The Bitter-Sweet Symphony Of Cancer: Integrins And Glycans

In the United States, half of all women and one-third of all men will develop cancer in their lifetime. A similar rate has been reported for the United Kingdom and Ireland. Cancer arises when just one cell in the body loses control and starts to multiply in too large of quantities. But what causes a cell to “lose control”? One reason is the abnormal function of a protein called an integrin.

Integrins are proteins that are embedded inside the cell membrane, a thin lipid layer that surrounds the cell. The top part of an integrin sticks out of the outside of the cell where it establishes connections to molecules of the extracellular matrix (ECM). The bottom part of an integrin is connected to molecules on the inside of the cell. Normally, integrins function as connective “bridges” between cells and the extracellular environment. Therefore, integrins are responsible for sensing and communicating information in a two-way system from the outside-in and the inside-out of the cell. Through integrins, what happens outside of the cell, affects the actions of the inside of a cell and vice versa. In this way, integrins ensure a flow of information that orchestrates a normal cell’s activities, such as proliferation and survival.

Glycans (sugars) are important components of the ECM and are also found on the cell’s surface. You could say that integrins are surrounded by a “sweet” microenvironment. Therefore, glycans are an important structural part of the integrin ECM-cell bridge. Some glycans are directly attached to the top part of an integrin on the outside of the cell. Additionally, other glycans are attached to the extracellular molecules that integrins bind to. Glycans are fundamental in ensuring the correct interaction of integrins with the extracellular environment, and therefore the correct flow of information.

There is an increased presence of integrins in several cancers, and this is an unfortunate sign of poor survival rates in patients. The presence of further bridge connections results in the abnormal cell’s capacity to proliferate and migrate to other tissues leading to metastasis, the spread of cancer cells.

In the last decade, it has also been observed that glycans have a crucial role in these bridge connections. In cancer, the alteration of glycan structures and quantities appears to have a negative effect on the functions of integrins. Changes in the glycans attached to an integrin influence the binding activities of the integrin, resulting in the cells to proliferate too much. The changes also compromise the integrin connections to the ECM, which makes the cells more capable of migrating and invading other tissues. Furthermore, alterations of the glycans that are attached to extracellular molecules can also influence the efficiencies of the bridges.

Grazia Marsico, a Ph.D. student at CÚRAM, the Science Foundation Ireland Research Centre for Medical Devices at the National University of Ireland Galway, collected the fragmentary literature about this hot topic. In collaboration with Prof Laura Russo, Prof Fabio Quondamatteo and under the supervision of Prof Abhay Pandit, the review presented in Trends in Cancer describes how sugars can regulate the function of integrins in the cancer process. Particularly, the focus is on how both glycosylation of integrins and integrin interaction with the cancer glyco-microenvironment can regulate cancer progression. The review also gives an overview of the open questions in the field. Can abnormal glycan-integrin structures be used to diagnose cancer and/or determine patient prognosis? How can we use tumor-associated integrin glycans to improve cancer therapy? And ultimately, can targeting abnormal glycan-integrin structures offer a new strategy for developing new cancer treatment drugs?

These findings are described in the article entitled Glycosylation and Integrin Regulation in Cancer, recently published in the journal Trends in Cancer. This work was conducted by Grazia Marsico and Abhay Pandit from the National University of Ireland, Laura Russo from the Università degli studi di Milano-Bicocca, and Fabio Quondamatteo from the University of Glasgow.