Epigenetic and Genetic Alterations in Netrin-1 Receptors UNC5C and DCC in Human Colon Cancer

Shin, Sung Kwan; Nagasaka, Takeshi; Jung, Barbara; Matsubara, Nagahide; Kim, Jae Hak; Carethers, John M.; Boland, C. Richard; Goel, Ajay

doi:10.1053/j.gastro.2007.08.074

Cited by 90 publications

(85 citation statements)

References 44 publications

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“…Along this line, DCC was proposed in the early 1990s to be a tumor-suppressor gene, whose expression is lost in the vast majority of human cancers (10,11). This hypothesis also fits with the observation that UNC5H genes are down-regulated in the vast majority of colorectal tumors, hence suggesting that the loss of UNC5H genes represents a selective advantage for tumor development (12)(13)(14). Interestingly, in mice, both inactivation of UNC5H3 and overexpression of netrin-1 in the gastrointestinal tract are associated with intestinal tumor progression (13,15), hence demonstrating per se that loss of netrin-1 dependence receptors in the human pathology is a causal factor for tumor progression (16).…”

supporting

confidence: 64%

“…Thus, as predicted by the dependence receptor model, we have now shown that a tumor cell can escape receptor dependency in at least three ways. First, expression of the dependence receptor can be down-regulated, as extensively described for DCC and more recently for UNC5H (10,(12)(13)(14)21). Second, the downstream death signaling can be shut down.…”

Section: Discussionmentioning

confidence: 99%

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Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Fitamant

Guenebeaud

Coissieux

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

196

251

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Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.apoptosis ͉ DCC ͉ dependence receptor N etrin-1, a diffusible laminin-related protein, has been shown to play a major role in the control of neuronal navigation during the development of the nervous system by interacting with its main receptors, DCC (Deleted in Colorectal Cancer) (1-3) and UNC5H (4, 5). However, more recently, netrin-1 has emerged as a completely different molecule that regulates cell survival. Indeed, the netrin-1 receptors DCC and UNC5H, i.e., UNC5H1, UNC5H2, and UNC5H3, belong to the so-called dependence receptor family (6, 7). Such receptors share the functional property of inducing cell death when disengaged from their ligands, whereas the presence of their ligands blocks this proapoptotic activity. Such receptors thus create cellular states of dependence on their respective ligands (8,9).This dependence effect has been suggested to act as a mechanism for eliminating tumor cells that would develop in settings of ligand unavailability: proliferation of tumor cells in a cell environment with constant and limited ligand presence or migration of metastatic tumor cells toward tissues where the ligand is not expressed. A selective advantage for a tumor cell would then be to lose the proapoptotic activity of its dependence receptors. Along this line, DCC was proposed in the early 1990s to be a tumor-suppressor gene, whose expression is lost in ...

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supporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Fitamant

Guenebeaud

Coissieux

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

196

251

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“…The loss of 18q chromosomal region has been correlated with poorer survival rate in stage II CRCs 69 . The region carrying the deleted in colorectal cancer gene (a dependence factor) is more frequently lost in advanced cancers 70 .…”

Section: Mutational Landscape In Chromosomal Instabilitymentioning

confidence: 99%

Colorectal cancer carcinogenesis: a review of mechanisms

Tariq¹,

Ghias²

2016

Cancer Biology &Amp; Medicine

228

138

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Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

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“…UNC5C is indeed the most downregulated member of the UNC5H family (74-77% of cases, A new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen whereas UNC5H1/UNC5A and H2/B show a reduced expression in 48 and 27% of the cases, respectively). This loss of expression observed in human primary tumors, as well as in cell lines, is essentially due to promoter methylation (Bernet et al, 2007;Shin et al, 2007). Furthermore, Bernet and colleagues took advantage of a natural UNC5H3 loss-of-function occurring in mice (rcm, rostral cerebellar malformation) to demonstrate that UNC5H3 loss of function is associated with tumor progression: mice that carry the APC 1638N germline mutation, known to predispose mice to the development of low-grade adenoma (Sieber et al, 2000), and are heterozygous or homozygous for mutant UNC5H3, develop adenomas that progress to adenocarcinoma at a higher frequency than what is seen in APC 1638N mice.…”

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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Epigenetic and Genetic Alterations in Netrin-1 Receptors UNC5C and DCC in Human Colon Cancer

Cited by 90 publications

References 44 publications

Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Colorectal cancer carcinogenesis: a review of mechanisms

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

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