Abstract
Endocytosis is a complex process whereby cell surface proteins, lipids and fluid from the extracellular environment are packaged, sorted and internalized into cells. Endocytosis is also a mechanism of drug internalization into cells. There are multiple routes of endocytosis that determine the fate of molecules, from degradation in the lysosomes to recycling back to the plasma membrane. The overall rates of endocytosis and temporal regulation of molecules transiting through endocytic pathways are also intricately linked with signalling outcomes. This process relies on an array of factors, such as intrinsic amino acid motifs and post-translational modifications. Endocytosis is frequently disrupted in cancer. These disruptions lead to inappropriate retention of receptor tyrosine kinases on the tumour cell membrane, changes in the recycling of oncogenic molecules, defective signalling feedback loops and loss of cell polarity. In the past decade, endocytosis has emerged as a pivotal regulator of nutrient scavenging, response to and regulation of immune surveillance and tumour immune evasion, tumour metastasis and therapeutic drug delivery. This Review summarizes and integrates these advances into the understanding of endocytosis in cancer. The potential to regulate these pathways in the clinic to improve cancer therapy is also discussed.
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Acknowledgements
F.S. acknowledges funding from the National Health and Medical Research Council Ideas Grant APP2001396 and philanthropic funding from Princess Alexandra Hospital Research Fund and Aveo communities.
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B.B., S.R.J. and F.S. researched data for the article. F.S. contributed substantially to discussion of the content and wrote the article. All authors reviewed and/or edited the manuscript before submission.
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F.S. holds several patents relevant to the field of this Review: PAT-02100-JP-01; 2015-538212; 02100-GB-01; 13848409.2; 02100-DE-01; 60 2013059561.5; 02100-AU-02; 2013334493; 02100-US-01 14/438440; 02100-JP-01 2015-538212. F.S. declares that she completed a 2019 contract with Merck (published as part of her group’s work in Cell 2020) and has presented at a conference sponsored by Telix (Melbourne, Australia). All other authors declare no competing interests.
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Glossary
- Antibody-dependent cellular cytotoxicity
-
(ADCC). A cytotoxic reaction mediated by immune cells (effector cells) against target cells sensitized by antibodies that are specific to the surface antigens of the target cell.
- Antibody–drug conjugates
-
(ADCs). A class of anticancer drugs in which monoclonal antibodies are conjugated to toxins, forming a single complex that can specifically target cancer cells and, after being internalized, deliver a cytotoxic payload.
- Autophagy
-
The process by which cells recycle, degrade and reuse their own components.
- Bin–amphiphysin–Rvs (BAR) domain
-
Banana-shaped protein dimerization domain that binds to and bends membranes.
- Caveolae
-
Pit-like invaginations of the plasma membrane that contain caveolin proteins, which form a subdomain of lipid rafts.
- Cavins
-
Peripheral membrane proteins that coat the caveolar surface in the interior membrane layer and specifically associate with caveolae in heteromeric complexes.
- Cell polarity
-
Spatial and directional differences in shape, structure and function within a cell.
- Clathrin-independent endocytosis
-
(CIE). This term refers to all endocytic pathways that do not require clathrin. CIE includes clathrin-independent carriers (CLICs), caveolae, fast endophilin-mediated endocytosis and micropinocytosis.
- Contact inhibition
-
A regulatory mechanism whereby cells are unable to move or proliferate when in contact with one another. This inhibitory mechanism is either aberrant or absent in cancer.
- Epithelial to mesenchymal plasticity
-
(EMP). The reversible process whereby epithelial cells go through a phenotype transition from a polarized adherent state to an unpolarized mesenchymal state.
- Fast endocytosis
-
Clathrin-independent endocytosis that takes place on a millisecond to second timescale in response to stimuli such as stress, chemotaxis or synaptic vesicle exocytosis. It includes macropinocytosis, activity-dependent bulk endocytosis, fast endophilin-mediated endocytosis, kiss-and-run and ultrafast endocytosis.
- Fast endophilin-mediated endocytosis
-
(FEME). A rapid endocytic pathway (a few seconds) that is triggered by ligand–receptor interactions and is regulated by endophilin A2 and dynamin recruitment as well as actin polymerization.
- Ferroptosis
-
A type of programmed cell death that is characterized by the accumulation of lipid peroxides and is dependent on iron accumulation.
- Glycosylphosphatidylinositol-anchored proteins (GPI-AP)-enriched early endosomal compartment
-
(GEEC). A specialized early endosomal compartment that results from the endocytosis, via a dynamin-independent endocytic route, of a class of lipid-anchored proteins called GPI-APs. They result from fusion of uncoated clathrin-independent tubulovesicular carriers called clathrin-independent carriers (CLICs), which originate directly from the cell surface. This process is named the CLIC/GEEC pathway.
- Innervation
-
The process by which nerves infiltrate tissues.
- Phagocytosis
-
The process by which a cell membrane extends to engulf particulate matter larger than about 0.5 μm in diameter, generating intracellular phagosomes.
- Pinocytosis
-
The process by which cells internalize fluids from the extracellular environment. This process may lead to the internalization of small particles suspended in the extracellular fluid, but this is a result of internalizing the fluid, and is not phagocytosis. Macropinocytosis is a form of endocytosis in which a large fluid-filled vesicle, or macropinosome, is pinched off from the cell membrane and brought into the interior of the cell, and micropinocytosis is a synonym of pinocytosis.
- Plasticity
-
Ability of cells to change their phenotypes in response to environmental signals.
- Radioligands
-
Radioactively labelled compounds, which bind at the target binding site.
- Residence time
-
The total duration of the ligand–receptor interaction.
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Banushi, B., Joseph, S.R., Lum, B. et al. Endocytosis in cancer and cancer therapy. Nat Rev Cancer 23, 450–473 (2023). https://doi.org/10.1038/s41568-023-00574-6
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DOI: https://doi.org/10.1038/s41568-023-00574-6
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