Michael A. Reale

The DCC protein and prognosis in colorectal cancer

BACKGROUND Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer. Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate. We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma. METHODS The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas. The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy. RESULTS The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). CONCLUSIONS DCC is a prognostic marker in patients with stage II or stage III colorectal cancer. In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers. These findings may thus have therapeutic implications in this group of patients.

Studies of the Deleted in Colorectal Cancer Gene in Normal and Neoplastic Tissues

Chromosome 18q is among the chromosomal regions thought to harbor a tumor suppressor gene(s) that is frequently inactivated during the development of several cancer types, particularly those of the gastrointestinal tract. Moreover, preliminary data suggest that colorectal cancers with 18q LOH have a more aggressive clinical behavior than those cancers without 18q LOH. A candidate tumor suppressor gene from 18q, termed DCC for deleted in colorectal cancer, has been identified. The DCC gene is contained within the common region of LOH on 18q, its expression is markedly decreased or absent in colorectal cancers and cell lines, and a subset of colorectal cancers have been shown to have somatic mutations within the DCC gene. Thus, DCC represents the most promising candidate tumor suppressor gene from 18q. At present, however, many questions remain regarding the mechanisms underlying the inactivation of DCC in the majority of colorectal cancers. In addition, although studies of 18q LOH and DCC gene expression in other cancer types suggest that DCC inactivation may contribute to the pathogenesis of other tumor types, few studies have provided definitive data to demonstrate that DCC inactivation is a critical genetic event in these tumors. Moreover, little is known about the function of DCC in the regulation of normal cell growth and tumor suppression. The predicted structural similarity of DCC to the N-CAM family of cell-surface proteins suggests that it may function through cell-cell and/or cell-extracellular matrix interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Truncated DCC reduces N-cadherin/catenin expression and calcium-dependent cell adhesion in neuroblastoma cells.

The deleted in colorectal cancer (DCC) protein is important in the pathway guidance of cells and cell processes during neural development, and DCC has also been implicated in the aberrant cellular migrations of neuroblastoma dissemination. We attempted to further define DCC protein function by the overexpression of full-length and truncated DCC constructs in a human neuroblastoma cell line. Overexpression of the truncated DCC protein resulted in a less epithelioid morphology. This was accompanied by decreases in expression of N-cadherin and α- and β-catenin by immunoblot and Northern blot analysis. Levels of desmoglein were relatively less affected, whereas endogenous DCC protein levels were increased in the truncated transfectants. N-cadherin immunofluorescence was consistent with the immunoblot studies and localized the protein to the cytoplasm and sites of cell-cell contact. Cell aggregation studies demonstrated diminished calcium-dependent aggregation in the truncated transfectants. In conclusion, overexpression of a truncated DCC protein in neuroblastoma cells resulted in the loss of an epithelioid morphology, diminished expression of N-cadherin and α- and β-catenin, and diminished calcium-dependent cell adhesion. These studies provide the first evidence of an apparent functional link between DCC and N-cadherin/catenin-dependent cell adhesion.

THE DCC PROTEIN -- NEURAL DEVELOPMENT AND THE MALIGNANT PROCESS

The deleted in colorectal cancer (DCC) gene encodes a neural cell adhesion family molecule that was originally identified as a candidate tumor suppressor target of 18q allelic loss in colorectal cancer. However, the importance of the DCC protein has been most clearly demonstrated in neural development. Mutational and subsequent biochemical studies in C. elegans, Drosophila and vertebrates have shown that DCC functions in the guided migration of cells and cell processes in response to stimuli from netrins, a family of secreted laminin-like proteins. It appears that DCC may act in this signal transduction pathway as a netrin receptor or a component of the receptor complex, though a definitive receptor:ligand relationship has not yet been demonstrated. It is also clear that DCC can affect migrations in a netrin-independent manner, implying the existence of other DCC ligands. Though the loss of DCCexpression appears to be a later event in several malignancies and is associated with disease dissemination, it has not been adequately demonstrated that DCC is the tumor suppressor gene targeted by 18q allelic loss. However, DCC expression does have potential clinical utility as it stratifies an important group of colorectal cancer patients into good and poor prognosis subgroups.