Receptors that mediate cellular dependence

Bredesen, Dale E.; Mehlen, Patrick; Rabizadeh, Shahrooz

doi:10.1038/sj.cdd.4401680

Cited by 80 publications

(64 citation statements)

References 119 publications

(198 reference statements)

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“…Firstly, Dale E Bredesen and colleagues will present an overview of the notion of dependence receptors and discuss the nature of the different dependence receptors isolated so far. 5 They will review what is known about the mechanisms these receptors use to trigger cell death, and how this implicates them in nervous system development, cancer progression, and neurodegenerative diseases. Hirofumi Arakawa will then sign an exciting review on a specific set of dependence receptors, the netrin-1 receptors DCC and UNC5H.…”

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confidence: 99%

The dependence receptor notion: another way to see death

Mehlen

2005

Cell Death Differ

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It has been known for over half a century that cells depend for their survival on stimulation that is mediated by various receptors and sensors. For example, cells may require specific soluble trophic factors, cytokines, hormones, extracellular matrix interactions, cell-cell interactions, or electrical activity for survival. In each case, withdrawal of the stimulus leads to apoptosis. It has generally been assumed that this occurs through the loss of the associated positive survival signals, such as Akt phosphorylation. While such survival signals are clearly very important, data obtained over the past 10 years argue for a complementary and novel form of signal transduction, which induces apoptosis and is activated by stimulus withdrawal. This 'negative signal transduction' is mediated by specific 'dependence receptors', which induce apoptosis only in the absence of the required stimulus (e.g. when unbound by a trophic ligand). Thus, the expression of various dependence receptors creates states of dependence on their respective ligands.From a very dubitative -and should we confess, sometimes aggressive -attitude towards this notion, for example, (i) 'how dare you even think that an unbound receptor could be active', (ii) 'everything about cell death following trophic factor withdrawal is known: a default program due to kinasesdependent pathways being shut off', or (iii) 'your data are simple artifacts of cell culture and protein overexpression' -we are slowly moving towards a more respectable view, maybe. The reason for this gain of interest is clearly due to the fact that from pure in vitro studies using immortalized cells, 1,2 this notion has recently been supported by studies in animals models. 3,4 However, there are many ramifications to the dependence receptor theory: for example, the expression of dependence receptors ties cells to a specific context, in which the ligand is available, and therefore may serve to block metastatic spread of neoplasms or growth beyond local ligand availability. Another example of the effects of dependence receptors is the mediation of developmental cell death in cells that do not receive trophic factor support. Therefore, dependence receptors often play a dual role, both as tumor suppressors and mediators of neuronal development. Indeed, the vast majority of the dependence receptors isolated so far has been shown to be involved in neuronal navigation and in the regulation of cancer progression. This special issue will deal with the different aspects of the duality of dependence receptors. Firstly, Dale E Bredesen and colleagues will present an overview of the notion of dependence receptors and discuss the nature of the different dependence receptors isolated so far. 5 They will review what is known about the mechanisms these receptors use to trigger cell death, and how this implicates them in nervous system development, cancer progression, and neurodegenerative diseases. Hirofumi Arakawa will then sign an exciting review on a specific set of dependence receptors, the netrin-1 ...

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confidence: 99%

The dependence receptor notion: another way to see death

Mehlen

2005

Cell Death Differ

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“…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.…”

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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.

190

246

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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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“…Indeed, netrin-1 receptors DCC and UNC5H-that is, UNC5H1, UNC5H2, UNC5H3, and UNC5H4, also called UNC5A, UNC5B, UNC5C, or UNC5D-belong to the so-called dependence receptor family (4)(5)(6). These dependence receptors, because of their ability to induce cell death when disengaged from their ligands, create cellular states of dependence on their respective ligands (7) and, consequently, may behave as tumor suppressors because they eliminate tumor cells that would develop in settings of ligand unavailability (3,8).…”

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confidence: 99%

Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression

Paradisi

Maisse

Coissieux

et al. 2009

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

103

111

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Chronic inflammation and cancer are intimately associated. This is particularly true for inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, which show a major increased risk for colorectal cancer. While the understanding of the molecular pathogenesis of IBD has recently improved, the mechanisms that link these chronic inflammatory states to colorectal cancer development are in large part unknown. One of these mechanisms is NF-B pathway activation which in turn may contribute to tumor formation by providing anti-apoptotic survival signals to the epithelial cells. Based on the observation that netrin-1, the anti-apoptotic ligand for the dependence receptors DCC and UNC5H is up-regulated in colonic crypts in response to NF-B, we show here that colorectal cancers from inflammatory bowel diseases patients have selected up-regulation of netrin-1. Moreover, we demonstrate that this inflammation-driven netrin-1 up-regulation is causal for colorectal cancer development as interference with netrin-1 autocrine loop in a mouse model for ulcerative colitis-associated colorectal cancer, while showing no effect on inflammation, inhibits colorectal cancer progression.

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Receptors that mediate cellular dependence

Cited by 80 publications

References 119 publications

The dependence receptor notion: another way to see death

The dependence receptor notion: another way to see death

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

Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression

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