Dependence receptors and colorectal cancer
Abstract
The research on colorectal cancer (CRC) biology has been leading the oncology field since the early 1990s. The search for genetic alterations has allowed the identification of the main tumour suppressors or oncogenes. Recent work obtained in CRC has unexpectedly proposed the existence of novel category of tumour suppressors, the so-called ‘dependence receptors’. These transmembrane receptors behave as Dr Jekyll and Mr Hyde with two opposite sides: they induce a positive signalling (survival, proliferation, differentiation) in presence of their ligand, but are not inactive in the absence of their ligand and rather trigger apoptosis when unbound. This trait confers them a conditional tumour suppressor activity: they eliminate cells that grow abnormally in an environment offering a limited quantity of ligand. This review will describe how receptors such as deleted in colorectal carcinoma (DCC), uncoordinated 5 (UNC5), rearranged during transfection (RET) or TrkC constrain CRC progression and how this dependence receptor paradigm may open up therapeutical perspectives.
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Dependence receptors promote cell survival, proliferation and differentiation in physiological conditions when cognate ligands are available, but activate lethal signaling cascades once ligand availability falls below threshold.
“Intriguingly, dependence receptors promote cell survival, proliferation and differentiation in physiological conditions (when their cognate ligands are normally available), but activate distinct (and not completely elucidated) lethal signaling cascades (generally impinging on caspase activation) once ligand availability falls below a specific threshold level [350].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [350]
Dependence receptor-driven RCD has been involved in multiple pathophysiological settings and exerts robust oncosuppressive functions.
“Dependence receptor-driven RCD has been involved in multiple pathophysiological settings, and exerts robust oncosuppressive functions [350].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [350]
In absence of ligands, DCC is cleaved by CASP3 and this promotes its association with APPL1 and CASP9, resulting in activation of CASP9-CASP3 cascade.
“(1) DCC is cleaved by CASP3 and this promotes its association with adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) and CASP9, resulting in the activation of the CASP9-CASP3 cascade [350, 351]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [350]
Family of dependence receptors consists of approximately 20 members, including NTN1 receptors DCC, UNC5A-D, NTRK3, and PTCH1.
“The family of dependence receptors consists of approximately 20 members, including: (1) the netrin 1 (NTN1) receptors DCC netrin 1 receptor (DCC), unc-5 netrin receptor A (UNC5A), UNC5B, UNC5C, and UNC5D; (2) the neurotrophin receptor neurotrophic receptor tyrosine kinase 3 (NTRK3); and (3) the sonic hedgehog (SHH) receptor patched 1 (PTCH1) [267, 349, 350].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [350]
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Flagged first, then by citations
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“The family of dependence receptors consists of approximately 20 members, including: (1) the netrin 1 (NTN1) receptors DCC netrin 1 receptor (DCC), unc-5 netrin receptor A (UNC5A), UNC5B, UNC5C, and UNC5D; (2) the neurotrophin receptor neurotrophic receptor tyrosine kinase 3 (NTRK3); and (3) the sonic hedgehog (SHH) re…”
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“Under normal homeostatic conditions, the dependence receptors promote cell survival; however, they activate signaling cascades resulting in caspase activation when their cognate receptors fall below the normal physiological threshold [78].”
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“In absence of their ligand, they are still active but rather induce a “negative signal” that triggers caspase-dependent apoptosis [5].”
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- Authors
- Mehlen, P., & Tauszig-Delamasure, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Tauszig-Delamasure, Servane
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-08-27
- Volume
- 63
- Issue
- 11
- Pages
- 1821-1829
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2143116221
- Cited by
- 44
- References
- 92
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 8 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 3
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- dependence receptors, colorectal cancer, tumour suppressor, DCC, RET, TrkC, apoptosis, tumor progression, cancer therapy
- MeSH terms
- Netrin Receptors, Animals, Humans, Inflammation, Ligands, Receptors, Cell Surface, Colorectal Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Disease Progression, Receptor Protein-Tyrosine Kinases, Tumor Suppressor Proteins, Hedgehog Proteins
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