Articles| Researchers’ work is hidden behind the effective...

Researchers’ work is hidden behind the effective drug

6. May 2015 - Moje zdraví “Our objective is to develop drugs that mitigate the impact of cancer on people,” says Jan Brábek, head of research into tumor cell invasiveness at the Department of Cell Biology at the Faculty of Science of Charles University in Prague.

Metastasis is responsible for more than 90% of cancer fatalities. In what way does your research relate to this fact?
More than seven million of the approximately eight million people with cancer die due to metastasis every year. In addition, the number of cancer fatalities is set to continue to rise, mainly due to the population’s increasing average age. Our research, dedicated to analyzing tumor cell plasticity, can be poised at the beginning of the development of drugs that will help to mitigate cancer’s devastating impact on humankind.

Can you explain the term ‘tumor cell plasticity’?
For a tumor cell to be able to metastasize (create a malignant site in some other part of the organism), it has to get there first. It penetrates through the intercellular substance from the primary tumor further down into the blood, arteries, and the lymphatic system. It then lives and proliferates there. But this cell’s absolutely most important ability is its capacity to ‘travel out’. The reason is that the intercellular substance puts up relatively strong resistance, since it is composed of a very dense mesh of collagen fibers. Imagine this as if you were in a mesh of strong steel bars, with a rubber membrane between them. If you were going to get through this barrier, you would have to use your own force to push through the rubber membrane or to split, or break, the steel fibers. But a tumor cell is much more ingenious, and has found a number of other ways of overcoming intercellular space. It can even dupe our own cells and make them work for it. For example, under its influence the connective tissue cells, the fibroblasts, change so much that they stop defending themselves and go out of their way to accommodate the tumor cell. By the same token, tumor cells are able to take over the immune system cells. They send out various chemical signals and the ‘healthy cells’ then start to secrete substances that support the growth of tumor cells. In brief, these ‘healthy cells’ think everything is just fine. In fact, the body even starts to take care of the tumor. There are more ways that metastasizing cells are invasive. However, one of these ways has been known for only a short time and is now the primary object of our research. It is called the amoeboid invasiveness. Basically, tumor cells change into amoebas, which do not have to split the intercellular substance, but just look for gaps there. They are capable of enlarging the tiniest cranny, on the rims of which tiny ‘muscles’ are formed, and these act on the collagen fibers, which start to stretch. An analogy to this exists in normal physiology; amoeboid movement is normal in nature, in small organisms and directly in the human body with leucocytes.

To what extent can your research bring about a breakthrough in this respect?
Apparently due to inertia, the criteria for tumor therapies are still mainly based on reducing the primary tumor. Thus, only drugs that have a chance to reduce the primary tumor are released. On the other hand, methods that work against metastases and may not even relate to the primary tumor are being sidelined. However, it is these methods that may be the only ones to prevent deadly metastases (the tumor) from propagating. In fact, reducing the primary tumor site is frequently not that important, as it frequently does not pose any direct risk to the patient’s life. Patients are usually killed by metastases, as I have mentioned. However, before we gain insight into the ways that cells use to migrate between different forms of invasiveness we will not be able to prevent them from such migration and therefore will not be able to suppress the proliferation of metastases. For our laboratory this is the core research program for which we have received a grant under the Science program operated by Mr. and Mrs. Kellner’s family foundation (The Kellner Family Foundation). It is helping us to tackle the analysis of tumor cell plasticity at a level on a par with the world’s best research laboratories in this field.

Do you work with real tumor cells in your research? How do you obtain them?
We use established tumor lines in our research; these are found in laboratories all over the world and can be regarded as the standard for the purposes of many experiments. But we also use cells directly isolated from human tumors. We obtain them, for example, in cooperation with Professor Karel Smetana Jr. (of Charles University’s First Faculty of Medicine) and Pavel Veselý (of CEITEC in Brno).

Have you always been determined to lock yourself up in a lab and explore?
When I was child I imagined I would be an ornithologist. I was interested in nature, but mostly fauna. Later, I turned to mathematics, physics and biochemistry and then, closing the circle, returned to cellular biology. The decisive step in my career was my post-doctoral fellowship at Vanderbilt University in the U.S.: meeting experts always informs and gives direction to young people.

Authors: Tereza Radváková and Markéta Ostřížková

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