News & Views | Published:

Cancer

Sugar-coated cell signalling

Nature volume 511, pages 298299 (17 July 2014) | Download Citation

Cell membranes are covered with sugar-conjugated proteins. New findings suggest that the physical properties of this coating, which is more pronounced in cancer cells, regulate cell survival during tumour spread. See Article p.319

The cell membrane serves as a signalling interface that allows cells to exchange information with their environment. It is constructed from lipids and contains both transmembrane and lipid-tethered proteins, which can be further modified through the covalent addition of sugars to build glycoproteins. Cancer cells frequently have higher levels of glycoproteins, such as mucin-1 (refs 1,2,3), than do healthy cells, and individual glycoproteins can transduce environmental signals that directly promote malignancy. However, glycoproteins also collectively organize into a glycocalyx. In this issue, Paszek et al.4 (page 319) show how the physical properties of this coating regulate the clustering of cell-surface receptors and thereby affect intracellular signalling in ways that can contribute to cancer metastasis.

The authors demonstrate that the thickness of the glycocalyx is a crucial determinant of the spatial and temporal features of receptor–ligand interactions. Specifically, they find that the thick glycocalyx of cancer cells serves as a 'kinetic trap', generating regions on the cell surface where the likelihood of receptor–ligand interactions is increased, driving receptor clustering (Fig. 1). Integrins are transmembrane receptors that bind extracellular matrix (ECM) proteins and are key interpreters and integrators of both the biochemical composition and the mechanical properties of the extracellular space5,6. Paszek and colleagues reveal that cells with a thick glycocalyx are more efficient at receiving cell-survival signals through integrins, owing to the kinetic-trap properties of the glycocalyx. This may facilitate metastatic spread by enabling cancer cells to survive in the varied tissue and fluid environments they must traverse to colonize distant organs.

Figure 1: Clustering for survival.
Figure 1

a, Paszek et al.4 show that cells with short synthetic glycopolymers (which mimic the physical properties of glycoproteins) attached to their cell membrane exhibit a close gap between the membrane and the extracellular matrix (ECM) and a relatively uniform distribution of glycopolymers and integrins in the membrane. b, By contrast, the presence of long synthetic glycopolymers or the natural glycoprotein mucin-1 (not shown) results in an expanded membrane–ECM gap, clustering of integrins, the exclusion of glycopolymers from regions of integrin adhesion, and membrane bending. These physical effects alter cell signalling through the MEK, PI3K and FAK pathways, leading to enhanced cell survival.

To uncouple the signalling properties of individual glycoproteins from the more general consequences of a bulky glycocalyx, the authors generated a series of synthetic glycopolymers to mimic the physical properties of glycoproteins of different sizes. They then tested how glycopolymers that projected 3 nanometres, 30 nm or 80 nm into the extracellular space influenced signalling through integrins, which have a reported length7 of about 20 nm. The long (80 nm) glycopolymers expanded the average gap between the cell membrane and the extracellular matrix and, as predicted by previous computational modelling8, reduced the overall rate of integrin binding to the ECM. New integrin–ECM interactions occurred preferentially near existing adhesion sites, thereby increasing the focal clustering of integrins on the cell surface (Fig. 1). The long glycopolymers were excluded from these clusters. By contrast, the short and medium-length synthetic glycopolymers did not affect integrin clustering, even when present at high surface densities.

The authors next evaluated the effects of the natural glycoprotein mucin-1 (Muc1), which is 10–100-fold upregulated in many cancers1,2,3 and extends 200 nm or more from the cell surface. Like the long synthetic glycopolymers, Muc1 expression increased the cell–ECM gap, increased total cell–ECM adhesion and enhanced the size of integrin clusters. As predicted by the kinetic-trap model, ECM-ligated integrins rarely entered regions occupied by Muc1. None of these effects required the signalling-competent cytoplasmic tail of Muc1, revealing a key role for the physical properties of the extracellular part of the glycoprotein.

Integrin-based cell-matrix signalling is important for many steps in metastasis, including the migration of cancer cells out of the primary tumour and through the ECM, their entry into the vasculature, survival in the circulation, adhesion to the vessel wall, exit from the vasculature, and migration to and proliferative expansion in a distant organ6. By reducing the rate of integrin binding and promoting clustering at existing adhesion sites, bulky glycoproteins act to promote a stable interaction between the cancer cells and the ECM.

Such stability is probably not optimal for the turnover of adhesions that is necessary for rapid migration. However, for cancer cells to metastasize, they must not only disseminate from the primary tumour to the secondary organ, but also survive in the many different microenvironments that they travel through. Integrins play a major part in cell survival6, as well as cell migration. Normal cells initiate a process of programmed cell death when they lack appropriate integrin ligation, and ECM–integrin binding therefore represents a mechanism for keeping cells in the correct place in the body. Paszek et al. demonstrate that bulky glycoproteins lower the threshold for reaching sufficient integrin ligation to survive and proliferate. This effect requires signalling through the MEK, PI3K and FAK intracellular pathways. They also show that the cytoplasmic domain of Muc1 is dispensable for its effects on cell survival, supporting the idea that the physical properties of the glycocalyx influence cell signalling.

This exciting paper establishes a new conceptual framework for the biological function of cell-surface glycoproteins. Independent of, and in addition to, their biochemical properties, the bulky constituents of the glycocalyx physically influence the spatial organization of integrin receptors and hence their activity. These effects are likely to be common to other cell-surface receptors that are regulated by receptor clustering or related intermolecular interactions. It will therefore be interesting to evaluate how the glycocalyx regulates other major signalling pathways. We expect that the optimal glycocalyx thickness for supporting different aspects of cancer-cell behaviour, including invasion, vascular spread and metastatic colonization, varies. But how cancer cells adapt their glycocalyx to the diverse surroundings that they experience during metastasis is an interesting open question.

References

  1. 1.

    & Cell Adhes. Migrat. 7, 187–198 (2013).

  2. 2.

    Cancer Res. 56, 5309–5318 (1996).

  3. 3.

    & Nature Rev. Cancer 4, 45–60 (2004).

  4. 4.

    et al. Nature 511, 319–325 (2014).

  5. 5.

    & Cold Spring Harb. Perspect. Biol. 4, a004903 (2012).

  6. 6.

    & Nature Rev. Cancer 2, 91–100 (2002).

  7. 7.

    & Cold Spring Harb. Perspect. Biol. 3, a004994 (2011).

  8. 8.

    , , & PLoS Comput. Biol. 5, e1000604 (2009).

Download references

Author information

Affiliations

  1. Andrew J. Ewald is in the Departments of Cell Biology and Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21218, USA.

    • Andrew J. Ewald
  2. Mikala Egeblad is in the Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

    • Mikala Egeblad

Authors

  1. Search for Andrew J. Ewald in:

  2. Search for Mikala Egeblad in:

Corresponding author

Correspondence to Mikala Egeblad.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nature13506

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing