Almost one in six deaths worldwide is caused by cancer. Most deadly, however, is not the primary tumor, but its spread to other parts in the body. Studying this 'metastasis' in humans is difficult, which is why Jelle Sleeboom developed small chips with cancer cells that mimic the human body. His techniques help in getting a better understanding of cancer metastasis. He will receive his doctorate on September 29.
The research done on new cancer treatments is mostly aimed at attacking the rapidly dividing cancer cells. However, things really go wrong when the cancer cells move to other organs, something known as metastasis. Metastasis is still poorly understood, and therefore it cannot be properly prevented or treated.
Difficult to follow
Investigating how metastasis works in humans is very difficult, because it takes place on a very small scale. Only one or a few cancer cells need to detach from the tumor, enter the bloodstream, and settle elsewhere. This is difficult to follow.
"What makes the understanding of metastasis even more difficult is that cancer cells do not spread on their own, but are influenced in all kinds of ways by their environment," says Sleeboom. This environment of the primary tumor is also referred to as the tumor microenvironment. In the tumor microenvironment there is often a low amount of oxygen and as a result, there is a gradient in and around the tumor from low to high oxygen concentration, which can control the cancer cells.
Cancer cells are also affected by the extracellular matrix, a fibrous network of proteins around cells that gives tissues structure and firmness. In tumors, the firmness and fiber structure of this matrix changes, which can affect the spread of cancer.
Small devices
In his research Sleeboom developed methods to study the effect of oxygen and the extracellular matrix outside the human body. Based on microfluidics, the science of manipulating fluids on a small scale, he developed tiny devices that he could make resemble the tumor microenvironment.
In these devices, called chips, he grew cancer cells in small fluid channels and chambers. "This makes the cancer cells believe they are in a human," says Sleeboom. "The big difference is that these chips provide control over the tumor microenvironment, so that the effect of the various factors on cancer cells can be systematically investigated." This technology is known worldwide as Cancer-on-a-chip.
To investigate the effect of oxygen, Sleeboom first developed a chip in which he could control the oxygen gradient. In this chip, he was able to monitor cancer cells and showed that a certain type of breast cancer cell is attracted to lower oxygen concentrations. Sleeboom: "That is surprising, because it is expected that cancer cells would actually look for more oxygen."
"This could possibly teach us more about behavior in humans. We then further developed this technique, so that we can check whether we also see the same behavior when the cells are in an extracellular matrix."
Invasion
Specifically, Sleeboom worked on a more realistic extracellular matrix than has been used in the research so far, mimicking better how it appears before cancer cells separate from the primary tumor. When cancer cells separate, they actually have to break through a thin membrane, which is called invasion.
Sleeboom developed a method to surround cancer cells with such a membrane before inserting the cells into the extracellular matrix. This allowed him to follow the invasion and further investigate this process, for example by varying the composition of the matrix.
"The techniques we have developed contribute to the further development of cancer-on-a-chip and will hopefully lead to a better understanding of, or even methods to prevent cancer metastasis in the future," says Sleeboom.
Title of PhD thesis: Microfluidic models of metastasis: In vitro approaches to study the tumor microenvironment. Supervisors: prof.dr.ir. Jaap den Toonder, TU/e and prof.dr. Cecilia Sahlgren, University of Turku, Finland
