Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Elena Magrini, Alessandra Villa, Francesca Angiolini, Andrea Doni, Giovanni Mazzarol, Noemi Rudini, Luigi Maddaluno, Mina Komuta, Baki Topal, Hans Prenen, Melitta Schachner, Stefano Confalonieri, Elisabetta Dejana, Fabrizio Bianchi, Massimiliano Mazzone, Ugo Cavallaro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4335-4350
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Magrini, E., Villa, A., Angiolini, F., Doni, A., Mazzarol, G., Rudini, N., Maddaluno, L., Komuta, M., Topal, B., Prenen, H., Schachner, M., Confalonieri, S., Dejana, E., Bianchi, F., Mazzone, M., & Cavallaro, U. (2014). Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization. Journal of Clinical Investigation, 124(10), 4335-4350. https://doi.org/10.1172/JCI70683