Netrin-4 regulates angiogenic responses and tumor cell growth

• Published in: Experimental cell research 2009-03, Vol.315 (5), p.784-794
• Main Authors: Nacht, Mariana, St. Martin, Thia B., Byrne, Ann, Klinger, Katherine W., Teicher, Beverly A., Madden, Stephen L., Jiang, Yide
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Akt; AMINO ACIDS; Angiogenesis; BRANCHING RATIO; Cell Differentiation - drug effects; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Cells, Cultured; Cellular biology; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; ELONGATION; Endothelial Cells - drug effects; Endothelial Cells - physiology; GROWTH; Humans; IN VITRO; Jnk; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; LUNGS; MAMMARY GLANDS; MOLECULES; MORPHOGENESIS; NEOPLASMS; Neoplasms - blood supply; Neoplasms - genetics; Neoplasms - pathology; Neovascularization, Pathologic - genetics; Nerve Growth Factors - genetics; Nerve Growth Factors - pharmacology; Nerve Growth Factors - physiology; Netrin-4; Netrins; Oncogene Protein v-akt - antagonists & inhibitors; PANCREAS; PHOSPHORYLATION; Proteins; RNA, Messenger - metabolism; Signal Transduction - drug effects; TUMOR CELLS; Tumors
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2008.11.018

Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.