Patients suffering from advanced prostate cancer have only a small chance of recovery. Therapy options are limited, and various drug-based hormone therapies lead to resistance within two to three years. One aspect is particularly harrowing: some cancer cells are also resistant to radiotherapy. In a project funded by the Austrian Science Fund FWF, molecular biologist Frédéric Santer from the Innsbruck University Clinic for Urology has investigated the causes of this radioresistance in greater detail.
The researcher focused on a special type of stem cells, so-called cancer stem cells, which are a controversial topic widely discussed in current cancer research. A popular research subject, stem cells are precursor cells for various body cell types. They play an important role in embryonic development, but also in tissue maintenance. Many types of cancer also involve a type of cell that shares many properties with stem cells. While regular stem cells are precursors of healthy body cells, cancer stem cells are precursors of different types of cancer cells. Stem cells and cancer stem cells therefore have many common aspects that are of interest to researchers.
Resilient stem cells
“Cancer stem cells are a very contentious issue,” explains Santer. “It is still unclear whether they originate from normal stem cells or from differentiated, degenerated cells that are regressing.” Such processes are difficult to detect in living organisms. However, Santer points out, the similarity of their properties is undisputed, in particular their resistance to therapy. The latter is a problem because cancer stem cells that survive therapy are held responsible for the recurrence of cancer in cured individuals. The resistance of stem cells can be explained by natural necessities. A certain resistance to environmental influences such as chemicals is useful for them, says Santer: “Regular cells have mechanisms that trigger cell death when DNA is damaged. Stem cells, on the other hand, are designed to regenerate damaged tissue. So it makes sense that they survive in situations where other cells die.” How they manage to do that has not, however, been sufficiently researched. “But that is enormously important for cancer therapy,” emphasizes Santer, for whom this information deficit was inspiration for his research project. “We wanted to look at what happens at the level of genes during radiotherapy.”
Tissue from prostate cancer patients
In order to do that Santer’s team, which is doing research at the Innsbruck University Clinic of Urology, used tissue samples from patients with prostate cancer. Unless it is very advanced, the primary therapy for prostate cancer is the surgical removal of the prostate. For the researchers this means they have direct access to cells from patients. After surgery, the removed tissue is routinely sent to the pathology department, where a report is drawn up. Only then can Santer’s team use it for research. “It is not easy to cultivate these cells in the laboratory,” explains the molecular biologist. “The process is complex and we had to invest a lot of time before we were able to create optimum conditions for the actual experiment.”
Genetic study conducted
After successful cultivation, the cell samples taken from the patients and propagated in the laboratory were irradiated in line with a protocol for radiotherapy that patients receive. “Irradiation causes DNA damage. If this damage is too extensive to be corrected by repair mechanisms, the cell normally dies,” explains Santer. However, some cells survived the irradiation process. These cells were subsequently compared with the original tissue. The researchers were particularly interested in gene expression, which refers to the process by which genes are translated into protein structures. In this process the genetic code in the cell nucleus is read and converted into RNA. An analysis of this RNA provides information about the processes taking place in a cell.
Disturbance of important cell mechanisms
“We found that two important processes of the radio-resistant cells are weakened,” reports Santer. One is the production of proteins that are regulated by so-called interferons. The immune system uses interferons to fight viruses and cancer cells. In the irradiated cells, the production of proteins in the interferon cell-signalling pathway was inhibited, an effect that was recently confirmed by another international study on breast cancer stem cells. Another disrupted process was the so-called cell cycle arrest which involves a mechanism that prevents cell division in the presence of damaged DNA.
This mechanism was disrupted: certain proteins required for the process were not produced in sufficient quantities. “This actually constitutes a malfunction, but it helps the cell to survive because it can continue to reproduce without constraint despite the DNA damage,” notes Santer. Both effects are problematic because they promote the development of cancer. According to Frédéric Santer, the more detailed understanding of these effects can now serve as a starting point for new cancer therapies.
Frédéric Romain Santer is a molecular biologist who conducts his research at the Department of Urology at the Medical University of Innsbruck. He is interested in exploring new therapies for advanced prostate cancer and the development of therapy resistances against existing therapy options.