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PubMed1999

In vitro analysis of the role of DCC in mucus-secreting intestinal differentiation.

The deleted in colorectal cancer (DCC) gene was initially described as a colon cancer-associated tumor suppressor gene and subsequently proposed to be involved in goblet cell differentiation, but its precise role in normal intestine physiology and in cancer remains to be established. We have analyzed DCC mRNA expression in a panel of human colorectal cancer cell lines with a variety of differentiation phenotypes by reverse transcription-polymerase chain reaction (RT-PCR) and have shown that (1) most cell lines showed lower levels of DCC mRNA than normal colonic tissue; (2) only 1 cell line lacked detectable levels of DCC mRNA expression; (3) a discrepancy was found between the detectability of RT-PCR products corresponding to the extracellular and intracellular domains of DCC; and (4) there was no association between the presence of DCC transcripts and the differentiation phenotype. Specifically, DCC was not exclusively associated with the mucus-secreting phenotype, as determined by Alcian blue staining and Northern blotting with mucin gene probes. This was further supported by immunohistochemical results on DCC product and mucins in normal colon: DCC was detected in both goblet and absorptive cells. The introduction of full-length DCC cDNA in undifferentiated HT-29 cells did not have any effect on their differentiation phenotype, as shown by morphological studies and analysis of markers for this process in colon, such as mucins, dipeptidylpeptidase IV, villin and sucrase-isomaltase. There were no effects on cell proliferation in vitro. Our results indicate that DCC is not selectively involved in the mucosecretory differentiation pathway and that it is neither sufficient nor essential for normal intestinal differentiation.

Cell Adhesion Molecules↗
PubMed2005

Cloning of full-length zebrafish dcc and expression analysis during embryonic and early larval development.

Members of the DCC family play key roles in axon guidance in vertebrates as well as invertebrates. In zebrafish, only a short partial sequence of the dcc gene has been reported to date. Here, we report the cloning of full-length zebrafish dcc. Zebrafish DCC shares the typical structure of the DCC subgroup of the immunoglobulin superfamily, consisting of four immunoglobulin and six fibronectin-type III repeats in the extracellular domain, a single transmembrane domain, and an intracellular domain with three conserved motifs. As a first step toward studying the function of dcc, we analyzed its sequence and characterized its expression pattern during embryonic and larval development. dcc is expressed highly in brain and spinal cord, but distinct staining was also observed in developing pectoral fins, pancreas, intestine, and heart. Thus, dcc may play roles not only in axon guidance, but in morphogenesis and functioning of these organs as well.

Amino Acid Sequence↗
PubMed2001

Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18.

We have previously reported that losses of genomic material from the long arm of chromosome 18 are frequent in atypical and anaplastic meningiomas but rare in benign meningiomas. In the present study, we have investigated a series of 37 meningiomas for mutation and expression of 4 tumor suppressor genes (MADH2, MADH4, APM-1 and DCC) located at 18q21. Comparative genomic hybridization or loss of heterozygosity analysis showed losses on chromosome 18 that included sequences from 18q21 in 15 of 37 tumors. Mutation analysis of APM-1 revealed a missense mutation (c. 1819G>A: G607S) in 1 atypical meningioma. None of the tumors showed mutations of MADH2 and MADH4 or loss of detectable transcripts from MADH2, MADH4, APM-1 and DCC. In contrast to human brain tissue, normal leptomeninges and meningiomas showed preferential expression of a DCC splice variant lacking 60 base pairs from exon 17. Taken together, our data do not support a significant role for MADH2, MADH4, APM-1 and DCC alterations in the pathogenesis of meningiomas. The targeted gene that is inactivated in most meningiomas with 18q losses remains to be identified.

Adiponectin↗
PubMed2006

Frequent gene dosage alterations in stromal cells of epithelial ovarian carcinomas.

Stromal cells are an active and integral part of epithelial neoplasms. We have previously observed allelic imbalance on chromosome 3p21 in both stromal and epithelial cells of ovarian tumors. This study was designed to explore gene dosage alterations throughout human chromosomes from stromal and epithelial cells of epithelial ovarian carcinomas. Thirteen stromal and 24 epithelial samples, microdissected from epithelial ovarian carcinomas, were analyzed using multiplex ligation-dependent probe amplification technique. Analysis covered 110 cancer related genes. Frequent genetic alterations were detected both in the stroma and epithelium of ovarian carcinomas. The mean number of altered genes per tumor was 10.8 in stroma and 23.6 in epithelium. In the stroma, the mean number of gains was 6.6 and of losses 4.2 and in the epithelium 13.7 and 9.9. The high number of changes associated with advanced tumor stage (p = 0.035) and death due to ovarian cancer (p = 0.032). The most frequent alteration was the deletion of the deleted in colorectal carcinoma (DCC) on chromosome 18q21.3 in 62% of samples. Loss of DCC was related to endometrioid subtype (p = 0.033). Large chromosomal aberrations were detected on the basis of alterations in adjacent genes. Most importantly, 38 genes showed similar genetic alterations (gain-gain or loss-loss) in stromal and epithelial compartments of 11 tumor pairs. Thus, frequent genetic alterations in stromal cells of epithelial ovarian carcinomas resembled those of malignant epithelial cells and may indicate a common precursor cell type. Epithelial-mesenchymal transition may generate transformed cancer cells and modify the tumor microenvironment with distinct properties.

Adult↗
PubMed2001

Interaction of Myc-associated zinc finger protein with DCC, the product of a tumor-suppressor gene, during the neural differentiation of P19 EC cells.

Expression of the DCC (deleted in colorectal cancer) protein is strongly induced during the neural differentiation of mouse P19 embryonal carcinoma (EC) cells that occurs when these cells are treated with retinoic acid (RA). Myc-associated zinc finger protein (MAZ) is a DNA-binding protein that is widely expressed and functions in human, mouse and hamster cells as an activator, an initiator or a terminator of transcription. However, the biological functions of MAZ remain elusive. We report here that MAZ associates with the cytoplasmic domain of the DCC protein in vivo and in vitro. Yeast two-hybrid assays confirmed this association. An immunofluorescence study demonstrated that DCC protein is expressed at elevated levels in neuron-like P19 EC cells, in particular in axons, in which the MAZ protein is also expressed. We found that MAZ was translocated from the nucleus to the cytoplasm during the RA-induced terminal differentiation of P19 EC cells with resultant loss of the ability of MAZ to bind to the ME1a1 site of the c-myc promoter. Taken together, our observations imply that the DCC protein might play a critical role as a signaling molecule in the regulation of the transcriptional activity of MAZ during the neural differentiation of P19 EC cells.

Active Transport, Cell Nucleus↗
PubMed1997

Molecular characterization of human neogenin, a DCC-related protein, and the mapping of its gene (NEO1) to chromosomal position 15q22.3-q23.

Neogenin was first identified in the chick embryo, and like a number of cell surface proteins of the immunoglobulin (Ig) superfamily, including N-CAM and L1 (generally called cell adhesion molecules or CAMs), it is expressed on growing nerve cells in the developing nervous system of vertebrate embryos. Neogenin is also expressed in other embryonic tissues, suggesting a more general role in developmental processes such as tissue growth regulation, cell-cell recognition, and cell migration. Neogenin, unlike the CAMs, is closely related to a unique tumor suppressor candidate molecule, deleted in colorectal carcinoma (DCC). Like DCC, the neogenin protein consists of four immunoglobulin-like (Ig-like) domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain. We now report the cloning and sequencing of cDNA clones coding for the human neogenin protein. Human neogenin shares 87% identity with its chicken homolog, and like its chicken counterpart it is expressed in at least two different isoforms derived from alternative splicing in the intracellular domain. Northern blot analysis revealed two mRNA species of about 5 and 7 kb. The chromosomal location of the human neogenin gene (HGMW-approved symbol NEO1) was determined as 15q22.3-q23, using fluorescence in situ hybridization. The gene therefore maps in the vicinity of a locus associated with Bardet-Biedl syndrome. The identification of human neogenin and its chromosomal location provides a basis for studying its involvement in genetic disorders or diseases.

Alternative Splicing↗
PubMed2002

Prediction of distant metastases after curative surgery for rectal cancer.

BACKGROUND: This study was performed to define selection criteria for adjuvant therapy in rectal cancer. MATERIALS AND METHODS: An immunohistochemical analysis using nine monoclonal antibodies against CEA, CD15s, CD44v6, DCC, E-cadherin, EGF-R, NM23, PAI-1, and P53 was performed on paraffin sections of two matched (age, gender, UICC stage [I-III], year of operation [1982-1991]) groups of patients (n = 2 x 64) with rectal carcinoma curatively treated by surgery alone. The two groups differed only with regard to metachronous distant metastatic spread. In order to exclude the influence of surgery, all patients had to meet the selection criterion "free of locoregional disease." Follow-up was prospective (median 80 months). Conventional staining procedures and immunohistochemical evaluation were used. Tumor grading and lymphatic and extramural venous invasion were also investigated. Analysis was performed with Fisher's exact test and Kaplan-Meier estimates of disease-free survival (log rank). The Cox model was used for multivariate analysis. RESULTS: In univariate analysis only grading (P < 0.001) and extramural venous invasion (P < 0.001) correlated significantly with metachronous metastases. In multivariate analysis, beside grading (P = 0.010) and extramural venous invasion (P = 0.011), CD15s (P = 0.042) was also of significance. All other immunohistochemical markers failed. CONCLUSIONS: The histopathological parameters grading and extramural venous invasion appear to be acceptable predictors of metachronous distant spread in curatively resected rectal cancer. In contrast to the immunohistochemical markers, grading seems to better reflect the individual tumor phenotype and its behavior.

Adult↗
PubMed1998

The DUTT1 gene, a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression.

A new member of the NCAM family mapping to 3p12 has been isolated and predicted to be arranged in five immunoglobulin-like domains and three fibronectin-like domains which are particularly homologous to L1. There is a transmembrane domain and a long cytoplasmic region with no detectable homology to other sequences. Although less closely related to DCC, another family member, both share a loop of positively charged amino acids within the first immunoglobulin domain, unique to these two members of this very large gene family. Preliminary studies of expression in mouse embryos support an inferred role in neural development, but the observation of widespread gene expression in adult human tissues indicates that this protein has additional functions to those performed in neural cells.

Amino Acid Sequence↗
PubMed1998

DCC protein as a predictor of distant metastases after curative surgery for rectal cancer.

PURPOSE: The aim of this study was to determine the value of DCC (deleted in colorectal cancer) protein for predicting metachronous distant metastases after curative surgery for rectal cancer. The DCC protein--for which a gene has been located on chromosome 18q--has recently been reported to have a prognostic value in colorectal cancer. This finding might have implications for treatment of International Union Against Cancer Stage II rectal carcinoma, in which distant metastases will develop in 14 percent of patients despite optimal surgery. METHODS: Paraffin-embedded tissues from 85 patients who developed distant metastases, but no local recurrence, after curative surgery for rectal cancer were matched with 85 samples from patients who remained disease-free. Matching criteria were tumor stage, age, gender, and date of surgery. Expression of DCC protein was assessed using immunohistochemistry. End points of follow-up were recurrence of disease and death. Mean follow-up was 9.6 years. No patient received either local or systemic adjuvant therapy. RESULTS: The DCC protein was found to be expressed in 64.9 percent of tumor samples. Nonexpression of DCC protein had an negative influence on survival (P = 0.03). For all tumor stages together, sensitivity of the test for subsequent occurrence of distant metastases was 42 percent and specificity was 71 percent. In Stage II cancers, the positive predictive value was 19 percent, and the negative predictive value was 88 percent. CONCLUSIONS: Our results confirm that DCC protein is a useful prognostic marker in patients with rectal carcinomas, but the positive predictive value of DCC protein for occurrence of metachronous metastases does not appear to be sufficient to justify adjuvant therapeutic measures in Stage II rectal cancer.

Biomarkers, Tumor↗
PubMed1999

Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer.

We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression.

Adenocarcinoma↗
PubMed2002

p53 and DCC immunohistochemistry in curative rectal cancer surgery.

BACKGROUND AND AIMS: In rectal cancer altered expression of p53 or DCC may be indicative of poor patient prognosis. This study determined by immunohistochemistry the tumour status of p53 protein and DCC protein in patients with rectal cancer who had a curative resection and were followed-up prospectively and examined the correlation to clinical and pathology variables. PATIENTS AND METHODS: The study included 171 who had a curative resection for rectal cancer: 88 at Concord Hospital (CH) followed up for a mean of 11 years and 83 at Royal Prince Alfred Hospital (RPAH) followed up prospectively for a mean of 4.3 years. Specimens were assessed by immunohistochemical assay of p53 expression ( n=170) and of DCC expression ( n=168). RESULTS: p53 over-expression was demonstrated in 58% of CH tumours and 59% of RPAH tumours. Absence of normal DCC expression was demonstrated in 66% of CH tumours and 52% of RPAH tumours. On both separate and combined analysis of these groups there were no significant associations by univariate analysis between p53 expression or DCC expression or combinations of p53 and DCC expression and the pathology variables: extent of penetration through bowel wall, lymph node involvement, presence of venous invasion, and tumour differentiation. CONCLUSION: The immunohistochemical p53 and DCC status of rectal tumours was not associated with other clinical or pathology variables, nor predictive of outcome.

Cell Adhesion Molecules↗
PubMed2004

Deleted in colorectal cancer protein expression as a possible predictor of response to adjuvant chemotherapy in colorectal cancer patients.

PURPOSE: The deleted in colorectal cancer (DCC) gene predicts a poor outcome for patients with colorectal carcinoma. This study was designed to investigate whether the expression of the DCC protein also can predict response to adjuvant chemotherapy. METHODS: The expression of DCC was evaluated immunohistochemically in 74 paraffin-embedded tumor samples from patients with Stage II (n = 41) and Stage III (n = 33) colorectal carcinomas. Follow-up time was at least 60 (median, 64) months. Follow-up was at least five years for all patients who are alive. End points of the study were recurrence of disease and death. Forty-eight patients received adjuvant therapy of 5-fluorouracil + levamisole; 28 were not treated. RESULTS: Fifty percent of tumors were deleted in colorectal cancer-positive (DCC+). Proportion of survival and disease-free survival were higher in the DCC+ patients (83 percent) than in deleted in colorectal cancer-negative (DCC-; 54 percent). In the DCC+ group, adjuvant treatment was a strong positive predictive factor for survival and disease-free survival. All DCC+ patients who received adjuvant chemotherapy (CHEMO+) are alive with no evidence of disease, whereas without chemotherapy (CHEMO-) only 54 percent are alive ( P = 0.0001). When stratification was performed by stage, patients in Stage II who were DCC+/CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO- survival rate was 75 percent and disease-free survival rate 62 percent ( P = 0.042). Patients in Stage III who were DCC+/ CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO- both dropped to zero ( P = 0.0002). On the other hand, in the DCC- tumors, there was no statistical significant relationship between chemotherapy and survival or disease-free survival (DCC-/CHEMO- had 57 percent survival; DCC-/CHEMO+ had 52 percent survival). CONCLUSIONS: DCC is a prognostic factor for colorectal cancer. Positive expression of DCC identifies a subgroup of patients who respond favorably to adjuvant chemotherapy, which resulted in our cases, in 100 percent survival and disease-free survival rates. Without treatment, the survival rate of DCC+ patients dropped significantly. We suggest that DCC immunostaining should be performed routinely. All DCC+ patients should receive adjuvant chemotherapy. For DCC- tumors, a larger cohort of patients should be studied before definitive conclusions can be drawn; however, clinical trials of new drug combinations should focus on DCC- patients.

Adjuvants, Immunologic↗
PubMed2006

The use of early and midpoint adenoma-carcinoma sequence biomarkers in prediction of neoplastic progression in patients with a history of colorectal neoplasia.

Since significant neoplasia after initial colonoscopy is low, we conducted this pilot study to compare the predictive role for colorectal neoplasia recurrence of anti-DCC with that of Adnab-9 binding to colonic effluent of high-risk patients. DCC and Adnab-9 effluent ELISA were performed at baseline colonoscopies. The results of follow-up colonoscopies were reviewed. To ensure specificity, immunohistochemistry and Western blot was performed with anti-DCC and for Adnab-9 where optimal fixation times were also evaluated. Mean follow-up was 2.6 years. Of 21 patients, 6 of 10 who progressed to CRN and 2 of 11 who did not had a positive Adnab-9 ELISA result (P=0.08). Despite an initial good correlation with Adnab-9 ELISA results in a smaller dataset, we were unable to obtain consistent subsequent DCC immunohistochemistry or Western blot data using antibody from two different sources. However, the original dataset of Adnab-9 results was reproducible on repetition of the ELISA with a larger set of samples that included this initial dataset and optimal fixation time was 20 min. We conclude that Adnab-9 appears to be a promising prognostic marker for neoplasia in the high-risk population. Industry standards need to be developed for DCC monoclonal antibodies that may have similar utility.

Adenoma↗
PubMed2005

Maternal dietary choline availability alters the balance of netrin-1 and DCC neuronal migration proteins in fetal mouse brain hippocampus.

Alterations in maternal dietary choline availability during days 12-17 of pregnancy led to an increase in the level of immunoreactive netrin-1 and a decrease in the level of DCC protein in the developing fetal mouse brain hippocampus compared with controls. Changes in the expression of cell migration cues during development could account for some of the lifelong consequences of maternal dietary choline availability for cognitive and memory processes.

Animals↗
PubMed2004

Deleted-in-colon-cancer protein expression in patients with adenocarcinoma of the urinary tract and a history of colorectal cancer.

OBJECTIVES: To assess whether immunostaining for deleted-in-colon-cancer (DCC) protein, a previously established prognostic marker in colon and bladder cancer, may assist in resolving the uncommon differential diagnostic dilemma of distinguishing primary from secondary urothelial adenocarcinoma. METHODS: The study group consisted of 12 patients with adenocarcinoma involving the bladder or ureter and previously resected colorectal carcinoma between 1988 and 2002. All patients were initially considered to have primary urothelial transitional cell carcinoma, and the management strategy was conducted accordingly. The clinical data were recorded from the charts, and immunohistochemical staining for DCC was performed on formalin-fixed paraffin-embedded tissues containing the primary colorectal cancer and ensuing urinary tract tumor. Staining was defined as positive when at least 25% of the tumor cells were immunoreactive for DCC. RESULTS: Of the 12 patients, 10 presented with bladder and 2 with ureteral adenocarcinoma. All secondary tumors originated from a primary carcinoma invariably located along the left colon or rectum. The overall 5-year disease-specific survival rate from the time of colectomy was 31% at a median follow-up of 50 +/- 8 months. Of the 12 patients, 5 (41%) had positive DCC immunoreactivity. In all cases, concordant expression of DCC was found in the primary colorectal cancer and the ensuing tumor in the urinary tract. The survival time from colectomy was significantly longer for the DCC-positive subgroup (median 59 months, 95% confidence interval 41 to 77) than in the DCC-negative subgroup (median 23 months, 95% confidence interval 13 to 37). Likewise, the time lag between colectomy and tumor recurrence in the urinary tract was significantly longer in the patients with DCC-positive tumors (median 35 months) than in those with DCC-negative tumors (median 10 months). CONCLUSIONS: DCC immunoreactivity was consistently observed in secondary bladder or ureteral adenocarcinoma when the primary colorectal lesion expresses DCC, and thus may serve to establish the origin of the tumor. Positive DCC protein expression in secondary urinary tract adenocarcinoma of colorectal origin may identify a subset of patients with a relatively favorable prognosis. Additional studies are required to confirm our results.

Adenocarcinoma↗
PubMed2004

Expression of DCC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis.

OBJECTIVE: Although DCC has been considered as a candidate tumor suppressor, the roles it plays in the uterine endometrium and in the carcinogenic process remains unclear. To define these roles more clearly, we examined the expression of DCC and its ligand, netrin-1, in the normal endometrium and in endometrial cancer. METHODS: The expression of DCC and netrin-1 in normal endometrial glands and in cancer cell lines was examined by RT-PCR and immunohistochemistry. The effects of exogenous DCC and netrin-1 expression were observed together with the respective expression vector transfection. RESULTS: Endometrial glands in the proliferative and early secretory phase expressed both DCC and netrin-1, but glands in the late-secretory phase tended to silence DCC expression. In addition, all of the endometrial cancer cell lines lost normal DCC expression. Restored DCC expression in the cancer cell lines in the absence of netrin-1 induced apoptosis. However, no changes were observed in the presence of netrin-1. CONCLUSION: Our observations suggest that DCC/netrin-1 signaling may commit cells to the transition of endometrial gland architecture or function from a proliferating to a secretory phase. In addition, the silencing of DCC expression may contribute to the escape of endometrial cancer cells from a DCC-regulated apoptotic program, thereby promoting malignant phenotypes.

Adult↗
PubMed2003

Inhibition of ubiquitin ligase Siah-1A by disabled-1.

Disabled-1 (Dab1) is a cytosolic adaptor protein that plays critical roles in cortical development. However, a detailed mechanism of action has not yet been clearly defined. Through yeast two-hybrid screening, we observed that mouse Siah-1A, an E3 ubiquitin ligase containing a RING finger motif, interacts with Dab1. Co-immunoprecipitation experiments and in vitro binding experiments both indicated direct interaction between Siah and Dab1. Steady-state expression of Siah was enhanced by the presence of Dab1 or lactacystin, a representative proteasomal inhibitor. Auto-ubiquitination of Siah was inhibited by the presence of Dab1, suggesting inhibition of Siah activity and subsequent increase of Siah expression by Dab1. Both Dab1-induced increase of steady-state expression of Deleted in colorectal cancer (DCC), one of the well-known substrates of Siah, and its inhibition by Siah Delta R suggest that Dab1 increases expression of DCC through inhibiting the activity of endogenous Siah. Our results suggest that Dab1 inhibits the activity of Siah.

Animals↗
PubMed2000

Colonic mucin-carbohydrate components in colorectal tumors and their possible relationship to MUC2, p53 and DCC immunoreactivities.

To clarify changes in mucus components during colorectal tumorigenesis, we developed novel monoclonal antibodies (Abs) against carbohydrate chains of human colorectal mucin (HCM) obtained from normal sigmoid and rectal mucosae. A hundred and ninety-nine cases of colorectal carcinoma and 67 cases of tubular adenoma, along with 250 normal colonic tissue samples, were investigated immunohistochemically. The results were compared with clinical stage, survival and MUC2 (core protein of the intestinal type mucin) expression, as well as with the status of the p53 and DCC (deleted in colorectal carcinomas) genes. In the normal colonic epithelium, HCM14 Ab reacted with the cytoplasmic regions of the goblet cells and enterocytes, while HCM21 Ab bound to mucous droplets in the former, suggesting a more mature carbohydrate structure. Both HCM14 and 21 scores were significantly decreased in adenomas and carcinomas. This is in line with an altered PAS-Alcian blue staining, indicating accumulation of mucins with incomplete or abnormal glycosylation in tumors. Levels of HCM14 and 21 binding tended to show a positive correlation with expression of MUC2 and DCC, and a negative association with p53 protein accumulation in carcinomas, although there was no apparent link to Duke's stage or the prognostic outcome. These findings suggest a possible involvement of alterations in mucin carbohydrate in colorectal tumor development. The observed changes may be associated with loss of MUC2 and DCC expression, as well as with p53 protein accumulation.

Adenocarcinoma↗