title: 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.affiliation: INSERM U965 (Paris 7 University), Hôpital Lariboisière, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Eveno
authors.forename: Dong
authors.initials: D
authors.lastname: Broqueres-You
authors.forename: Jean-Guillaume
authors.initials: JG
authors.lastname: Feron
authors.forename: Aurore
authors.initials: A
authors.lastname: Rampanou
authors.forename: Annemilaï
authors.initials: A
authors.lastname: Tijeras-Raballand
authors.forename: Stanislas
authors.initials: S
authors.lastname: Ropert
authors.forename: Laurence
authors.initials: L
authors.lastname: Leconte
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Levy
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D015179:Colorectal Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D000075385:Netrins; D011509:Proteoglycans / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen