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

Paradisi, Andrea; Maisse, Carine; Coissieux, Marie–May; Gadot, Nicolas; Lépinasse, Florian; Delloye-Bourgeois, Céline; Delcros, Jean‐Guy; Svrcek, Magali; Neufert, Clemens; Fléjou, Jean‐François; Scoazec, Jean‐Yves; Mehlen, Patrick

doi:10.1073/pnas.0901767106

Cited by 108 publications

(121 citation statements)

References 24 publications

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“…New perspectives are currently arising, consisting in characterizing tumors that express both a dependence receptor and its ligand and trying to interfere with production of the latter. [38][39][40][41] We provide strong evidences supporting an evolutionary acquisition of dependence behavior for Krm1, which might be one of the mechanisms by which placental mammals tackled the necessity to develop protective strategies against cancers. We further suggest that in humans, Krm1 apoptotic behavior can be regulated by alternative splicing.…”

Section: Discussionmentioning

confidence: 63%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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In multicellular organisms, a tight control of cell death is required to ensure normal development and tissue homeostasis. Improper function of apoptotic or survival pathways can not only affect developmental programs but also favor cancer progression. Here we describe a novel apoptotic signaling pathway involving the transmembrane receptor Kremen1 and its ligand, the Wnt-antagonist Dickkopf1. Using a whole embryo culture system, we first show that Dickkopf1 treatment promotes cell survival in a mouse model exhibiting increased apoptosis in the developing neural plate. Remarkably, this effect was not recapitulated by chemical Wnt inhibition. We then show that Dickkopf1 receptor Kremen1 is a bona fide dependence receptor, triggering cell death unless bound to its ligand. We performed Wnt-activity assays to demonstrate that the pro-apoptotic and anti-Wnt functions mediated by Kremen1 are strictly independent. Furthermore, we combined phylogenetic and mutagenesis approaches to identify a specific motif in the cytoplasmic tail of Kremen1, which is (i) specifically conserved in the lineage of placental mammals and (ii) strictly required for apoptosis induction. Finally, we show that somatic mutations of kremen1 found in human cancers can affect its pro-apoptotic activity, supporting a tumor suppressor function. Our findings thus reveal a new Wnt-independent function for Kremen1 and Dickkopf1 in the regulation of cell survival with potential implications in cancer therapies.

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Section: Discussionmentioning

confidence: 63%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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“…Moreover, according to the well-admitted link between inflammation and colorectal cancer predisposition, it has been suggested that nuclear factor-kB activation resulting from inflammatory stimulus could lead to local netrin-1 production, and thus to tumor promotion by apoptosis inhibition. Along this line, colorectal tumor formation in an animal model for chronic inflammation was inhibited by treatment with netrin-1 titrating agents (Paradisi et al, 2009). …”

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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“…Moreover, the biologic has a dramatic effect on tumor progression, as it triggers an increased frequency of low grade adenoma associated with a decreased incidence of high-grade adenoma and adenocarcinoma. 23 The effect of netrin-1 inhibition in inflammationdriven tumorigenesis is quite similar to the specific ablation of IKKβ in IECs, with some difference: the effect of the netrin-1 blocking agent in tumor promotion (i.e., number of tumors) is modest, as compared to enterocyte-IKKβ knockout mice, indicating a partial inhibition of pre-malignant cell apoptosis by netrin-1. The mild effect of netrin-1 inhibition in tumor promotion was quite expected, as netrin-1 is not the only survival factor dependent on NFκB activation.…”

Section: Discussionmentioning

confidence: 83%

“…22 In AOM/DSStreated mice, netrin-1 is strongly expressed in IECs of inflamed mucosa, in which neoplastic lesions progressively developed, including adenomas and adenocarcinomas, showing a marked netrin-1 expression at immunohistochemical examination. 23 Furthermore, strong netrin-1 expression appears to be a characteristic feature of neoplastic lesions found in human IBD. A strong expression of netrin-1 is detected in epithelial cells of IBD patients, especially in areas of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…7 In the same line, a netrin-1 gain has recently been described in several human cancers, such as colorectal cancer, 22,23 metastatic breast cancers, 24 lung cancer, 25 and neuroblastoma 26 and this netrin-1 overexpression has been shown as a selective advantage for tumor progression. [23][24][25][26] The netrin-1/dependence receptors pair represents therefore a relevant mechanism to control tumor development and cellular escape. While several evidences show that, at genetic or epigenetic level, the downregulation of dependence receptor expression occurs through loss of heterozygosity or promoter methylation, 17,20,27 the mechanism allowing netrin-1 upregulation is not completely understood.…”

Section: Netrin-1 a Missing Link Between Chronic Inflammation And Tumentioning

confidence: 99%

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Netrin-1, a missing link between chronic inflammation and tumor progression

Paradisi

Mehlen²

2010

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N etrin-1, discovered as a neuronal navigation cue, has been recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. This survival activity is mediated via the inhibition of the so-called netrin-1 dependence receptors. The netrin-1 receptors, DCC (for Deleted in Colorectal Cancer) and UNC5H (UNC5 homologues), indeed belong to the functional family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands and such a trait has been hypothesized to confer these receptors a tumor suppressor activity as their presence render cell survival dependent on ligand availability. As a consequence, human tumors show either a loss of dependence receptors or a gain of netrin-1, allowing tumors to escape this safeguard mechanism. We recently found that netrin-1 is a direct transcriptional target of the transcription factor NFκB, and that a fraction of colorectal tumors show a netrin-1 gain parallel to NFκB activation. Moreover, colorectal cancers from patients affected by inflammatory bowel diseases (IBD) show upregulation of netrin-1. Several evidences suggest a tight link between chronic inflammation and tumorigenesis, mainly through NFκB activation. We propose that induction of netrin-1 expression via NFκB in IBD patients could affect colorectal tumor promotion and progression and that inhibition of netrin-1 could be an innovative target for drug therapy in inflammation-driven colorectal cancers.

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

Cited by 108 publications

References 24 publications

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

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

Netrin-1, a missing link between chronic inflammation and tumor progression

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