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A central role for vesicle trafficking in epithelial neoplasia: intracellular highways to carcinogenesis

Nature Reviews Cancer volume 13, pages 813–820 (2013)Cite this article

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Abstract

Epithelial cell carcinogenesis involves the loss of cell polarity, alteration of polarized protein presentation, dynamic cell morphology changes, increased proliferation, and increased cell motility and invasion. Membrane vesicle trafficking underlies all of these processes. Specific membrane trafficking regulators, including RAB small GTPases, through the coordinated dynamics of intracellular trafficking along cytoskeletal pathways, determine the cell surface presentation of proteins and the overall function of both differentiated and neoplastic cells. Although mutations in vesicle trafficking proteins may not be direct drivers of transformation, components of the machinery of vesicle movement have crucial roles in the phenotypes of neoplastic cells. Therefore, the regulators of membrane vesicle trafficking decisions are essential mediators of the full range of cell physiologies that drive cancer cell biology, including initial loss of cell polarity, invasion and metastasis. Targeting of these fundamental intracellular processes may permit the manipulation of cancer cell behaviour.

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Figure 1: Vesicle trafficking stands at the centre of epithelial carcinogenesis.
Figure 2: Paradigms for exocytic and endocytic trafficking in polarized epithelial cells.
Figure 3: The complex web of interactions regulating RAB activation and interaction with downstream effectors.

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Acknowledgements

J.R.G.'s work is supported by the US National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants RO1 DK048370 and RO1 DK070856 and a VA Merit Review.

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  1. Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA,

    James R. Goldenring

  2. and the Nashville Veternas Affairs Medical Center, Nashville, Tennessee 37212, USA.,

    James R. Goldenring

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Correspondence to James R. Goldenring.

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Glossary

Adherens junction

Intercellular adhesion structures that seal the lateral spaces between cells in simple epithelia and serve as a reference point for basolateral trafficking. They contain the intercellular adhesion molecules E-cadherin and p120 catenin.

Apico–basal polarity

Separation in polarized epithelial cells between apical membrane surfaces that face the external environment and the basolateral membrane, which faces the internal milieu.

Autophagosomes

Specialized lysosomal vacuoles that are responsible for degradation of intracellular organelles and recycling of components for use in de novo synthesis.

Exocyst

An evolutionarily conserved (from yeast to humans) multiprotein complex that mediates exocytosis at the plasma membrane.

Glycosylated

Pertaining to the addition of sugar residues to the external regions of membrane proteins.

Microvilli

Organized plasma membrane protrusions on the apical surface of cells that increase the surface area and facilitate absorption and secretion.

Primary cilia

In mammalian cells, a specialized protrusion with sensory functions.

Resting short circuit current

The electrical manifestation of epithelial polarity manifested by junctional characteristics and directed ion pumps and channels.

TBC domains

TBC (TRE2-BUB2-CDC16) domains are conserved motifs that are present in many RAB-GTPase activating proteins.

Tight junction

Intercellular junctions that are composed of proteins such as ZO1, occludin and claudins and are responsible for the tightness of the barrier between epithelial cells.

Tubulation of the recycling system

Part of a range of intracellular morphologies between small vesicles and tubules that indicates the process of trafficking dynamics.

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Goldenring, J. A central role for vesicle trafficking in epithelial neoplasia: intracellular highways to carcinogenesis. Nat Rev Cancer 13, 813–820 (2013). https://doi.org/10.1038/nrc3601

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