Human Netrin-1 (netr: Sanskrit for “one who guides”) is a 75 kDa glycoprotein that is closely related to the laminin  gamma  domain and functions as a chemoattractive or chemorepulsive guidance cue in the central nervous system (CNS) during development (1, 2). The protein is synthesized as a 604 amino acid (aa) precursor that contains a 24 aa signal sequence and a 580 aa mature chain. Residues 46-283 constitute a laminin N-terminal domain (domain VI), while 285-453 make up three laminin-type epidermal growth factor‑like domains. There is a final domain that runs from aa 487-601 that qualifies as a Netrin-1 like domain. It is also known as domain C in the context of C. elegans. There are four potential sites for N‑linked glycosylation. Human Netrin-1 is 99% aa identical to mouse and rat Netrin-1. Netrin-1 is expressed in adult and embryonic tissues. In the adult, the protein is expressed in Schwann cells, oligodendrocytes and multiple neurons. In embryonic tissues, Netrin-1 is found in somatic mesoderm, heart, branchial pouch, and neuroepithelium. Netrin-1 is a secreted protein that, in addition to its involvement in outgrowth and migration orientation in the developing CNS, plays a significant role in the morphogenesis of endothelial cells and vascular smooth-muscle cells. It is also involved in the processes of cytoskeleton reorganization, angiogenesis, epithelial cell adhesion, and cell migration in the lungs, mammary gland, and pancreas (1, 3).

Netrin-1 effects are controlled through different transmembrane receptors (2). Four of the receptors exist in the Unc-5 (Unc=uncontrolled behaviorally) family of proteins, and these include Unc5h1, Unc5h2, Unc5h3/RCM, and Unc5h4. There are also two receptors that belong to the UNC-40 family of molecules. The first is DCC (deleted in colorectal cancer), and the second is neogenin (newly‑generated). UNC-5 receptors are noted to mediate the attraction response of axons and netrins. However, UNC-5 molecules, when co‑expressed with DCC in the presence of Netrin-1, will mediate repulsion by varying cellular calcium levels (3). The adenosine A2b receptor may also be involved in chemoattraction, either by binding directly with Netrin-1 or by serving as a co‑receptor for DCC. These receptors are known as dependence receptors because they depend on their ligand, in this case Netrin-1, for survival (4). Unbound, the receptors induce a specific death signal (4). It is the dysregulation of these receptor systems that may have important roles in tumor biology. DCC and UNC5 proteins make up a system for either initiating or inhibiting apoptosis (4), and it is now believed that Netrin-1 and its dependence receptors play a major role in tumor biology (4-6).