Missing Receptor Molecule Causes Tumor Growth

A missing receptor molecule contributes to the growth of tumors in human ovaries. This surprisingly evident connection has now been proven by a team at the Medical University of Vienna, who published their data in the science journal Molecular Cancer Research. The team, who is supported by funding from the Austrian Science Fund FWF, also discovered the possible genetic reason why the receptor molecule, which is an important factor in regulating cell growth, is missing.

In healthy tissue, cells grow and divide – this is also true of cancerous tumors. The difference between the two lies in the regulation, which functions well in healthy tissue, but not in tumors. An important mechanism of this regulation is programmed cell death, known as apoptosis. It causes the controlled death of single cells, if this is to the advantage of the whole organism. If this process of self-protection does not work then the destructive cells can proliferate uncontrollably.

Signal Without Effect

Prof. Michael Krainer and his team from the Medical University of Vienna have now been able to prove that programmed cell death does not function in cells of certain tumors in the ovaries. Not because the starting signal is missing, but because this signal cannot be received by the cell.

This finding, published today in the American science journal Molecular Cancer Research, shows that these cells lack a receptor molecule called DR4. DR4 is responsible for receiving the signal molecule TRAIL, which initiates apoptosis in these cells.

Prof. Krainer explains: “To begin with it was not evident what was missing in the signal transmission. The signal or the receptor molecule? To answer this question, we examined ten different ovarian cancer cell lines. In doing this we found out that 40% of these specimens contained none or only a few DR4 receptor molecules.” It was proven in further tests that these cells react particularly badly to TRAIL. This proves that the missing receptor and not the missing signal can contribute significantly to tumor growth.

Silenced Genes

Further tests proved why there was such a small number of receptors. Prof. Krainer: “There can be two reasons for the loss of a receptor molecule like DR4. Firstly, the responsible gene could have been lost or damaged. Secondly, this gene could have been modified in a way which would prevent it from functioning.” It was exactly the latter. Prof. Krainer and his team ascertained that in 75% of the specimens which contained only a few DR4 receptors the responsible gene was modified. Some components of this gene were modified by attaching methyl groups. Methylation is indeed a common way in which cells silence genes, but in the affected tumor cells, it obviously happens at the wrong time.

To conclude their research, Prof. Krainer and his colleagues retested their findings: Their results were confirmed by testing 36 different tumor tissues taken directly from patients. In comparison, these cells represent the real causes of disease much better than cell cultures commonly used for experimental research. It was determined that in 20% of the tissues examined the gene responsible for DR4 was methylated to a higher degree and DR4 was missing.

This research supported by funding from the Austrian Science Fund, FWF, paves the way for future therapy through the important discovery that the methylation of the gene for DR4 can contribute to the formation of tumors. These therapies could manipulate the malfunctioning signal transfer system, DR4-TRAIL, to make cancer cells return to the originally programmed cell death.