Journal of the National Cancer Institute Advance Access originally published online on February 10, 2009
JNCI Journal of the National Cancer Institute 2009 101(4):217-219; doi:10.1093/jnci/djn511
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© The Author 2009. Published by Oxford University Press.
EDITORIALS |
To Die or Not to Die, That's the Question—And the Answer May Depend on Netrin-1
Affiliations of authors: Department of Dermatology and Venereology (MPS) and Department of Molecular and Cellular Immunology (MS), Georg August University, Göttingen, Germany
Correspondence to: Michael P. Schön, MD, Department of Dermatology and Venereology, Georg August University, Von-Siebold-Str 3, 37075 Göttingen, Germany (e-mail: michael.schoen{at}med.uni-goettingen.de).
Dependence Receptors
Few fields in oncology highlight the excitement towards potential new therapies as vividly as targeted manipulations of signaling pathways, although the clinical outcome of several such therapies has been sobering. Over the past decade, there has been increasing appreciation of the concept of dependence receptors, ie, receptors that induce a specific death signal when their ligand is absent, and another (survival) signal when ligand is bound. The presence of these receptors leads to the cell becoming "dependent" on the presence of the ligand for its survival. The group of dependence receptors includes the integrins 
5β1 and vβ3 (1), the p75 neurotrophin receptor (p75NTR) (2), Patched (the human homolog of a Drosophila segment polarity gene) (3), RET (rearranged during transfection) (4) and the netrin-1 receptors DCC (deleted in colorectal cancer) and UNC5 (a family of several homologous receptors) (5). Such receptor systems, if dysregulated, may have important roles in tumor biology, although most were discovered in other systems, where they regulate development, proliferation or migration of cells.
Dual Role for Netrin-1 in Axon Guidance and Tumor Progression
Netrin-1 and its receptors, DCC and UNC5 proteins, constitute such a system for either induction or suppression of apoptosis (5,6). DCC (with the adenosine A2B receptor as coreceptor) and UNC5 proteins act as dependence receptors that induce apoptotic cell death unless their ligand, netrin-1, is present. Netrin-1 is a secreted, laminin-related protein that was discovered because of its ability to direct the migration of neuronal axons in the developing spinal cord (7,8). The functions of netrin proteins in axon guidance have been extensively studied (9,10).
Over the past decade, evidence has accumulated indicating that the system of netrin-1 and its receptors has an equally important role in tumor biology (11). Indeed, as first demonstrated in colorectal tumors, in some human cancers the proapoptotic signaling pathway of the netrin-1 system is inactivated. Under normal conditions, for example, netrin-1 contributes to the homeostasis of the intestinal epithelium through induction of cell proliferation within the crypts, where netrin-1 expression is high. In contrast, on the tips of the villi, where netrin-1 levels are low, both DCC and UNC5 promote apoptosis and cell shedding, because the receptors are expressed rather evenly throughout the villus length (12). In colorectal cancer, a chromosomal region containing DCC is frequently deleted (13). As one may expect for a tumor suppressor gene, this is accompanied by low or absent DCC expression. Strong evidence that DCC and UNC5 proteins are involved in the regulation of cancer progression stems from experiments showing that in some tumor lines, DCC and UNC5 proteins promote apoptosis when netrin-1 is absent, but enhance cell survival, invasion, and metastasis when netrin-1 is present (6). In addition, mice in which netrin-1 is overexpressed, thus inhibiting DCC-induced cell death, are prone to develop colorectal tumors (12).
However, the specific mechanisms by which netrin-1 and its interaction with DCC or UNC5 affects cell survival or death are not completely understood (5). Caspase activation appears to be an important step in the dependence receptor–initiated apoptosis including that of DCC and UNC5H (14,15), but this is in common with death receptor–induced apoptosis (eg, through CD95) (16). In fact, little is known about downstream signal transduction, although caspase-mediated cleavage of cytoplasmic domains in DCC and UNC5H appears to be a common trait in the netrin-1 receptors (14,15). Binding of netrin-1 to its receptors impairs p53-dependent apoptosis, but p53 is directly involved in transcriptional regulation of netrin-1 and its receptors (5,14). Because p53 pathways are defective in many cancers, it is unclear whether the netrin-1 effect is direct. Moreover, DCC and UNC5 integrate other signaling pathways, such as Rac1, Cdc42, MAPK, src and Fak (17,18). Given that such pathways have also been implicated in tumor progression, the molecular network in which netrin-1 and its receptors are embedded is complex, and this makes it difficult to discern the relative roles of the players. In addition, it is conceivable that functional redundancy within this signaling network will limit the efficacy of therapeutic approaches that specifically target one of the key molecules.
Netrin-1 as a Novel Molecular Target in Lung Cancer?
Based on survival advantages of some tumors through autocrine expression of netrin-1 and/or downregulation of its receptors, and regardless of the complexity of the downstream signaling cascade, selectively targeting netrin-1 in malignant diseases is a logical next step. In this issue of the Journal, Delloye et al. (19) describe a potential novel role of netrin-1 as a therapeutic target in non–small cell lung cancer (NSCLC), a group of tumors for which there is a need for effective new therapies. In a thorough study, they first demonstrated that a considerable proportion of NSCLC, mostly adenocarcinomas, express high levels of netrin-1, along with at least two UNC5H receptors, but not DCC. The tumor cells themselves rather than stroma cells were presumed to be the site of netrin-1 production. Using two complementary experimental approaches, interfering with dependence receptor expression using small interfering RNAs (siRNAs) and exposure of cells to a DCC decoy ectodomain, they demonstrated that inhibiting the netrin-1–receptor interaction leads to tumor cell apoptosis in three netrin-1–expressing tumor lines, in a process that was dependent on UNC5H1 and UNC5H2 receptors, but not DCC or other UNC5H receptors. Blocking of caspase-9 resulted in inhibition of the proapoptotic activity of UNC5H receptors, whereas inhibition of caspase-8 had no such effect. This is consistent with earlier findings demonstrating that caspase-9 interacts with an intracellular domain of DCC in the absence of netrin-1 (20). Although similar data on molecular interactions have not been published for UNC5 receptors, the new findings by Delloye et al. (19) suggest that UNC5H also affects primarily the mitochondrial pathway of apoptosis (21), a pathway that is influenced by many cytostatic compounds (22). This opens the possibility of combining netrin-directed therapeutics with activation of death receptors (23). Finally, in a preclinical xenotransplantation model using immunocompromised mice, the authors demonstrate that DCC-4Fbn decoy receptor or netrin-1 siRNA inhibition of tumor growth through induction of apoptosis occurred using a cell line with high levels of netrin-1 expression (H358) but not with a tumor cell line with low levels of netrin-1 (H460). Analyses of netrin-1 receptor expression in the transplanted tumors were not reported, however.
Although the data of Delloye et al. (19) show that netrin-1 is a promising target in a preclinical setting, it remains to be determined whether this concept stands the test of clinical application, where imponderables such as variability of tumor clones, mutual compensation of signaling pathways in tumor cells, and immune responses influence the outcome. Given that netrin-1 and its receptors are involved in the development and function of some immune-relevant cells (24–26), the situation in humans may be more complex than in the experimental systems studied. Additional studies will be needed to determine whether selectively targeting netrin-1 will become a useful addition to the therapeutic armamentarium in NSCLCs.
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J Natl Cancer Inst 2009 101: 215.
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