to the development of novel strategies for the treatment of human tumors. However, little is known concerning the existence and the functional significance of cryptic laminin epitopes in regulating angiogenesis and tumor cell metastasis. Here, we report the isolation and characterization of a synthetic peptide that binds to a cryptic epitope in laminin. The STQ peptide selectively bound denatured and proteolyzed laminin but showed little interaction with native laminin. The cryptic laminin epitope recognized by this peptide was selectively exposed within malignant melanoma in vivo, whereas little if any was detected in normal mouse skin. Moreover, the STQ peptide selectively inhibited endothelial and tumor cell adhesion, migration, and proliferation in vitro and inhibited angiogenesis, tumor growth, and experimental metastasis in vivo. This inhibitory activity was associated with a selective up-regulation of the cyclin-dependent kinase inhibitor P27(KIP1) and induction of cellular senescence. These novel findings suggest the existence of functionally relevant cryptic laminin epitopes in vivo and that selective targeting of these laminin epitopes may represent an effective new strategy for the treatment of malignant tumors by affecting both the endothelial and tumor cell compartments.
Akalu
Abebe
A
Department of Radiation Oncology, New York University School of Medicine, New York, New York 10016, USA.
Roth
Jennifer M
JM
Caunt
Maresa
M
Policarpio
Desiree
D
Liebes
Leonard
L
Brooks
Peter C
PC
D000818:Animals; D017104:Bacteriophage M13 / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005109:Extracellular Matrix / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000098:blood supply* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011489:Protein Denaturation
D000939:Epitopes; D007797:Laminin; D010455:Peptides; D050760:Cyclin-Dependent Kinase Inhibitor p27