9 December 2016

Publication Developmental Cell

Unravelling mechanisms of cancer treatments

Some cancer treatments that inhibit cell division also appear to work in another way, by preventing cells from migrating through tissue. Together with their colleagues at TU Delft, researchers at Utrecht University have uncovered the mechanism responsible for this activity. The results of their study are now available online in the prestigious journal Developmental Cell. Metastases are a major cause of cancer deaths, so this mechanism may present a promising opportunity to improve cancer therapies.

Cancer cell trough three-dimensional network of fibers
A cancer cell migrating through a three-dimensional tissue matrix

Many types of cancer can be treated effectively using surgery or radiation therapy. But if a tumour spreads to another part of the body, or ‘metastasises’, then it is often much more difficult to treat. Inhibiting metastases is one of the important objectives for developing new cancer therapies. “In order to spread from the original tumour to other organs, tumour cells have to be able to migrate,” explains the leader of the research group, Professor of Cell Biology Anna Akhmanova. “To do that, they have to work their way through the fibres of connective tissue.” This process relies on the function of microtubules. Prof. Akhmanova’s research group focuses specifically on these tiny tubes, which are present in every cell and which perform a wide range of functions.

Cell migration in 3D

Microtubules are involved in the process of cell division, so they are an important target for cancer therapies. For example, the drug paclitaxel, better known under its commercial name Taxol, inhibits cell division by perturbing formation of microtubules. Research in this field has primarily been conducted using cells grown on a flat surface. Akhmanova examined what happens when these drugs are administered to cells grown in a three-dimensional environment. “In a Petri dish, cells resemble a pancake. This makes it easier to observe the effects on cell division. In a three-dimensional tissue matrix, however, the cells have a completely different shape: they are more elongated and form long protrusions, which enable them to pull themselves through the matrix. When you perturb microtubules in such 3D culture, cells cannot form long protrusions, and therefore they cannot move.”

Trend

Together with scientists at UMC Utrecht, Akhmanova illustrated the same principle using a mouse model. In this model, tumours grew but the tumour cells could not invade surrounding tissues. The researchers uncovered which proteins were important to this process. “It seems that you can inhibit the formation of metastases in this manner, or even prevent them from forming”, says Akhmanova.

Using existing treatments in different and more effective ways is an important trend in modern medicine
prof. Anna Akhmanova

In order to continue to improve cancer therapies, she believes that research using these tools should not focus solely on inhibiting cell division, but also the migration of the cells. “Using existing treatments in different and more effective ways is an important trend in modern medicine”, according to Prof. Akhmanova.

PUBLICATION

Benjamin P. Bouchet, Ivar Noordstra, Miranda van Amersfoort, Eugene A. Katrukha, York-Christoph Ammon, Natalie D. ter Hoeve, Louis Hodgson, Marileen Dogterom, Patrick W.B. Derksen and Anna Akhmanova

Mesenchymal cell invasion requires cooperative regulation of persistent microtubule growth by SLAIN2 and CLASP1

doi: 10.1016/j.devcel.2016.11.009