UMLS:C0009402 - FACTA Search

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Query: UMLS:C0009402 (colorectal cancer)
53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC(+/-)) showed a similar frequency of tumor formation compared with the wild-type mice (DCC(+/+)). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2'-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC.
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PMID:Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma. 1701 94

Netrins are a family of secreted protein related to laminin and act as tropic cues directing axon growth and cell migration during neural development. Netrin-4 is a novel member of netrin family recently identified in the vertebrate with neuritis elongation promoting activity; however, the receptors for netrin-4 are still unknown. To better understand the function and signal transduction pathway of netrin-4, the potential receptors for netrin-4 were studied in this paper. The netrin-4 protein was prepared by introducing a eukaryotic expression vector with a secretable alkaline phosphatase tag (AP4) into COS7 cells to allow the expression of AP4-netrin4 fusion protein. Axon guidance activity of netrin-4 was confirmed by using the cortical explants. After incubation with cultured primary cortical neurons, the neurons were distinctly labeled by the AP4-coupled netrin-4 ligands. In contrast, the binding activity of AP4-netrin4 to neurons could be completely competed by the exogenously expressed netrin-4 protein without AP4 tag, indicating specificity of netrin-4 binding to the potential receptors. Moreover, netrin-4 could also bind to CHO cells transfected with the plasmids expressing two known receptors for netrin-1, Deleted in Colorectal Cancer (DCC) and UNC5 homolog 1 (UNC5H1) respectively. As there are three domains in netrin-4, we further tried to narrow down the region containing binding sites with the receptors. Interestingly, only the N-terminal domain (LNT) could bind to DCC and UNC5H1. A further ligand-receptor binding analysis showed that both the N- and the C-terminal domain (NCT) but not the EGF-like (EGFL) domain of netrin-4 could bind to the surface of cultured primary neurons, indicating the existence of novel receptors for netrin-4. After competed by netrin-4, we confirmed that the binding of AP tagged netrin-4 domains to neurons were also netrin-4 dependent. The binding activity of the N-terminal domain of netrin-4 is about 3-fold higher than that for the C-terminal domain. In summary, our data here indicated that the two known receptors for netrin-1, DCC and UNC5H1, are also receptors for netrin-4, while only LNT but not EGFL and NCT is the key domain for specific binding. In addition, there are novel receptors for netrin-4, where both LNT and NCT but not EGFL are key domains for binding.
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PMID:Characterization of the receptors for axon guidance factor netrin-4 and identification of the binding domains. 1717 65

Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. Evidence is now accumulating that Neogenin is a multi-functional receptor regulating many diverse developmental processes, including neural tube and mammary gland formation, myogenesis and angiogenesis. Little is known of the function of Neogenin in the adult, however, a novel role in the regulation of iron homeostasis is now emerging. While the signal transduction pathways activated by Neogenin are poorly understood, it is clear that the functional outcome of Neogenin activation, at least in the embryo, depends on both the developmental context as well as the nature of the ligand.
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PMID:Neogenin: A multi-functional receptor regulating diverse developmental processes. 1720 44

Netrins regulate axon path-finding during development, but the underlying mechanisms are not well understood. Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. The involvement of Myo X in netrin-1 function was further supported by the effects of inhibiting Myo X function in neurons. Cortical explants derived from mouse embryos expressing a motor-less Myo X exhibit reduced neurite outgrowth in response to netrin-1 and chick commissural neurons expressing the motor-less Myo X, or in which Myo X is silenced using microRNA (miRNA), show impaired axon projection in vivo. Taken together, these results identify a novel role for Myo X in regulating netrin-1 function.
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PMID:Myosin X regulates netrin receptors and functions in axonal path-finding. 1723 72

Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.
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PMID:Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. 1733 89

More than 10 years after its initial discovery, netrin-1 - the first described chimioattractive molecule controlling the guidance of the commissural axons - has recently known a unsuspected wave of interest because of its implication in the development of the nervous system but also, more recently, fot its role in angiogenesis and tumorigenesis. Because, of a series of recent publications on netrin-1 signaling, we propose here to describe the recent insight in netrin-1 signaling via its main receptor DCC (deleted in colorectal cancer), and the recent discovery that netrin controls the assymetric distribution of beta-actin in the growth cone. Thus, it seems that netrin-1, but also the neurotrophic factor BDNF, controls acute growth cone responses such as collapse and turning by the regulation of localized protein translation, such as beta-actin. This process involves both transport of beta-actin mRNA, bound to Vg1RBP, to specific locations, and mRNA translation upon stimulation by local activation of the translation initiation regulator eIF-4E-binding protein 1. Indeed, Netrin-1 induces the movement of Vg1RBP granules into filopodia, and triggers a polarized increase in beta-actin translation on the near side of the growth cone before growth cone turning. The binding of BDNF to its receptor Trk has a similar effect for growth cone attraction, althought it is differentially regulated. Thus, this asymetrically synthesized beta-actin may direct actin polymerization and consequently the migration of the growth cone toward the cue.
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PMID:[Netrin-1 and axonal guidance: signaling and asymmetrical translation]. 1734 94

There is increasing evidence that heparan sulfate (HS) plays an essential role in various axon guidance processes. These observations, however, have not addressed whether HS is required cell autonomously as an axonal coreceptor or as an environmental factor that modulates the localization of guidance molecules in the terrain in which growing axons navigate. Here we demonstrate that netrin-1-mediated commissural axon guidance requires cell-autonomous expression of HS in commissural neurons in vivo. We used the Wnt1-Cre transgene to drive region-specific ablation of Ext1, which encodes an enzyme essential for HS synthesis, in the dorsal part of the spinal cord. Remarkably, Wnt1-Cre-mediated ablation of Ext1 causes commissural axon pathfinding defects that share similarities with those of Netrin-1-deficient and DCC (deleted in colorectal cancer)-deficient mice. Neither Ext1-deficient dorsal spinal cord explants nor wild-type explants in which HS expression was ablated could extend axons in response to netrin-1. Intracellular signaling downstream of netrin-1 and DCC was defective in Ext1-deficient commissural neurons and in DCC-transfected HEK293T cells from which HS was removed. These results demonstrate that the expression of HS by commissural neurons is essential for these neurons to transduce netrin-1 signals, thus providing evidence for a cell-autonomous role of HS in netrin-1/DCC-mediated axon guidance.
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PMID:Netrin-1/DCC signaling in commissural axon guidance requires cell-autonomous expression of heparan sulfate. 1744 18

A novel way of seeing cellular receptors has recently emerged. While a receptor used to be considered as inactive until bound by its ligand, it has been proposed that some receptors may also be active in the absence of their ligand. These so-called dependence receptors induce a specific death signal when the ligand is absent from the cell: Therefore, the expression of one of these receptors leads to the cell becoming dependent on the presence of the ligand for its survival. We have hypothesized that such a trait is a mechanism that allows inhibition of tumor growth, by inducing apoptosis "abnormal" cells that would usually grow in settings of ligand unavailability, i.e. local growth of tumor cells or growth beyond primary tumor site. Along this line, back in the early 90s, Vogelstein and colleagues suggested that a gene called DCC (for deleted in colorectal cancer) could be a tumor suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last fifteen years, controversial data have failed to firmly establish whether DCC is indeed a tumor suppressor gene. However, our observation that DCC behaves as a dependence receptor that induces cell death unless its ligand netrin-1 is present, together with the fact that mice engineered to block DCC-induced cell death by overexpressing netrin-1 are predisposed to develop colorectal tumors, strengthen the role of dependence receptors as tumor suppressors. In this review, we will describe the implication of the netrin-1/receptor pairs as novel negative regulators of tumor development.
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PMID:Dependence receptors: when apoptosis controls tumor progression. 1744 33

It is very important to investigate the mechanism of axonal growth in the ischemic brain in order to consider a novel mean of therapy for stroke. Netrins are chemotropic factors for axon with chemoattractant or chemorepellant guidance activities, and deleted in colorectal cancer (DCC) and neogenin are receptors for netrins. In this study, we examined expressions of netrin-1, DCC, and neogenin in the brain after 90 min of transient middle cerebral artery occlusion (tMCAO). Netrin-1 was expressed in neurons at the peri-ischemic area with a peak at 14 days. DCC was expressed both in neurons and astrocytic feet with a peak at 14 days, though neogenin was expressed in endothelial cells at MCA territory with a peak at the same time point. These results suggest that netrin-1 is involved in the promotion of axonal growth. The expression of netrin-1 and DCC was overlapped both in the spatial and temporal patterns, indicating that DCC plays a role in netrin-1's axonal growth promoting effects. The location of neogenin positive cells differed from that of netrin-1 positive cells, thus its angiogenic activity may not have relevance with netrin-1.
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PMID:Expression of netrin-1 and its receptors DCC and neogenin in rat brain after ischemia. 1757 19

Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name 'pontine tegmental cap dysplasia' (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI.
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PMID:Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. 1771 79

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