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PubMed1999

Altered phenotype of HT29 colonic adenocarcinoma cells following expression of the DCC gene.

On 18q, frequently deleted in late stage colorectal cancers, a gene, Deleted in Colon Cancer (DCC), has been identified and postulated to play a role as a tumor suppressor gene. DCC is retained in the majority of mucinous tumors, which produce high levels of mucins, and seems to be preferentially expressed in intestinal goblet cells. To investigate whether DCC is related to mucin expression and can modulate the transformed phenotype, we introduced a full-length DCC cDNA into HT29 cells, which can be induced in vitro to express MUC2, the gene that encodes the major colonic mucin. Expression of DCC did not modulate constitutive or induced expression of MUC2, nor did DCC induce a mature goblet cell phenotype. However, HT29 clones expressing high and low levels of DCC protein showed a significant decrease in cell proliferation and tumorigenicity. Furthermore, increased shedding and an elevated rate of spontaneous apoptosis were associated with higher levels of expression of DCC. In summary, while restoration of DCC expression in a human colon carcinoma cell line did not influence expression of differentiation markers, DCC expression did affect the growth and tumorigenic properties of the cells suggesting that DCC can modulate the malignant phenotype of colon cancer.

Adenocarcinoma↗
PubMed1996

Deleted in Colorectal Cancer (DCC) encodes a netrin receptor.

The guidance of developing axons in the nervous system is mediated partly by diffusible chemoattractants secreted by axonal target cells. Netrins are chemoattractants for commissural axons in the vertebrate spinal cord, but the mechanisms through which they produce their effects are unknown. We show that Deleted in Colorectal Cancer (DCC), a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses netrin-1-binding activity. Moreover, an antibody to DCC selectively blocks the netrin-1-dependent outgrowth of commissural axons in vitro. These results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans and Drosophila.

Amino Acid Sequence↗
PubMed1988

Correlation between ERICA and DCC assay in hormone receptor assessment of human breast cancer.

To study the basic relationships between estrogen receptor immunocytochemical assay (ERICA) and dextran-coated charcoal (DCC) techniques, 116 women affected by breast cancer were admitted to the study from June 1985. In 56% of cases the tumor sample came from patients with operable disease and in 44% from patients with advanced inoperable disease. We found an overall agreement of 80% between the two methods characterized by a high sensitivity (95%) and a low specificity of ERICA versus DCC. ER/ICA negative results were found in 20 out of 78 ER/DCC positive cases; on the contrary, discordant results were found in only 3 out of 38 cases described by DCC as ER negative. 29 patients with advanced disease and ER/DCC positive tumors were considered for clinical analysis and reliability of each hormone receptor assay. A clinical response was reached in 69% of ER/DCC positive patients and on 64% of ER/ICA positive ones (16/25). However, it must be noted that 4/29 cases described as negative by ERICA were clinically responsive to hormone therapy.

Breast Neoplasms↗
PubMed1999

The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation.

1. Neuronal migration is one of the principal events in laying out the architectural plan of the embryonic central nervous system (CNS). In addition, the correct navigation of axonal growth cones to their specific targets is essential for the establishment of the intricate network of axon projections found within the mature CNS. 2. The Deleted in Colorectal Cancer (DCC) guidance receptor, together with its ligands, the netrins, is now emerging as a major navigational system driving both neuronal and axonal migrations. Members of the netrin family of secreted guidance cues are also likely to be ligands for a second DCC-like receptor, neogenin. 3. The present paper reviews the current understanding of DCC-netrin-dependent axon pathfinding within the embryonic spinal cord and suggests novel modes of action for both DCC and neogenin.

Animals↗
PubMed2006

FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5.

During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.

Animals↗
PubMed2006

Netrin/DCC-mediated attraction of vagal sensory axons to the fetal mouse gut.

Vagal sensory axons and migrating neural crest-derived precursor cells follow similar pathways to reach the gut. The crest-derived cells express the netrin receptor deleted in colorectal cancer (DCC) and migrate toward netrins expressed by the intestinal mucosa and pancreas; this attraction is required for the formation of submucosal and pancreatic ganglia. We tested the hypothesis that enteric netrins also attract vagal sensory fibers. These axons were located as a function of age in fetal mice by applying the lipophilic tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) bilaterally to nodose ganglia. DiI-labeled axons were found in the esophagus and proximal stomach by E12 and, more distally, in the small bowel at E14-E16. Transcripts encoding DCC were expressed in the nodose ganglia of mice from E12 to adulthood but were developmentally regulated. Paraesophageal anterior and posterior vagal trunks were DCC immunoreactive from E12 to E16. Transcripts encoding netrin-1 were expressed in the developing foregut and midgut; netrin-1 immunoreactivity was detected in the outer gut mesenchyme and mucosal epithelium. Neurites from explanted E14 nodose ganglia grew selectively toward cocultured E14 distal foregut explants (P < 0.01). Antibodies to DCC specifically abolished this preferential outgrowth (P < 0.05). Nodose axons also grew selectively toward cocultured netrin-secreting 293-EBNA cells (P < 0.005); antibodies to DCC again blocked this preferential outgrowth (P < 0.05). These data suggest that netrins, which are expressed in the bowel, attract DCC-expressing vagal sensory axons.

Age Factors↗
PubMed2005

Enhanced expression of netrin-1 protein in the sciatic nerves of Lewis rats with experimental autoimmune neuritis: possible role of the netrin-1/DCC binding pathway in an autoimmune PNS disorder.

Netrin-1 is a chemotropic factor that plays an important role as a survival factor in the adult nervous system. To investigate whether netrin-1 is involved in autoimmune injury of the peripheral nervous system (PNS), the temporal expression of netrin-1 protein was analyzed in the sciatic nerves of Lewis rats with experimental autoimmune neuritis (EAN). Western blot analysis revealed a significant increase in the level of netrin-1 protein in the sciatic nerves of rats on days 11 to 24 post-immunization (p.i.) compared to controls; netrin-1 expression declined by day 30 p.i. Immunohistochemistry revealed that netrin-1 protein was expressed weakly in Schwann cells and vessels in the sciatic nerves of normal and CFA-immunized control rats. In the sciatic nerves of EAN-affected rats, netrin-1 immunoreactivity was increased mainly in the cell membrane and extracellular matrix of OX42-positive macrophages and S100-positive Schwann cells at the peak and recovery phases of EAN. Moreover, the putative netrin-1 receptor, deleted in colorectal cancer (DCC), was expressed mainly in axons, some macrophages, and Schwann cells in EAN-affected sciatic nerves, although the level of protein expression did not change significantly over the course of EAN. We suggest that a significant increase in netrin-1 expression contributes to host cell survival and axon regeneration to counter autoimmune injury and inflammation, which may play a role in recovery from EAN-induced paralysis.

Animals↗
PubMed1999

Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1.

Long distance cell migration occurs throughout the developing CNS, but the underlying cellular and molecular mechanisms are poorly understood. We show that the directed circumferential migration of basilar pontine neurons from their origin in the neuroepithelium of the dorsal hindbrain to the ventral midline involves the extension of long (>1 mm) leading processes, which marker analyses suggest are molecularly distinct from axons. In vivo analysis of knockout mice implicates the axonal chemoattractant netrin-1, functioning via its receptor Deleted in Colorectal Cancer (DCC), in attracting the leading process to the ventral midline. Direct evidence for this chemoattractant mechanism is provided, using explant cultures and time-lapse analysis in vitro. Our results demonstrate the attraction of migrating neurons in the mammalian brain by an axon guidance molecule and the chemotactic responsiveness of their leading processes.

Animals↗
PubMed2005

Deleted in colorectal cancer binding netrin-1 mediates cell substrate adhesion and recruits Cdc42, Rac1, Pak1, and N-WASP into an intracellular signaling complex that promotes growth cone expansion.

Extracellular cues direct axon extension by regulating growth cone morphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural axon extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neurons with netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), and N-WASP (neuronal Wiskott-Aldrich syndrome protein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, and Pak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest that DCC influences growth cone morphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin.

Analysis of Variance↗
PubMed1993

[Determination of steroid hormone receptors with the biochemical DCC method in endometrial cancer and tumor margin-endometrium relations to cellular changes and hormone level].

In endometrial carcinoma and the surrounding marginal endometrium from 48 postmenopausal patients, the concentrations and dissociation constants of steroid hormone receptors were studied by the dextran-coated charcoal method (DCC), parallel to ploidy and morphology of tumour cell nuclei, grading, and the hormonal status. The results show, that the proportion of receptor-positive tumours is decreased in an advanced stage of disease. The mean receptor concentrations correlate both with nuclei parameters and the morphological results and reflect the process of dedifferentiation in the tumour centre. The higher receptor concentrations, especially the estradiol receptor concentration observed in the marginal endometrium, and the increased estradiol level in serum, demonstrate a raised tendency to proliferation in this region and could support the hypothesis, that a higher receptor level in adenomatous-hyperplastic tissues participates in tumour genesis. In patients with an advanced stage of the disease, determination of both receptors can yield indications for a purposeful adjuvant hormone therapy (anti-estrogen and/or gestagen), in addition to providing an aid to prognosis.

Aged↗
PubMed2002

Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.

Neuronal growth cones are guided to their targets by attractive and repulsive guidance cues. In mammals, netrin-1 is a bifunctional cue, attracting some axons and repelling others. Deleted in colorectal cancer (Dcc) is a receptor for netrin-1 that mediates its chemoattractive effect on commissural axons, but the signalling mechanisms that transduce this effect are poorly understood. Here we show that Dcc activates mitogen-activated protein kinase (MAPK) signalling, by means of extracellular signal-regulated kinase (ERK)-1 and -2, on netrin-1 binding in both transfected cells and commissural neurons. This activation is associated with recruitment of ERK-1/2 to a Dcc receptor complex. Inhibition of ERK-1/2 antagonizes netrin-dependent axon outgrowth and orientation. Thus, activation of MAPK signalling through Dcc contributes to netrin signalling in axon growth and guidance.

3T3 Cells↗
PubMed2004

Apoptosis initiated by dependence receptors: a new paradigm for cell death?

A distinct group of receptors including DCC, UNC5, RET and Ptc1 is known to function in ligand-dependent neuronal growth and differentiation or axon guidance. Acting as "dependence receptors", they may also regulate neuronal cell survival by inducing apoptosis in the absence of cognate ligand. Receptor-initiated apoptosis requires proteolytic (caspase) cleavage and exposure of a pro-apoptotic region in the cytoplasmic domains of the receptors. In contrast, classical apoptosis induced by growth factor or cytokine deprivation involves loss of survival signaling without receptor cleavage. DCC, UNC5, RET and Ptc1 are downregulated or mutated in diverse cancers, and show properties characteristic of tumor suppressors, consistent with their ability to promote neuronal cell death. Dysfunctional dependence receptors have been linked to the loss of specific neurons in certain inherited and neurodegenerative diseases. Dependence receptor-initiated apoptosis represents a novel paradigm for the controlled removal of specific cells during neural development and elimination of malignant cells that have strayed beyond regions of ligand availability.

Animals↗
PubMed1998

Decreased DCC mRNA expression in human gastric cancers is clinicopathologically significant.

Loss of heterozygosity (LOH) or decreased expression of the deleted in colorectal cancer (DCC) gene, a candidate tumor suppressor gene, has been suggested to correlate with progression in several types of tumors. In human gastric cancers, although DCC LOH has been reported to be frequent in expanding-type tumors, the relation of decreased DCC mRNA expression with clinicopathological features, including metastatic events, remains to be investigated in detail. Therefore, expression levels of DCC mRNA were examined in 52 advanced gastric cancers by the reverse transcription-polymerase chain reaction method combined with Southern blot analysis. Overall, decreased DCC mRNA expression was observed in 27 of the tumors (52%). According to Ming's [Cancer 39, 2475-2485 (1977)] classification, the expanding type showed a significantly higher incidence (71%) than the infiltrative type (17%) (p = 0.0002). Immunohistochemical analysis demonstrated the presence of DCC expression in cancer but not non-cancerous cells in infiltrative-type lesions. An additional follow-up study of tumor recurrence in 42 patients undergoing curative resection implicated decreased DCC expression in metachronous liver metastasis. The results indicate that decreased DCC mRNA expression is closely associated not only with the expanding-type phenotype but also with liver metastasis of gastric cancers. Assessment of this parameter in primary lesions may thus find predictive application.

Adult↗
PubMed2003

p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy.

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction-single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction-single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.

Adenocarcinoma↗
PubMed2000

[Dependence receptors: links between apoptosis, nervous system development and control of tumorigenesis].

The dependence receptor notion was based on the observation that the effects of a number of receptors that function in both nervous system development and tumorigenesis (especially metastasis) cannot be explained simply by a positive effect of signal transduction induced by ligand binding. Receptors such as the common neurotrophin receptor p75NTR, the androgen receptor (AR), DCC (deleted in colorectal cancer), and RET (rearranged during transfection) demonstrate effects that are more adequately explained when these are considered to be dependence receptors. These receptors show two distinct forms of signal transduction depending on their respective ligand availability: in the presence of their ligands, they transduce a signal for either proliferation or differentiation; however, they are not inactive in the absence of their ligands, but rather induce an active signal for cell death. Such receptors thus create a cellular state of dependence on their ligands, the loss of ligand availability inducing cell suicide or enhancing the likelihood of cellular suicide. This new concept is reviewed here enlightening the molecular mechanisms of these receptors and their potential relevance in vivo in the development of the nervous system and in the control of tumorigenesis.

Animals↗
PubMed2003

The expression of DCC protein in female breast cancer.

BACKGROUND: The deleted in colorectal cancer (DCC) gene has been shown to be frequently deleted or its expression reduced or absent in glioblastomas, colorectal, gastro-intestinal, pancreatic and prostatic tumors. In the present study, we investigated the expression of DCC in surgical specimen from 75 patients with primary breast cancer. METHODS: The expression of the DCC, estrogen receptors (ER), and progesterone receptors (PR) was studied in 75 surgical specimens of primary breast cancer using an immunohistochemical method. To evaluate the outcomes of the breast cancer patients, we followed up the patients during minimum of 10 years. RESULTS: Reduced or loss of expression of DCC was identified in 45 out of 75 samples. There were significant differences between cases without metastasis or local recurrences versus these with metastasis or local recurrences (p = 0.006), and between patients alive with no evidence of malignancy versus those with recurrence or dead of disease (p = 0.005). There were no significant differences between the DCC status and age, sex, tumor location, stage, grade, or proportion of patients who received adjuvant therapy. CONCLUSIONS: These findings suggest that a decrease in DCC expression may influence the prognosis of breast carcinoma patients.

Breast↗
PubMed1990

Oestrogen and progesterone receptor content as a prognostic factor in advanced epithelial ovarian carcinoma.

Levels of oestrogen receptor (ER) and progesterone receptor (PgR) in ovarian cancer tissue were examined with regard to their prognostic importance for survival in 179 patients with primary epithelial ovarian cancer stage III or IV in relation to: FIGO-stage, histological type, histological grade, age, ascites, and postoperative residual tumour. Hormone receptor content was determined with the DCC-method, receptor values higher than 9 fmol/mg protein were considered positive. Response to postoperative chemotherapy was significantly correlated with PgR content (80% responders in the group with PgR positive tumours and only 61% responders in the group with PgR negative tumours). A Cox proportional hazards regression model identified histological grade, residual tumour, age and PgR content as independent prognostic factors for survival in advanced epithelial ovarian carcinoma. PgR content had particularly significant prognostic relevance for patients with postoperative residual tumour mass less than or equal to 2 cm in diameter. Within this group of patients, those who are PgR positive have a 2-years survival probability of 83% compared with only 51% in the PgR-negative group.

Female↗
PubMed2002

Deleted in colorectal carcinoma and differentially expressed integrins mediate the directional migration of neural precursors in the rostral migratory stream.

Precursors of the olfactory interneurons migrate from the subventricular zone via the rostral migratory stream (RMS). To investigate the molecular mechanisms by which RMS cells migrate, we used a slice preparation, which allows the migrating cells to be imaged at very high temporal and spatial resolution in the presence of added inhibitors. Using immunohistochemistry, we first determined that the alpha1-, beta8-, and beta1-integrin subunits and the alpha5- and gamma1-laminin subunits are expressed during embryonic day 16 to the early postnatal stage. During early postnatal days, alpha(v)- and beta6-integrins appeared, and their expression persisted throughout adulthood. The migrating cells also expressed the netrin receptors neogenin and Deleted in Colorectal Carcinoma (DCC). Netrin-1 is expressed in olfactory mitral cells. Anti-integrin antibodies inhibited the production of protrusions as well as cellular translocation. In contrast, anti-DCC antibodies primarily altered the direction of the protrusions; consequently, the migration was no longer unidirectional, and the speed was reduced. Thus, the interaction of DCC, possibly through an interaction with netrin-1, contributes to the direction of migration by regulating the formation of directed protrusions. In contrast, the integrins function in production of protrusions and cellular translocation, with different integrins participating at different developmental stages.

Aging↗