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Journal of Clinical Oncology, Vol 22, No 16 (August 15), 2004: pp. 3420-3428 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.019
Role of the Dependence Receptor DCC in Colorectal Cancer PathogenesisFrom the Apoptosis/Differentiation Laboratory, Equipe labelisée ‘La Ligue’ Molecular and Cellular Genetic Center, University of Lyon, Villeurbanne; International Agency For Research in Cancer, Lyon, France; and Division of Molecular Medicine & Genetics, University of Michigan Medical Center, Ann Arbor, MI Address reprint requests to P. Mehlen, MD, Apoptosis/Differentiation Laboratory–Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622 Villeurbanne, France; e-mail: mehlen{at}univ-lyon1.fr
More than a decade ago, the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. Data supporting this proposal included observations that one DCC allele was deleted in roughly 70% of colorectal cancers, some cancers had somatic mutations of the DCC gene, and DCC expression was often reduced or absent in colorectal cancer tissues and cell lines. Despite subsequent studies which have supported DCC's potential role as a tumor suppressor gene, the rarity of point mutations identified in DCC coding sequences, the lack of a tumor predisposition phenotype in mice heterozygous for DCC inactivating mutations, and the presence of other known and candidate tumor suppressor genes on chromosome 18q have raised questions about DCC's candidacy. Following its initial characterization, the DCC protein was identified as a transmembrane receptor for netrins, key factors in axon guidance in the developing nervous system. At first glance, the established role of DCC and netrin-1 during organization of the spinal cord could be viewed as a further challenge to the position that DCC inactivation might play a significant role in tumorigenesis. However, recent observations on DCC's functions in intracellular signaling have renewed interest in the potential contribution of DCC inactivation to cancer. In particular, data indicate that, when engaged by netrin ligands, DCC may activate downstream signaling pathways. Moreover, in settings where netrin is absent or at low levels, DCC can promote apoptosis. Here, we review DCC's candidacy as a tumor suppressor gene, with an emphasis on how recent molecular analyses of DCC have offered support for the notion that DCC may function as a tumor suppressor gene.
Colorectal cancer, like many other common epithelial cancers, is believed to arise in part through the accumulation of multiple somatic mutations in oncogenes, tumor suppressor genes, and DNA repair pathway genes (Fig 1).1,2 The specific constellation of somatic mutations present in a cancer likely reflects the fact that the mutations either singularly or collectively endow the neoplastic cells with novel traits, such as competence for evading apoptosis, self-sufficiency for proliferation and/or resistance to antiproliferative signals, infinite replication potential, the ability to stimulate and sustain new blood vessel growth, and ultimately the capability to escape to and seed growth at distant sites in the body (metastasis).2 Based on early studies of tumor suppressor genes such as the retinoblastoma gene3 and groundbreaking conceptual work by Knudson,4 allelic loss (also known as loss of heterozygosity [LOH]) has been implicated as an important mechanism of tumor suppressor gene inactivation. Efforts in the late 1980s to identify chromosomal regions most likely to harbor tumor suppressor genes in colorectal cancer revealed that chromosome regions 5q, 17p, and 18q were commonly affected by LOH.5,6 LOH of chromosome 5q was initially inferred and subsequently established to reflect, in many cases, inactivation of an adenomatous polyposis coli (APC) allele, while 17p LOH often reflected inactivation of a p53 allele.1,7
In large part because no known tumor suppressor genes had been mapped to chromosome 18q, the finding that approximately 70% of primary colorectal cancer had LOH of chromosome 18q suggested inactivation of one or more novel genes on 18q might play a significant role in colorectal cancer.8 Attempts to further localize the specific region of chromosome 18q likely to contain the tumor suppressor gene(s) were not possible, since in most colorectal cancers, LOH affected the entire chromosomal arm. However the identification of somatic mutations nearby an anonymous DNA marker from the 18q21 region in two primary colorectal cancers ultimately led to the identification of the DCC (deleted in colorectal cancer) gene (Fig 2).8 Subsequent studies suggested the DCC gene has 29 or more exons and spans a very large genomic region.9,10 Analysis of human genome sequence data indicates DCC is indeed an enormous gene, encompassing about 1.2 million base pairs (Mb). The mouse DCC gene is also gigantic, spanning roughly 1.1 Mb on chromosome 18.
The DCC gene encodes several different protein products as a result of alternative splicing,10,11 though all known isoforms appear to be type I transmembrane glycoproteins proteins of roughly 175 to 190 kDa with a single membrane spanning domain (Fig 3). The sequences present in DCC's large extracellular domain of roughly 1,100 amino acids bear strong similarity to those found in neural cell adhesion molecule (NCAM) protein family members, and include four immunoglobulin-like domains and six fibronectin type III-like motifs. The DCC cytoplasmic domain of roughly 325 amino acids shows little similarity to proteins with well-established functions. DCC has a homolog in mammals named neogenin,12 but very little is known about it. Well-conserved DCC orthologs—similar genes from another species—have been identified in C elegans (UNC40), Drosophila (Frazzled), and Xenopus.13–16 In man, DCC expression has been detected in many adult tissues, though expression is highest in brain, and most tissues seem to express only low levels of DCC transcripts and protein.8,11,12 During development, the highest levels of DCC expression appear to be present in the nervous system.17
As noted above, LOH of chromosome 18q has been found in a large fraction of colorectal cancers.6,8,18 Interestingly, in most reports, allelic losses of 18q are infrequent in early stage tumors (eg, small adenomas), but are common in primary colorectal carcinomas and nearly 100% of hepatic metastases arising from colorectal primaries, implying that chromosome 18q LOH may contribute more to progression rather than initiation of colorectal cancer. In greater than 90% of primary colorectal cancers with LOH of chromosome 18q, DCC is included in the region of allelic loss.8,19 Several studies have linked chromosome 18q LOH in colorectal cancers to a reduction in DCC expression at the RNA level19,20 and at the protein level,21–23 though some studies have failed to find evidence for reduced DCC transcript and/or protein levels in colorectal cancers.24 LOH of chromosome 18q and/or decreased DCC expression have also been seen in various other cancers, including gastric,25–27 prostate,28–30 endometrial,31–35 ovarian,33,36 esophageal,37–39 breast,40–42 testicular,43,44 glial,45–47 neuroblastoma,48,49 and hematologic50–53 malignancies. Chromosome 18q LOH has been associated with poor prognosis in colorectal cancer patients lacking lymph node or distant metastases at the time of their surgery (so-called stage II) as well as in patients who have lymph node but not distant metastases at the time of surgery (stage III).54–57 In other studies, chromosome 18q LOH has also been associated with decreased responsiveness to fluorouracil-based adjuvant chemotherapy regimens in stage III colorectal cancer patients.18,58 In a few studies, loss of DCC expression has been associated with poor prognosis and increased risk of metastasis,59–61 though at least one study has questioned the linkage between loss of DCC expression and risk of metastasis in colorectal cancer patients.62 The data indicating that 18q allelic loss and decreased DCC expression are associated with poor prognosis and potentially decreased response to adjuvant chemotherapy in colorectal cancer patients are interesting and of potential clinical significance. Nevertheless, the findings do little to establish whether DCC loss/inactivation is a critical factor in tumorigenesis or merely an epiphenomenon. Some evidence that DCC inactivation may in fact be associated with tumorigenic growth properties in colon and other cancers has been obtained. For example, introduction of an intact copy of chromosome 18 into a colorectal cancer cell line lacking endogenous DCC expression yielded detectable levels of DCC transcripts and resulted in suppression of growth in soft agar and tumorigenicity in nude mice.63 Also, ectopic expression of DCC in a tumorigenic keratinocyte cell line lacking endogenous DCC expression was shown to suppress tumorigenic growth of the cells in nude mice.64 Interestingly, in this study, it was observed that tumorigenic reversion was associated with loss of DCC expression and loss/rearrangement of the transfected DCC expression vector.64 Several more recent studies also indicate restoration of DCC expression can suppress tumorigenic growth properties in vitro or in nude mice.65,66
Much of the data on DCC loss and inactivation reviewed above is circumstantial and it falls far short of offering conclusive support that DCC functions as a tumor suppressor gene. Indeed, a sizeable number of genes with decreased or absent expression in cancers have been discovered. On the basis of their decreased expression, these genes are sometimes proposed to be tumor suppressors. Similarly, other genes, like DCC, that can antagonize tumorigenic or in vitro growth properties of cancer cell lines may be put forth as tumor suppressors. Undoubtedly, some of these genes may prove critical in growth regulation and some may even prove to be targets for loss-of-function mutations or other specific epigenetic inactivating mechanisms in human cancer. However, it is entirely possible that altered expression of many genes in cancer might simply reflect the altered growth properties of cancer cells. Also, as is the case for the retinoblastoma-related gene termed p107, the p53-related gene known as p73, and the p53 target gene known as p21/WAF1/CIP1, some genes may have particularly potent growth suppressive properties when ectopically overexpressed in cancer cells, but may be rarely, if ever, inactivated by specific genetic defects or epigenetic mechanisms in human cancer. Bearing these points in mind, data on mechanisms of DCC inactivation in cancer and its potential consequences should be considered, perhaps from the perspective that DCC does not function as a tumor suppressor gene. One argument put forth to counter the view that DCC is a tumor suppressor gene is that to date, no evidence has been obtained that DCC germline mutations play a role in a heritable cancer predisposition syndrome in man. On the surface, this is not an unreasonable argument, because the identification of inactivating germline mutations that segregate with cancer predisposition represents very convincing evidence for the authenticity of a candidate tumor suppressor gene. Nonetheless, some tumor suppressor genes with critical roles in cancer, when present in mutant form in the germline, may not predispose to cancer or may give rise to atypical and/or poorly penetrant cancer syndromes. Hence, somatic inactivating mutations in one or more types of cancer may be among the most compelling data available to implicate certain tumor suppressor genes. Because somatic mutations often play a major and definitive role in the inactivation of tumor suppressor genes, and few somatic mutations in DCC in colorectal cancer have been reported in the literature, it has been argued that DCC is not a tumor suppressor gene. In fact, somatic mutations in DCC have been reported in a number of cancer types, including rare homozygous deletions of portions of the DCC gene in colorectal,8,19 testicular,43 and pancreatic67 cancers. In colorectal cancers, the most common somatic mutations in DCC noted to date are 120 to 300 bp expansions in a dinucleotide repeat tract located in an intron region immediately downstream of exon 7.8 DCC alleles with expansions were seen in approximately 10% to 15% of all colorectal cancers, and the expansions seemed to be restricted to those tumors that displayed generalized genomic microsatellite instability (MSI+).68 Tumors with DCC microsatellite tract expansions have reduced levels of DCC transcripts,8 though there was no definite evidence that the expansions actually caused loss of DCC expression. It is worth bearing in mind that certain tumor suppressor genes, such as the transforming growth factor beta (TGF-ß) type II receptor, are targeted by small insertion and deletion mutations in MSI+ tumors, but the mutations usually involve the gain or loss of only 1 to 3 base pairs rather than the enormous expansions seen at the DCC locus. While localized inactivating mutations in DCC exons have only rarely been reported in cancers in studies to date, because most cancers show reduced or absent DCC transcripts, point mutations in one of the 29 or more DCC exons might not be expected. Consistent with the notion that other genetic or epigenetic mechanisms may inactivate DCC, aberrant splicing leading to the generation of transcripts encoding truncated or defective DCC proteins has been seen in some brain tumors.10 Finally, given the accumulating evidence that epigenetic mechanisms, such as repression by transacting factors, chromatin remodeling, and promoter hypermethylation, may contribute to inactivation of tumor suppressor genes in cancer, one might even question the proposal that frequent somatic mutations in DCC coding regions must be demonstrated to validate its function as a tumor suppressor gene. Another argument that has been raised regarding DCC's candidacy as a tumor suppressor gene is that in region of allelic loss on chromosome 18q, other well-established or candidate tumor suppressor genes also reside. Indeed, the SMAD4 and SMAD2 genes were localized in or nearby the minimal region affected by 18q LOH in colorectal cancers.19 SMAD4 and SMAD2 encode proteins that play key roles in TGF-ß signaling,69 and given the potent inhibitory effects of TGF-ß on colonic epithelial cells, their inactivation could be important in colorectal cancer development. Because SMAD2 expression is retained in colorectal cancers and mutations in the gene are rare in colorectal cancers,19,70–74 there is little evidence that chromosome 18q LOH is commonly targeting SMAD2 for inactivation. Several lines of evidence suggest SMAD4 deserves much greater consideration as a target of chromosome 18q LOH in colorectal cancer. In some families, germline inactivating mutations in SMAD4 underlie predisposition to the juvenile polyposis syndrome,75 a condition in which affected individuals manifest hamartomatous polyps in the intestine and colon and increased risk of colon and other gastrointestinal cancers. The SMAD4 gene was initially discovered because it was affected by inactivating mutations in approximately 50% of pancreatic cancers.76 The increased susceptibility to tumor progression observed in mice heterozygous for APC and SMAD4 inactivation compared to mice heterozygous for only APC inactivation supports the potential significance of SMAD4 inactivation in colorectal tumorigenesis.77 Nonetheless, while SMAD4 is somatically mutated in approximately 15% of colorectal cancers,71,74,78,79 because SMAD4 is only mutated in about one-third of colorectal cancers with 18q LOH and SMAD4 expression is retained in those cancers lacking mutations,79–81 SMAD4 is unlikely to constitute the major chromosome 18q target for inactivation in colorectal cancers with chromosome 18q LOH. Yet another argument offered in support of the view that DCC has no role as a tumor suppressor gene is the observation that mice carrying heterozygous inactivating mutations in the murine DCC ortholog did not show a cancer predisposition phenotype.82 Nor did Fazeli et al82 observe an obvious effect on tumor multiplicity or progression when mice carrying mutations in both APC and DCC were studied. The absence of a clearcut predisposition to intestinal or other tumors in mice carrying a germline mutation in one DCC allele has been construed by some as definitive evidence that DCC inactivation has no role in cancer. However, it may be worth bearing in mind that mice heterozygous for germline mutations in genes with unquestioned tumor suppressor function in man, including the WT1, BRCA1, BRCA2, VHL, and E-cadherin genes, have not been reported to be associated with any significant tumor predisposition phenotype when mice carrying constitutional, heterozygous inactivating mutations have been studied.83 The studies by Fazeli et al,82 in which no obvious effect on tumor multiplicity or progression was seen when mice carrying mutations in both APC and DCC were studied, are worthy of consideration, particularly because, as noted above, enhanced tumor progression was seen in mice heterozygous for APC and SMAD4 inactivation. However, it is possible that the defects that contribute to small intestinal tumor formation and progression in the mouse differ to some degree from those that contribute to colorectal cancers in man. In this regard, the tumors which develop in the APC± animal models do not accumulate mutations in K-ras and p53,84,85 despite the fact that in human colorectal cancers K-ras and p53 mutations are present in roughly 50% and 70% of colorectal carcinomas, respectively.1,7 Consistent with the failure of tumors arising in the APC± model to manifest K-ras and p53 mutations, no enhancement of the intestinal tumor phenotype has been reported in APC± mice carrying K-ras or p53 defects in their intestine.86–88 Along this line, an open question for tumor suppressor genes in general is whether haploinsufficency of one gene—due to LOH or mutation—may cooperate with haploinsufficency of another (ie, that the "two-hits" may be in unrelated genes). Thus, a similar combination of the two-hits may drive colorectal tumors in humans while it will not be sufficient to do so in mice. In light of the rather slim body of data on mutational mechanisms inactivating DCC in human cancer and an inability of the DCC mouse model studies to definitively exclude a role for DCC in cancer, perhaps it is fairest to say that it is still a matter of debate whether DCC remains a viable candidate tumor suppressor gene or not. Based on review of the criticisms regarding DCC's potential role in tumor suppression, it seems that a major question is whether loss of DCC function offers a selective advantage for cancer cells in vivo. Therefore, in the last part of this review, we will focus on recent observations on DCC function in signaling, in large part because the recent functional studies offer some interesting hints regarding the potential biologic significance of DCC inactivation in cancer.
In light of DCC's similarity to NCAM family members and the fact that NCAM and related proteins were known to function in homophilic cell-cell interaction,89–90 it was initially hypothesized that DCC might regulate cell-cell adhesion through homophilic interactions, and some data to support this proposal were obtained.91 However, elegant genetic studies in C elegans initially implicated the DCC-related protein UNC40 as a receptor for UNC6, an ortholog of the vertebrate netrin-1 factor.13,14 Subsequent studies in vertebrate systems soon established that DCC functioned as part of a receptor complex for netrin-113,17,92–96 (Fig 3). The netrins are a family of laminin-related secreted proteins with critical roles in determining direction and extent of cell migration and axonal outgrowth in the developing nervous system.97,98 The UNC6/netrin family in mammals, includes netrin-1 (also named NTN1L in humans99), netrin-3,100 netrin-4 (or ß-netrin101), netrin-G1, and netrin-G2.102 As noted above, studies led by Tessier-Lavigne demonstrated the important role of DCC in mediating effects of netrin-1 in directing the growth and the orientation of axons (eg, commissural axons) during development of the nervous system.17,74,85,103,104 DCC functions in netrin-mediated signaling as a component of a multiprotein receptor complex, interacting with other cell surface receptors, such as Robo, UNC5H, or A2b.105–107 While DCC's interaction with netrin-1 is well-substantiated,82,93,99,103 it is still unclear whether DCC interacts physically and functionally with other netrins. Although the role of DCC in mediating netrin-1 effects has been clearly demonstrated during nervous system development, DCC's cellular function outside of the nervous system remains unknown. As noted above, DCC transcripts and protein have been detected in various adult normal tissues outside of the nervous system.8,11,12,22,30,34,42,61,108 Consistent with a possible role for DCC in transmitting netrin signals in tissues outside the nervous system, netrin-1 is also expressed in various adult tissues.99 Northern blot studies indicate that netrin-1 transcripts may in fact be considerably more abundant in adult heart, small intestine, and colon tissues than in the adult brain.99 Within adult intestinal tissue, netrin-1 expression appears to be greatest at the base of crypts.109 Given the absence of an obvious role for DCC and netrin-1 in the development of the intestine,82,93 what might be the significance of DCC and netrin-1 expression in the intestine? It is well known that tight regulation of epithelium proliferation and differentiation in the intestine is crucial for its normal function and likely for inhibition of tumorigenesis.110 The bulk of proliferating cells are located in the lower third of the crypt, and presumably, intestinal stem cells reside near the base of the crypt. As cells migrate toward the villus tip, they become more differentiated. On reaching the tip, the cells are shed into the intestinal lumen, where they likely undergo programmed cell death (apoptosis). Perhaps the DCC/netrin-1 interaction may contribute to regulation of proliferation or differentiation. Consistent with this idea, in certain cell lines, forced DCC expression has been shown to induce G2/M cell cycle arrest,111 and in other cells, ectopic DCC expression has been linked to a marked loss of proliferation.65 Unfortunately, the role of netrin-1 in DCC's effects on cell cycle progression or proliferation was not explored in these studies. Similarly, an initial study indicated that DCC might play a role in goblet cell differentiation.108 However, a role for DCC in in vitro differentiation along the globlet cell lineage has not been supported.65,112 Additionally, the possible role of DCC in differentiation does not fit neatly with data from some recent reports. In particular, in various cell lines, DCC, on netrin-1 binding, activates the extracellular signal-regulated kinase (ERK) -1/2 mitogen-activated protein kinase (MAPK) pathway,104,113 while ERK-1/2 MAPK activation has been suggested to inhibit intestinal epithelium differentiation.114 DCC was also recently shown to activate the small GTPases (small G proteins) Cdc42 and Rac-1 when netrin-1 is present.115,116 This activation seems to require the interaction of the intracellular domain of DCC with an adaptor molecule Nck-1.117 Small GTPases have been implicated in numerous cell processes, especially in actin organization and cell motility.118 While the DCC-dependent Cdc42/Rac-1 activation may have a major role in axon guidance,115–117 it is of some interest to consider the possible role of netrin-1-mediated DCC-dependent small GTPases activation in the intestine. Indeed, transgenic mice expressing a constitutive form of Rac-1 in the intestine showed a precocious differentiation of the epithelium with accompanying alterations in their apical actin.119 Hence, DCC-mediated Rac-1 activation may be important for epithelium differentiation.
However, activation of small GTPases and MAPK by DCC are unlikely to account for DCC tumor suppressor activity, since both small GTPase and MAPK have been shown to be activated in cancer and/or participate directly in promoting tumor development.120,121 An alternative hypothesis for DCC/netrin-1 function in the intestine that may fit with DCC tumor suppressor activity is the possibility that DCC and netrin-1 have roles in regulating cell survival. Indeed, numerous reports have demonstrated that expression of DCC in the absence of netrin-1 induces apoptosis,65,111,116,122–124 while the presence of netrin-1 blocks DCC-induced cell death.122–124 Hence, DCC appears to be a member of the emerging family of the so-called dependence receptor. Members of this family, besides DCC, include p75ntr, the androgen receptor, RET, UNC5H, or The specific molecular mechanisms by which DCC exerts its pro-apoptotic effects when netrin ligand is absent have not been fully clarified. However, a first clue for the nature of DCC's pro-apoptotic activity is that DCC requires the activation of the cysteine aspartic protease caspases for its pro-apoptotic activity. When unbound to its ligand, DCC is cleaved roughly in the middle of its intracellular domain (aspartic acid residue 1290) by an unknown active caspase.122 As shown in Figure 4, the cleavage of DCC allows the release of DCC's inhibitory C-terminal domain and the exposure of a domain located upstream to the caspase cleavage site. This upstream DCC domain is sufficient for cell death induction and is named for addiction/dependence domain (ADD). This DCC domain is then able to interact with the initiator caspase-9 and to promote caspase activation and caspase-dependent cell death.123 The interaction of DCC with caspase-9 is probably indirect and may require an adaptor protein, perhaps DIP13 (DCC-interacting protein 13), a protein that specifically interacts with the DCC ADD.124
The pro-apoptotic activity of DCC in the absence of netrin ligand would be consistent with a role for the pair DCC/netrin-1 in homeostatic regulation of intestinal epithelium and possibly as well in suppression of tumorigenesis. Specifically, the observation that netrin-1 is produced mainly at the bottom of the crypt, and DCC is expressed along the villus, might allow DCC and netrin-1 to play key roles in intestinal epithelium fate. Within the crypt, cells at the base of the crypt express DCC in an environment that is also rich in netrin-1. As the intestinal cells cease proliferation and move toward the tip of the villus, they will encounter progressively less netrin-1, perhaps leading to DCC-mediated apoptosis (Fig 5).
The loss of DCC appears to be a relatively late event in colorectal tumorigenesis, 6,131 perhaps even one that is linked in some fashion to the acquisition of invasive and metastatic properties. As such, it is tempting to speculate that there might be a powerful selective advantage for a transformed colonic epithelial cell to lose DCC function in order not to be dependent on a high local concentration of netrin-1 for its survival. This speculation also fits well with several recent observations on another family of netrin-1 receptors termed the UNC5H family, because of their similarity to the C elegans ortholog UNC5. The type I transmembrane UNC5H receptors (ie, UNC5H1, H2, and H3 in rodent or UNC5A, B, and C in humans; Fig 3) were first shown to be involved in the process of neuronal migration and axon repulsion mediated by netrin-1.95,96 Recent reports have shown that UNC5H receptors are also dependence receptors inducing apoptosis in the absence of netrin-1, while netrin-1 presence blocks their pro-apoptotic activity.128,132,133 These findings on the role of both DCC and UNC5H receptors in apoptosis has led to the view that netrin-1 may not only regulate cell migration and axonal outgrowth, but it may also be a survival factor during nervous system development.128 The various UNC5H receptors are expressed in the developing nervous system as well as in multiple adult tissues, including the intestine.133 Of note, it has been found that expression of the UNC5H2/B receptor is regulated by the tumor suppressor p53 and UNC5H2/B has a role in p53-induced apoptosis.132 Moreover, like DCC expression, UNC5H expression is lost or reduced in the vast majority of colorectal tumors, and the loss/reduction is in part related to LOH affecting the chromosome regions which harbor the respective UNC5H loci.133 In closing, the DCC and UNC5H receptors appear to show some intriguing similarities with respect to their pro-apoptotic activities and frequent loss of expression in cancer. Clearly, additional data are needed to support the argument that the DCC and UNC5H proteins do indeed have vital negative regulatory roles in epithelial tissues, such as colonic epithelium, and that their inactivation during tumorigeneis is intimately linked to more robust growth and survival of the cancer cells. Nevertheless, rather than sealing the case against any role for DCC inactivation in cancer, it would seem that the functional studies may have served to renew interest in further studies to address the linkage between DCC inactivation and cancer. Note: Since the original submission, the authors have demonstrated that inhibition of the cell death induced by DCC or UNC5H in mouse gut leads to tumor formation.109
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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TOP
ABSTRACT
DCC Identification
vß3-integrin.
