title: Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo.
abstract: Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, 400 East 34th St., New York, NY 10016, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Roth
authors.forename: Abebe
authors.initials: A
authors.lastname: Akalu
authors.forename: Anat
authors.initials: A
authors.lastname: Zelmanovich
authors.forename: Desiree
authors.initials: D
authors.lastname: Policarpio
authors.forename: Bruce
authors.initials: B
authors.lastname: Ng
authors.forename: Shannon
authors.initials: S
authors.lastname: MacDonald
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Peter C
authors.initials: PC
authors.lastname: Brooks
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002642:Chick Embryo; D024141:Collagen Type IV / Q000737:chemistry* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D012878:Skin Neoplasms / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D008024:Ligands; D011994:Recombinant Proteins
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