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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

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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 1

Ablation of endothelial L1 in Tie2-Cre;L1floxed mice and related effects on tumor development and mouse survival.

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Ablation of endothelial L1 in Tie2-Cre;L1floxed mice and related effects...
(A) Sections of normal pancreas and Panc02 tumors from L1floxed and Tie2-Cre;L1floxed mice were costained for L1 (green) and the vascular marker PECAM-1 (red), followed by confocal analysis. Arrows indicate vessels coexpressing PECAM-1 and L1; arrowheads indicate L1-positive nerves that served as internal control. Scale bars: 10 μm. (B and C) The volume (B) and weight (C) of pancreatic tumors from L1floxed and Tie2-Cre;L1floxed mice were recorded 14 days after Panc02 injection. Data represent mean ± SEM from 10 mice per group. (D) Images of explanted tumors. (E) Survival rates in Panc02 tumor–bearing L1floxed (n = 14) and Tie2-Cre;L1floxed mice (n = 13). **P < 0.01; ***P < 0.001.
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