Making the Case for DCC and UNC5C as Tumor-Suppressor Genes in the Colon

Abstract

See “Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer” by Shin SK, Nagasaka T, Jung BH, et al on page 1849; and “Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies” by Bernet A, Mazelin L, Coissieux M-M, et al, on page 1840. See “Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer” by Shin SK, Nagasaka T, Jung BH, et al on page 1849; and “Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies” by Bernet A, Mazelin L, Coissieux M-M, et al, on page 1840. It is well established that DNA alterations in epithelial cells in the colon play a pivotal role in the pathogenesis of colorectal cancer (CRC). The discovery of frequent and recurring allelic imbalance events (termed loss of heterozygosity [LOH]) and oncogenic mutations in colorectal neoplasms firmly established the concept that the accumulation of DNA mutations is a fundamental aspect of CRC formation that is true of cancer in general. One of the most common LOH events originally discovered in CRC is the loss of a region of chromosome 18q21.1Vogelstein B. Fearon E.R. Hamilton S.R. et al.Genetic alterations during colorectal-tumor development.N Engl J Med. 1988; 319: 525-532Crossref PubMed Scopus (5911) Google Scholar The 18q21 LOH is commonly found in advanced CRCs, and the genes in this locus have been considered to be important tumor-suppressor genes because of the frequency of LOH at this locus. One of the first genes discovered in this region was DCC (which is Deleted in CRC), which led to intense research activity to determine whether this gene was the tumor-suppressor gene that was targeted by the LOH events on chromosome 18. However, a relative dearth of mutations in DCC and the lack of a CRC phenotype in mice carrying heterozygous inactivating mutations in Dcc, even when crossed with mice carrying Apc mutations, raised questions about DCC’s role in CRC.2Cho K.R. Oliner J.D. Simons J.W. et al.The DCC gene: structural analysis and mutations in colorectal carcinomas.Genomics. 1994; 19: 525-531Crossref PubMed Scopus (201) Google Scholar, 3Mehlen P. Fearon E.R. Role of the dependence receptor DCC in colorectal cancer pathogenesis.J Clin Oncol. 2004; 22: 3420-3428Crossref PubMed Scopus (105) Google Scholar, 4Fazeli A. Dickinson S.L. Hermiston M.L. et al.Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene.Nature. 1997; 386: 796-804Crossref PubMed Scopus (673) Google Scholar Indeed, these data and the discovery of other plausible tumor-suppressor genes in the 18q21 locus, namely SMAD2 and SMAD4, led to waning enthusiasm for DCC as a legitimate tumor-suppressor gene in the colon. However, interest in DCC as a tumor-suppressor gene was revived with the discovery that DCC is a netrin-1–dependence receptor that can regulate apoptosis and also likely plays a role in directing cell motility.5Pierceall W.E. Reale M.A. Candia A.F. et al.Expression of a homologue of the deleted in colorectal cancer (DCC) gene in the nervous system of developing Xenopus embryos.Dev Biol. 1994; 166: 654-665Crossref PubMed Scopus (41) Google Scholar, 6Keino-Masu K. Masu M. Hinck L. et al.Deleted in colorectal cancer (DCC) encodes a netrin receptor.Cell. 1996; 87: 175-185Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar This discovery of DCC’s role in apoptosis led to an appreciation that DCC was most likely involved in tumor suppression through its function as a netrin receptor rather than as a modulator of cell–cell adhesion, which had been predicted by its similarity to NCAM family members.3Mehlen P. Fearon E.R. Role of the dependence receptor DCC in colorectal cancer pathogenesis.J Clin Oncol. 2004; 22: 3420-3428Crossref PubMed Scopus (105) Google Scholar In fact, in retrospect, it appears as though at least some of the controversy related to DCC’s status as a tumor-suppressor gene is the consequence of a lack of understanding related to its biological role in epithelial cells. In this issue of Gastroenterology, studies by Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and Bernet et al8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar provide more evidence that makes the case for DCC and UNC5C (another member of the netrin receptor family) being tumor suppressors in the colon. In independent studies, both groups found that the netrin receptors are often inactivated in colon cancer. Through a careful analysis of genetic and epigenetic alterations in DCC and UNC5C, the research teams led by Goel and by Mehlen have discovered that DCC LOH and loss of expression of UNC5C through LOH or aberrant methylation occur commonly in colorectal neoplasms. Moreover, and perhaps of most interest, they provide evidence that inactivation of the netrin receptors may affect both the establishment and progression phases of colon cancer formation. This is exciting news because DCC loss/18q21 LOH has been predominantly found in advanced CRCs and metastases, which has led to the belief that the netrin receptors are most likely playing a role in the invasive and metastatic behavior of CRC and not in the initiation of CRC formation.3Mehlen P. Fearon E.R. Role of the dependence receptor DCC in colorectal cancer pathogenesis.J Clin Oncol. 2004; 22: 3420-3428Crossref PubMed Scopus (105) Google Scholar, 9Vogelstein B. Fearon E.R. Kern S.E. et al.Allelotype of colorectal carcinomas.Science. 1989; 244: 207-211Crossref PubMed Scopus (1180) Google Scholar, 10Fearon E.R. Cho K.R. Nigro J.M. et al.Identification of a chromosome 18q gene that is altered in colorectal cancers.Science. 1990; 247: 49-56Crossref PubMed Scopus (1535) Google Scholar, 11Watanabe T. Wu T.-T. Catalano P.J. et al.Molecular Predictors of survival after adjuvant chemotherapy for colon cancer.N Engl J Med. 2001; 344: 1196-1206Crossref PubMed Scopus (786) Google Scholar The results of the study by Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and the demonstration that netrin-1 may be a regulator of cell proliferation and apoptosis in the intestinal epithelium provides evidence that targeting netrin signaling may not only have therapeutic potential in advanced CRC but also in early cancers or even advanced adenomas.7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 12Mazelin L. Bernet A. Bonod-Bidaud C. et al.Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.Nature. 2004; 431: 80-84Crossref PubMed Scopus (249) Google Scholar, 13Mehlen P. Llambi F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers.Br J Cancer. 2005; 93: 1-6Crossref PubMed Scopus (38) Google Scholar To appreciate the significance of the studies by Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and Bernet et al,8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar it is essential to understand the biology of netrin signaling in epithelial cells. The discovery of the netrin family was made over a decade ago through the genetic analysis of nematode mutants with defects in the unc-6 gene, which led to the identification of netrin-1, the vertebrate homolog of UNC6, as a diffusible protein that could attract commissural axons.14Hedgecock E.M. Culotti J.G. Hall D.H. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans.Neuron. 1990; 4: 61-85Abstract Full Text PDF PubMed Scopus (729) Google Scholar, 15Serafini T. Kennedy T.E. Galko M.J. et al.The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6.Cell. 1994; 78: 409-424Abstract Full Text PDF PubMed Scopus (1166) Google Scholar Netrin-1 is 1 member of a family of laminin-related secreted proteins that include netrin-1, netrin-2, netrin-G1, netrin G2, and netrin-4/β-netrin, which all signal through a class of immunoglobulin-like transmembrane receptors.16Rodrigues S. De Wever O. Bruyneel E. et al.Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis.Oncogene. 2007; 26: 5615-5625Crossref PubMed Scopus (85) Google Scholar These receptors are divided into 2 main families of type I receptors, which include DCC and its homolog neogenin, and the UNC5H (UNC5 homolog) receptors, which include UNC5A, UNC5B, UNC5C, and UNC5D (also known as UNC5H1-4). The identification of this family of ligands and receptors in the developing nervous system suggested that they mainly regulated neuron outgrowth. However, it is now clear netrin signaling can affect sprouting angiogenesis, cell motility, and apoptosis and that the netrin ligands and receptors are expressed widely throughout the body demonstrating that they are involved in a broad variety of cellular processes in epithelial cells as well as endothelial cells.17Larrivee B. Freitas C. Trombe M. et al.Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis.Genes Dev. 2007; 21: 2433-2447Crossref PubMed Scopus (173) Google Scholar, 18Wilson B.D. Ii M. Park K.W. et al.Netrins promote developmental and therapeutic angiogenesis.Science. 2006; 313: 640-644Crossref PubMed Scopus (286) Google Scholar Indeed, the netrin receptors have been shown to regulate morphogenesis of endothelial cells, induce cytoskeletal reorganization of vascular smooth muscle cells, and control adhesion and migration of epithelial cells in the lungs, pancreas, and colon.18Wilson B.D. Ii M. Park K.W. et al.Netrins promote developmental and therapeutic angiogenesis.Science. 2006; 313: 640-644Crossref PubMed Scopus (286) Google Scholar, 19Shekarabi M. Kennedy T.E. The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1.Mol Cell Neurosci. 2002; 19: 1-17Crossref PubMed Scopus (151) Google Scholar A major question related to the studies of DCC in CRC is why has it been so difficult to establish the role of DCC and the netrin receptor family members in the pathogenesis of colon neoplasms. This is in part because of the complex and fascinating biology of this family of ligands and receptors. Unlike with classic receptor biology in which a receptor is in the “off” position when not bound with a ligand, the netrin receptors are a class of receptors, called dependence receptors, that are biologically active in both the ligand bound (“on”) and unbound (“off”) state.20Mehlen P. Bredesen D.E. The dependence receptor hypothesis.Apoptosis. 2004; 9: 37-49Crossref PubMed Scopus (92) Google Scholar Dependence receptors include not only the netrin receptors, but also the androgen receptor AR, RET, and PTCH as well as others.21Ellerby L.M. Hackam A.S. Propp S.S. et al.Kennedy’s disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity.J Neurochem. 1999; 72: 185-195Crossref PubMed Scopus (208) Google Scholar, 22Bordeaux M.C. Forcet C. Granger L. et al.The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.EMBO J. 2000; 19: 4056-4063Crossref PubMed Scopus (208) Google Scholar, 23Thibert C. Teillet M.A. Lapointe F. et al.Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog.Science. 2003; 301: 843-846Crossref PubMed Scopus (261) Google Scholar These dependence receptors all share the quality that, when bound to their specific ligand, they typically transmit positive signals of proliferation, differentiation, migration, and so on, and when unbound induce apoptosis13Mehlen P. Llambi F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers.Br J Cancer. 2005; 93: 1-6Crossref PubMed Scopus (38) Google Scholar (Figure 1). For instance, when DCC is not bound to netrin-1, it triggers apoptosis in epithelial cells through caspase-dependent mechanisms.24Mehlen P. Rabizadeh S. Snipas S.J. et al.The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.Nature. 1998; 395: 801-804Crossref PubMed Scopus (365) Google Scholar Interestingly, both DCC and UNC5H appear to require caspase cleavage to expose a proapoptotic domain named addiction dependence domain (ADD) in the intracellular domains of the proteins; however, DCC appears to trigger the activation of caspase-9, whereas UNC5C appears to regulate caspase-mediated apoptosis through other mechanisms such as death-associated protein kinase (DAPK) or NRAGE, a member of the MAGE (melanoma antigen) family of apoptosis regulators.20Mehlen P. Bredesen D.E. The dependence receptor hypothesis.Apoptosis. 2004; 9: 37-49Crossref PubMed Scopus (92) Google Scholar, 25Llambi F. Lourenco F.C. Gozuacik D. et al.The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase.EMBO J. 2005; 24: 1192-1201Crossref PubMed Scopus (131) Google Scholar, 26Williams M.E. Strickland P. Watanabe K. et al.UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE.J Biol Chem. 2003; 278: 17483-17490Crossref PubMed Scopus (98) Google Scholar, 27Forcet C. Ye X. Granger L. et al.The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation.Proc Natl Acad Sci U S A. 2001; 98: 3416-3421Crossref PubMed Scopus (176) Google Scholar In contrast and in keeping with the Jekyll-and-Hyde nature that characterizes this family of receptors, when the netrin receptors are engaged, they mediate a set of effects that would be considered oncogenic, such as the induction of cell migration and cytoskeleton reorganization.16Rodrigues S. De Wever O. Bruyneel E. et al.Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis.Oncogene. 2007; 26: 5615-5625Crossref PubMed Scopus (85) Google Scholar, 19Shekarabi M. Kennedy T.E. The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1.Mol Cell Neurosci. 2002; 19: 1-17Crossref PubMed Scopus (151) Google Scholar In retrospect, it is now clear that the initial studies that focused attention strictly on DCC neglected key aspects that affect the biological consequences of DCC inactivation. It has only been through study of the bound and unbound receptors that we have begun to understand how DCC and its family members might act as tumor-suppressor genes in the colon. Support for DCC as a tumor-suppressor gene in the colon has been tumultuous at best and definitive evidence for DCC as a colon cancer tumor-suppressor gene remains to be shown. The initial discovery of DCC in the 18q21 locus led to the expectation that it would be quickly proven a bona fide tumor-suppressor gene. However, the discovery that only 10%–15% of colon cancers carry mutations in DCC and the lack of an effect of inactivation of Dcc in mouse models to affect tumor formation suggested that DCC had little to no biological role in colon cancer. The elegant studies from the research groups led by Goel and by Mehlen in this issue of Gastroenterology as well as other studies of netrin and UNC5C in CRC have garnered evidence in support of DCC and the netrins and netrin receptors as being biologically important tumor-suppressor genes in the colon.7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 10Fearon E.R. Cho K.R. Nigro J.M. et al.Identification of a chromosome 18q gene that is altered in colorectal cancers.Science. 1990; 247: 49-56Crossref PubMed Scopus (1535) Google Scholar, 12Mazelin L. Bernet A. Bonod-Bidaud C. et al.Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.Nature. 2004; 431: 80-84Crossref PubMed Scopus (249) Google Scholar, 16Rodrigues S. De Wever O. Bruyneel E. et al.Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis.Oncogene. 2007; 26: 5615-5625Crossref PubMed Scopus (85) Google Scholar, 28Thiebault K. Mazelin L. Pays L. et al.The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment.Proc Natl Acad Sci U S A. 2003; 100: 4173-4178Crossref PubMed Scopus (168) Google Scholar Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar have shown that the aberrant methylation of UNC5C silences its expression in cell lines and that UNC5C methylation is common in colon cancer and occurs in adenomas, as well as adenocarcinomas. Indeed, the studies by both Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and Bernet et al8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar as well as prior studies showing the reduced expression of UNC5A, UNC5B, and UNC5C in 48%, 27%, and 74%–77% of CRCs, respectively, reinforce the concept that DCC and UNC5C are legitimate tumor-suppressor genes.28Thiebault K. Mazelin L. Pays L. et al.The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment.Proc Natl Acad Sci U S A. 2003; 100: 4173-4178Crossref PubMed Scopus (168) Google Scholar Furthermore, Mazelin et al12Mazelin L. Bernet A. Bonod-Bidaud C. et al.Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.Nature. 2004; 431: 80-84Crossref PubMed Scopus (249) Google Scholar found that approximately 7% of colon cancers overexpress the DCC ligand, netrin-1, and that induced overexpression of netrin-1 in the colon results in decreased apoptosis and histologically advanced adenomas when crossed with mice that carry a germline mutation in Apc (Apc1638N/wt).12Mazelin L. Bernet A. Bonod-Bidaud C. et al.Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.Nature. 2004; 431: 80-84Crossref PubMed Scopus (249) Google Scholar These studies are in stark contrast to those in which mice that carry inactivating mutations in both Apc and Dcc do not develop colon neoplasms.4Fazeli A. Dickinson S.L. Hermiston M.L. et al.Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene.Nature. 1997; 386: 796-804Crossref PubMed Scopus (673) Google Scholar Our current understanding of netrin biology suggests that the differences in tumor formation between these mouse models may be the result of compensation by other netrin receptor family members. Indeed, netrin-1 may affect tumor formation through activation of alternative receptors, such as A2br or integrins or possibly through effects on the UNC5H receptors.13Mehlen P. Llambi F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers.Br J Cancer. 2005; 93: 1-6Crossref PubMed Scopus (38) Google Scholar Consistent with the concept that UNC5C is the critical compensating netrin receptor, Bernet et al8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar have shown mice that carry an Apc1638N germline mutation and that are heterozygous or homozygous for mutant Unc5c develop adenomas that progress to adenocarcinoma at a higher frequency than seen in the Apc1638N mice.8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar A2b receptor activation is another compelling possibility given that this receptor can activate a variety of pathways, including Rho-ROCK and PI3K, which have been shown to be activated by netrin-1. Netrin-1 can activate a variety of other pathways that can induce proinvasive behaviors, including FAK and PKA, with the determination of which pathways are activated likely depending on the specific netrin receptors that are present on the cell membrane.29Nguyen Q.D. De Wever O. Bruyneel E. et al.Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.Oncogene. 2005; 24: 8240-8251Crossref PubMed Scopus (46) Google Scholar, 30Yebra M. Montgomery A.M. Diaferia G.R. et al.Recognition of the neural chemoattractant Netrin-1 by integrins alpha6beta4 and alpha3beta1 regulates epithelial cell adhesion and migration.Dev Cell. 2003; 5: 695-707Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar Particularly interesting findings by Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar are that DCC and UNC5C inactivation occur concurrently in roughly half of all colon cancers and that UNC5C loss appears to precede DCC loss in the polyp→cancer progression sequence.7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Questions that these findings raise are as follows: (1) What is the selective pressure for inactivating multiple receptors that bind netrins? and (2) Why does UNC5C loss occur early and DCC loss occur late in colon cancer formation if both are netrin receptors? One answer to these questions can be found by assessing the biological consequences of activating the UNC5 receptors vs. DCC receptor. Genetic and biochemical studies indicate that DCC usually mediates attractive responses to netrin, whereas UNC5 mediates repulsive responses to netrin.31Geisbrecht B.V. Dowd K.A. Barfield R.W. et al.Netrin binds discrete subdomains of DCC and UNC5 and mediates interactions between DCC and heparin.J Biol Chem. 2003; 278: 32561-32568Crossref PubMed Scopus (85) Google Scholar Even of potentially more interest, it appears that the 2 receptors can interact at a biological level and that DCC only mediates attractive responses in the absence of UNC5 and that UNC5 can convert DCC-mediated attraction to repulsion.32Hong K. Hinck L. Nishiyama M. et al.A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion.Cell. 1999; 97: 927-941Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar Thus, the finding that UNC5C is silenced by aberrant methylation in the adenoma phase of colon cancer formation suggests that DCC can then mediate attractive responses until it is eventually lost in the advanced cancers. Furthermore, the UNC5 receptors appear to have some unique biological effects not observed with DCC, such as on angiogenesis, creating the potential for differential and potentially additive tumor-promoting effects by inactivating UNC5C and DCC.13Mehlen P. Llambi F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers.Br J Cancer. 2005; 93: 1-6Crossref PubMed Scopus (38) Google Scholar, 17Larrivee B. Freitas C. Trombe M. et al.Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis.Genes Dev. 2007; 21: 2433-2447Crossref PubMed Scopus (173) Google Scholar, 31Geisbrecht B.V. Dowd K.A. Barfield R.W. et al.Netrin binds discrete subdomains of DCC and UNC5 and mediates interactions between DCC and heparin.J Biol Chem. 2003; 278: 32561-32568Crossref PubMed Scopus (85) Google Scholar In addition, the UNC5 receptors and DCC appear to induce different signaling pathways and to be regulated by different pathways, which could result in a growth advantage for a developing tumor to inactivate both netrin receptor family members.32Hong K. Hinck L. Nishiyama M. et al.A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion.Cell. 1999; 97: 927-941Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar The studies by Bernet et al8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and by Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar provide clear evidence that UNC5C is inactivated in colon cancer, but they also raise several questions. Given that DCC and UNC5C are dependence receptors, it would be interesting to know the concurrent expression levels of the whole family of netrin ligands as well as the expression of the other netrin receptors UNC5A, UNC5B, and neogenin. It would also be interesting to know what effect inactivation of the receptors has on apoptosis and proliferation in primary tumors in humans as well as on markers of invasive behavior of the tumors. Furthermore, determination of which of these effects requires inactivation of both or just one of the receptors is needed to understand how netrin signaling deregulation affects colon cancer formation. The studies by Bernet et al8Bernet A. Mazelin L. Coissieux M.-M. et al.Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.Gastroenterology. 2007; 133: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and Shin et al7Shin S.K. Nagasaka T. Jung B.H. et al.Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007; 133: 1849-1857Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar have provided compelling evidence to justify further study of the pathophysiologic effects of UNC5C and DCC inactivation in the colon. These studies are critical if the netrins and their receptors are ever to be successfully used for targeted therapies. Epigenetic and Genetic Alterations in Netrin-1 Receptors UNC5C and DCC in Human Colon CancerGastroenterologyVol. 133Issue 6PreviewBackground & Aims: DCC and UNC5C, Netrin-1 dependence receptors, perform an important role in intestinal epithelial biology. Both receptors frequently are down-regulated in colorectal cancer (CRC). Although CRCs frequently lose DCC owing to deletions at 18q, the mechanism for the UNC5C loss is poorly understood. We hypothesized that UNC5C is silenced epigenetically in CRC, and that there are interactions between losses of UNC5C and DCC in colorectal tumorigenesis. Methods: Gene expression and epigenetic analysis of UNC5C was examined in 8 CRC cell lines, 147 sporadic CRCs with corresponding normal mucosa, and 52 adenomatous polyps (APs). Full-Text PDF Inactivation of the UNC5C Netrin-1 Receptor Is Associated With Tumor Progression in Colorectal MalignanciesGastroenterologyVol. 133Issue 6PreviewBackground & Aims: The UNC5H netrin-1 receptors (UNC5H1-3 also called UNC5A-C) belong to the functional dependence receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies. Full-Text PDF