Netrin-4 delays colorectal cancer carcinomatosis by inhibiting tumor angiogenesis.

Abstract

A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor-induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.

• Authors: Clarisse Eveno, Dong Broqueres-You, Jean-Guillaume Feron, Aurore Rampanou, Annemilaï Tijeras-Raballand, Stanislas Ropert, Laurence Leconte, Bernard I Levy, Marc Pocard
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 4 Pg. 1861-9 (Apr 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21406174 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Drug Combinations
• Laminin
• NTN4 protein, human
• Nerve Growth Factors
• Netrins
• Proteoglycans
• matrigel
• Collagen

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Carcinoma (pathology)
• Cell Line, Tumor
• Collagen (chemistry)
• Colorectal Neoplasms (metabolism)
• Disease Progression
• Drug Combinations
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Laminin (chemistry)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Nerve Growth Factors (biosynthesis, physiology)
• Netrins
• Proteoglycans (chemistry)