The DCC Protein and Prognosis in Colorectal Cancer

Shibata, David; Reale, Michael A.; Lavin, Philip T.; Silverman, Mark L.; Fearon, Eric R.; Steele, Glenn; Jessup, J. Milburn; Loda, Massimo; Summerhayes, Ian C.

doi:10.1056/nejm199612053352303

Cited by 282 publications

(154 citation statements)

References 32 publications

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“…The DCC gene located at 18q21 was first considered to be an important target gene and to play an important role in colorectal pathogenesis (Fearon et al, 1990;Shibata et al, 1996). However, there have been several cases with 18q deletion in which no inactivation of DCC was observed, implying the existence of another target gene (Cho et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

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Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

et al. 2006

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Smad4 protein, whose gene is coded at chromosome 18q21.1, is an important tumour suppressor that mediates transforming growth factor-beta. It has been reported that inactivation of the Smad4 gene and allelic loss of chromosome 18q correlate with liver metastasis and poorer prognosis in colorectal cancers. Utilising a recently developed method of immunohistochemical staining for Smad4 protein, we focused on the specific impact of Smad4 protein expression on liver metastasis in colorectal cancer. We also evaluated the association between chromosome18q deletion and liver metastasis. We selected 20 colorectal cancers with liver metastasis for the experimental group, and 20 cases without liver metastasis for the control. In order to exclude the influence of lymph node metastasis, all cases were lymph node negative. In addition, the two groups were matched for tumour depth, tumour differentiation and tumour location. We compared the expression level of Smad4 protein immunohistochemically in these 20 matched pairs. We also compared the loss of heterozygosity status at chromosome 18q in these 20 matched pairs. Immunohistochemical staining revealed a significant difference (P ¼ 0.024) in the level of Smad4 protein between the two groups. We also observed a significantly different (P ¼ 0.0054) ratio of allelic deletion at chromosome 18q21. Smad4 protein expression level and allelic loss at 18q21 are associated with the process of liver metastasis in colorectal cancers evaluated when excluding clinical and pathological features except for liver metastasis. (Vogelstein et al, 1988(Vogelstein et al, , 1989Benhattar et al, 1993;Kinzler and Vogelstein, 1996;Span et al, 1996;Kambara et al, 2004;Nassif et al, 2004). Loss of heterozygosity (LOH) is one of the major types of genetic inactivation, and the long arm of chromosome 18 is the most frequently deleted region in colorectal cancers. To date, many reports suggest that this deletion is a molecular predictor that affects survival (Fearon et al, 1990;Jen et al, 1994;Chung, 1998;Lanza et al, 1998;Ogunbiyi et al, 1998;Jernvall et al, 1999;McLeod and Murray, 1999;Sarli et al, 2004). We too reported that the allelic deletion of chromosome 18q was associated with poorer prognosis in stage III colon cancer after adjuvant chemotherapy (Watanabe et al, 2001. These reports suggest that there might be tumour suppressor genes located at chromosome 18q, which has a strong influence on survival. Smad4 gene, which mediates the intracellular signalling pathway of transforming growth factor (TGF)-beta receptor, has been detected as one of the target genes at 18q21 (Wang et al, 1995;Eppert et al, 1996;Hahn et al, 1996;Thiagalingam et al, 1996;Carethers et al, 1998;Markowitz, 2000;Fink et al, 2003;Alazzouzi et al, 2005;Li et al, 2005). Recently, an immunohistochemical method for evaluating Smad4 protein has been developed and several studies found higher frequency of Smad4 protein inactivation in the cases with liver metastasis and in the cases presenting unfavourable survival (Maitra et al, 20...

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Section: Discussionmentioning

confidence: 99%

“…However, there have been several cases with 18q deletion in which no inactivation of DCC was observed, implying the existence of another target gene (Cho et al, 1994). Subsequently, Smad4 gene was detected as another target at 18q21.1, whose mutations were detected up to 35% of colorectal cancers (Shibata et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

et al. 2006

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“…Observation that DCC expression is reduced or lost in colorectal cancer led to the proposal that DCC expression represented a constraint for disease progression and is therefore a tumor suppressor. This hypothesis was supported by the fact that DCC expression is lost or reduced in various cancers (Mehlen and Fearon, 2004) and that its loss of expression is associated with poor prognosis (Shibata et al, 1996;Sun et al, 1999). In addition, restoration of DCC expression can suppress tumorigenic property in vitro and in nude mice (Klingelhutz et al, 1993;Velcich et al, 1999).…”

Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

“…DCC is also submitted to loss of heterozygosity and/or to decreased expression in various other cancers including gastric, prostate, endometrial, ovarian, esophageal, breast and testicular cancer, as well as neuroblastoma and hematological malignancies (Mehlen and Fearon, 2004). Loss of DCC expression is often associated with poor prognosis and advanced cancer or metastasis (Shibata et al, 1996;Saito et al, 1999), suggesting a role of DCC loss in cancer progression rather than in cancer initiation. Moreover, restoration of DCC expression can suppress tumorigenic growth properties in vitro or in nude mice (Klingelhutz et al, 1993;Velcich et al, 1999;Kato et al, 2000;Rodrigues et al, 2007).…”

Section: Drs Are Altered During Tumor Progressionmentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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“…These deletions account for the reduced expression of the tumor suppressor DCC (deleted in colorectal carcinoma) (27)(28)(29)(30) as well as SMAD4/DPC4 (deleted in pancreatic carcinoma 4) (31-33).…”

Section: Deletions Of Chromosome Arm 18qmentioning

confidence: 99%

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

Tassi

Wellstein

2006

Seminars in Oncology

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Tumor angiogenesis has been related to the initiation as well as progression toward more aggressive behavior of human tumors. We will discuss genetic events underlying the initiation and progression of colorectal and pancreatic adenocarcinoma with a particular focus on the modulation of angiogenesis. A secreted fibroblast growth factor (FGF) binding protein (FGF-BP), which is an extracellular chaperone molecule for FGFs, has been shown to enhance FGF-mediated biochemical and biologic events and to be a crucial rate-limiting factor for tumor-dependent angiogenesis. Histochemical and in situ hybridization studies with archival samples show that FGF-BP is induced early during the initiation of colorectal and pancreatic adenocarcinoma. We will discuss the potential of this secreted protein as a serum marker to identify at-risk subjects.

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The DCC Protein and Prognosis in Colorectal Cancer

Cited by 282 publications

References 32 publications

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

Dependence receptors: a new paradigm in cell signaling and cancer therapy

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

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