Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization
Elena Magrini, … , Massimiliano Mazzone, Ugo Cavallaro
Elena Magrini, … , Massimiliano Mazzone, Ugo Cavallaro
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4335-4350. https://doi.org/10.1172/JCI70683.
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Research Article

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

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

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Figure 4

L1 confers an angiogenic phenotype to ECs and enhances endothelial permeability.

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L1 confers an angiogenic phenotype to ECs and enhances endothelial perme...
(A) Proliferation curves of mock- and L1-transfected luECs. (B) Growth curves of hemangiomas formed by mock- or L1-transfected luECs injected subcutaneously into nude mice, as determined by volume measurement at the indicated time points. Representative images of hemangiomas explanted are shown (insets). (C) Weight of hemangiomas explanted 33 days after injection of mock- or L1-transfected luECs. (D) Migration assays of mock- and L1-transfected luECs were performed as described in Methods. (E) Matrigel-based tube formation assays of mock- and L1-transfected luECs were performed as described in Methods. (F) Mock- or L1-transfected luECs were stained for PECAM-1 (red) or VE-cadherin (green) prior to confocal analysis. Scale bars: 10 μm. (G) qRT-PCR analysis of claudin-5 mRNA in mock- and L1-transfected luECs. Transcript levels were normalized as described in Methods and are shown as fold changes in L1-transfected cells relative to mock-transfected cells (n = 3). (H) FITC-dextran permeability assays were performed on monolayers of mock- and L1-transfected luECs as described in Methods. Data in A, D, E, and H represent the mean ± SD from a representative experiment performed at least in triplicate. Data in B and C represent mean ± SEM from 10 to 12 mice per group. *P < 0.05; **P < 0.01; ***P < 0.001.