The tops and bottoms of cells do different jobs, and healthy organs and tissue contain well-organized cells that are the right way up. One of the first signs of cancer is when cells become disorganized and can end up upside down. Now researchers in the UK have discovered how cells know when they are the right way up, and suggest this knowledge will help in the fight against cancer.

Charles Streuli and Nasreen Akhtar of the Wellcome Trust Centre for Cell-Matrix Research, an interdisciplinary unit in the Faculty of Life Sciences at the University of Manchester, describe what they discovered about “cell polarity” in a paper that was published online in Nature Cell Biology on 23 December.

The extracellular matrix is a protein-rich “scaffolding” that holds cells in place to form three-dimensional tissue. It is essential to the design and shape of organs.

However, unlike the inert scaffolding used on building sites, the extracellular matrix interacts with the cells that it holds in place.

For instance, in a recently published study led by the Massachusetts Institute of Technology, scientists uncovered a clue to an important question in cancer research: how do cancer cells spread? They found molecular interactions with tumor cells alter the stickiness of the matrix so the cells become unstuck and travel to other parts of the body to start new tumors.

Other studies have shown that the extracellular matrix not only sticks to the cells but also guides them into the right positions.

But what Streuli and Akhtar wanted to explore was an area that was still a mystery: how does the extracellular matrix communicate the guiding messages to the cells so they assume the correct position, the right way up?

For their study, they decided to look at epithelial cells, which make up the majority of body tissue. The particular epithelial cells they studied were the ones in the milk-producing glandular tissue of the breast. These cells also line the mammary ducts that carry milk to the nipple.

If these cells aren’t organized correctly, the breast can’t send milk to the nipple when a baby is suckling. And one of the first signs of cancer is that the epithelial cells become disorganized.

One of the ways the extracellular matrix connects with breast epithelial cells is via receptors called integrins. These receptors tell cells about their environment, and also send messages from within cells to their environment.

Streuli and Akhtar conducted experiments with the integrins in breast epithelial cells to see how they affected cell behavior.

In one experiment, they found cells that lacked the gene for integrins ended up the wrong way up in the extracellular matrix and also in the wrong place.

In another experiment, they discovered that removal of integrins in cultured breast cells led to the same disordered effect.

A further experiment helped the researchers understand how cells know they are the right way up.

They discovered that inside cells, the integrin receptors connect to a protein called ILK that in turn links to microtubules, a protein transport network inside cells.

They found it is the combination of integrins and microtubules within a cell that makes sure the correct proteins are sent to the top and the bottom of the cell to ensure the cell goes into position the right way up.

Streuli says in a statement that they discovered “a vital interplay between the transport machinery and the integrin receptors which makes sure that proteins are transported to the correct area of the cell.”

“Without this interplay the proteins end up in the wrong place, and this can lead to cells becoming disorganized,” says Streuli.

He goes on to explain that when they compared breast tissue from their experiments with that of patients in early stages of breast cancer, they appeared very similar:

“The cells were upside down and disorganized so they couldn’t carry out their functions.”

“We hope that our work to better understand cell polarity could ultimately lead to better diagnosis for cancer patients,” he adds.

Although they only experimented with breast epithelial cells, Streuli and Akhtar believe epithelial cells from other organs would behave in the same way.

An important aspect of their work is the use of special 3D cultures to grow the cells, where they formed tiny organs that looked remarkably similar to breast tissue.

“Growing the breast cells so that they can form 3D structures rather than on hard petri dishes means they develop in a way that is much more akin to how they grow in the body,” says Akhtar.

“Over 90% of cancers come from epithelial cells, which is why we chose to study them,” she adds.

Streuli and Akhtar now plan to test whether changing levels of integrin leads to the disorganization of cells that is seen in the early stages of cancer.

Written by Catharine Paddock PhD