title: Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization.
abstract: While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6-mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies.
authors.forename: Elena
authors.initials: E
authors.lastname: Magrini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Villa
authors.forename: Francesca
authors.initials: F
authors.lastname: Angiolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Doni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.forename: Noemi
authors.initials: N
authors.lastname: Rudini
authors.forename: Luigi
authors.initials: L
authors.lastname: Maddaluno
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.forename: Baki
authors.initials: B
authors.lastname: Topal
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bianchi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
mesh_terms: D000818:Animals; D001808:Blood Vessels; D002199:Capillary Permeability; D002277:Carcinoma / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006391:Hemangioma / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010539:Permeability; D010641:Phenotype; D034622:RNA Interference; D042787:Receptor, TIE-2 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D039842:Neural Cell Adhesion Molecule L1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse