Dependence Receptors and Cancer: Addiction to Trophic Ligands
Abstract
Data accumulating over the last 20 years support the notion that some transmembrane receptors are activated not only by their respective ligands but also, differentially, by the withdrawal or absence of these same ligands. In this latter setting, these receptors actively trigger apoptosis. They have been dubbed dependence receptors because their expression confers a state of ligand dependence for survival on the expressing cells. Twenty of these receptors have been identified to date, and several have been shown to inhibit tumor progression by inducing apoptosis. As a corollary, these receptors, or their transduced death signals, are frequently silenced in cancer cells as a selective mechanism to prevent cell death, allowing invasion and metastasis. Drugs aimed at inducing programmed cell death in neoplastic cells by re-engaging the proapoptotic activity induced by unliganded dependence receptors are in late-stage preclinical tests, poised for clinical evaluation. This approach may offer novel opportunities for patient treatments. In this review, we discuss the implications of dependence receptors in limiting cancer progression and address the therapeutic perspectives brought to light by this paradigm. Cancer Res; 75(24); 5171–5. ©2015 AACR.
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Extrinsic apoptosis is mostly driven by either death receptors or dependence receptors.
“Extrinsic apoptosis is mostly driven by either of two types of plasma membrane receptors: (1) death receptors, whose activation depends on the binding of the cognate ligand(s), and (2) dependence receptors, whose activation occurs when the levels of their specific ligand drop below a specific threshold [267 269–271].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [267]
Death receptor activation depends on the binding of the cognate ligand(s).
“death receptors, whose activation depends on the binding of the cognate ligand(s)”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [267]
Extrinsic apoptosis is an RCD modality initiated by perturbations of the extracellular microenvironment.
“Extrinsic apoptosis is an RCD modality initiated by perturbations of the extracellular microenvironment [265–268].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [267]
Dependence receptor activation occurs when the levels of their specific ligand drop below a specific threshold.
“dependence receptors, whose activation occurs when the levels of their specific ligand drop below a specific threshold [267 269–271].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [267]
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 [267]
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Self-citation
- Authors
- Gibert, B., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Mehlen, Patrick
- Venue
- Cancer Research
- Published
- 2015-12-14
- Volume
- 75
- Issue
- 24
- Pages
- 5171-5175
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2187222358
- Cited by
- 73
- References
- 46
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 12 · 2022: 14 · 2021: 3 · 2020: 7 · 2019: 11 · 2018: 8 · 2017: 2 · 2016: 3
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-LABX-0061)
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Conseil National de la Recherche Scientifique
- 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 › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- dependence receptors, apoptosis, tumor progression, metastasis, cancer therapy, programmed cell death, receptor signaling, tumor cell survival
- MeSH terms
- Animals, Humans, Ligands, Neoplasms, Receptors, Cell Surface, Signal Transduction, Apoptosis
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