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Derailed endocytosis: an emerging feature of cancer

Key Points

  • Along with material uptake, endocytosis regulates signal transduction, as well as morphogenetic aspects of normal physiology (such as cell adhesion and migration). The multiple routes of endocytosis share a canonical, convergent structure: they begin at coated invaginations of the plasma membrane, progress through several endosomal compartments and culminate in lysosomes. An escape pathway enables internalized proteins to return to the plasma membrane through a recycling compartment.

  • Endocytic pathways present multiple abnormalities in human tumours. For example, dissolution of cell–cell junctions (adherens and tight junctions) and loss of morphological polarity precedes full malignant transformation; the underlying process encompasses enhanced internalization and unbalanced partitioning of junctional proteins (such as epithelial cadherin) between the lysosomal pathway and the recycling route.

  • A burgeoning body of evidence indicates that tumours gain self-sufficiency in growth signals by delaying endocytosis-mediated inactivation of growth factor receptors. Multiple oncogenic mechanisms intercept receptor endocytosis: defects in key endosomal proteins, evasion of ubiquitylation-mediated sorting to degradation, and malfunctioning of collaborative processes such as actin remodelling.

  • To conquer tissue barriers and colonize distant organs, tumour cells dynamically disintegrate cell-to-matrix adhesion sites and re-assemble them at the front of invading protrusions. This polar re-distribution is propelled by enhanced recycling of adhesion molecules of the integrin family, a process enabled by aberrant microtubules and small GTP-binding proteins of the Rab family.

  • Future studies are likely to uncover additional links between cancer and endocytosis, as well as unravel common biochemical interfaces (such as phosphoinositol homeostasis and cytoskeletal perturbations) amenable for therapeutic interventions.

Abstract

Once engaged by soluble or matrix-anchored ligands, cell surface proteins are commonly sorted to lysosomal degradation through several endocytic pathways. Defective vesicular trafficking of growth factor receptors, as well as unbalanced recycling of integrin- and cadherin-based adhesion complexes, has emerged in the past 5 years as a multifaceted hallmark of malignant cells. In line with the cooperative nature of endocytic machineries, multiple oncogenic alterations underlie defective endocytosis, such as altered ubiquitylation (Cbl and Nedd4 ubiquitin ligases, for example), altered cytoskeletal interactions and alterations to Rab family members. Pharmaceutical interception of the propensity of tumour cells to derail their signalling and their adhesion receptors may constitute a novel target for cancer therapy.

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Figure 1: Aberrant endocytosis of transmembrane proteins contributes to malignant transformation.
Figure 2: Routes of endocytosis.
Figure 3: Endocytic mechanisms underlying dissolution of cell–cell contacts and loss of tumour cell polarity.
Figure 4: Endocytic mechanisms controlling growth factor signalling.
Figure 5: Endocytic mechanisms underlying tumour cell migration and invasion through tissue barriers.

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Acknowledgements

We thank Y. Zwang and T. Goldkorn for insightful comments. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. His laboratory is supported by research grants from the U.S. National Cancer Institute (NCI; CA072981), the Israel Science Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the German–Israeli Foundation. G.B.M. is supported by the Komen Foundation and the NCI (PO1CA099031).

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National Cancer Institute

bladder cancer

breast cancer

cervical cancer

colon cancer

endometrial cancer

gastric cancer

head and neck cancer

lung cancer

oral cancer

ovarian cancer

pancreatic cancer

prostate tumours

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S1 (figure)

Glossary

Clathrin triskelion

A basic building block of clathrin coats, comprising three heavy chains that assemble into a three-pronged radial structure ('triskelion'), and three light chains that regulate formation of higher-order structures.

Dynamins

Large GTPases that form a helix around the neck of nascent vesicles and separate them from parent membranes.

Epsins

Three genes encoding epsin 1, 2 and 3 have been identified in mammals. Epsin 3 shows restricted expression compared with epsins 1 and 2.

Caveolae

Cholesterol-rich membrane microdomains that are stabilized by caveolin.

Lipid raft

A dynamic membrane microdomain formed through lipid-based interactions, that is rich in sphingolipids and sterols. Lipid rafts provide a platform to compartmentalize signalling events, including facilitating endocytosis of protein and lipid constituents.

Caveolin

Proteins that are associated with clathrin-independent endocytosis and are encoded by CAV1, CAV2, and CAV3. Caveolin 1 and 2 have similar expression patterns, but calveolin 3 is restricted to striated and smooth muscle.

Anoikis

A form of apoptotic cell death induced by loss of adhesion to the ECM.

Apical–basolateral polarity

A characteristic feature of epithelial cells in which the plasma membrane is divided into an apical surface facing the lumen and a basolateral surface contacting the underlying extracellular matrix.

Cadherin

Cadherins are the major adhesive units of AJs. Cadherin cytoplasmic domains interact with a catenin-based complex, which couples to the actin cytoskeleton and regulates adhesion-dependent signalling.

Adherens junction

(AJ). A macromolecular structure below TJs that is pivotal in cell–cell adhesion and polarization of epithelial cells. Primary constituents are adhesive units (cadherins and nectins) and cytoplasmic regulators (catenins), which link membranes to cytoskeletal components at discrete contact sites.

Tight junction

(TJ). Also termed zona occludens, a TJ mediates cell–cell adhesion and serves as a semi-permeable barrier between apical and basolateral surfaces of epithelial sheets. They comprise transmembrane units, including claudins, occludins and JAMs, which associate with cytoplasmic PDZ domain scaffold proteins.

Transcytosis

Vesicular trafficking of protein and lipid components between apical and basolateral membranes, bypassing the degradative lysosomal pathway. This is essential for maintenance of cell polarity.

Total internal reflection fluorescence microscopy

Light is directed at an angle sufficient to cause total reflection at regions proximal to the interface between the sample and coverslip. This technique offers resolution of dynamic processes at the plasma membrane, such as localized actin polymerization and recruitment of effector proteins.

Focal adhesions

Large cellular sites of adhesion (several micrometres long) to the ECM. Adhesion is mediated by integrins, mainly α5β1 and αvβ3, which bind ECM constituents, and coordinate anchoring proteins that couple to actin stress fibres.

Focal complexes

Small precursors of FAs (less than a micrometre long) continuously formed and disassembled under extending lamellipodia during cell migration. Retraction or arrest of lamelllipodia transforms a minority of focal contacts into larger, more stable FAs.

Perinuclear recycling compartment

A collection of tubular organelles associated with microtubules, engaged in recycling of endocytosed cargos to the cell-surface by a Rab11-dependent process.

Detyrosinated microtubules

Microtubules in which the carboxy-terminal tyrosine of the α-tubulin subunits is removed, revealing a charged glutamate residue. Regulates microtubule stability and differential interactions of effectors, and positively correlates with proliferating cancer cells.

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Mosesson, Y., Mills, G. & Yarden, Y. Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8, 835–850 (2008). https://doi.org/10.1038/nrc2521

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