Missing Molecule Triggers Ovary Tumors

This unexpected connection has now been confirmed by researchers at the Medical University of Vienna (Austria), who published their findings in the June 15, 2005, issue of the journal Molecular Cancer Research. The team also found out the possible genetic reason why the receptor molecule, which is a significant factor in controlling cell growth, is missing.

Programmed cell death, known as apoptosis, brings about the controlled death of single cells, if this proves to be beneficial for the entire organism. If this self-protective mechanism does not function correctly, then the destructive cells can grow unchecked. The investigators have now been able to ascertain that programmed cell death does not function in the cells of specific tumors in the ovaries, not because the starting signal is missing, but because this signal cannot be received by the cell.

This discovery demonstrated that these cells are missing a receptor molecule called DR4. DR4 is responsible for receiving the signal molecule tumor necrosis factor-related apoptosis inducing ligand (TRIAL), which triggers apoptosis in these cells.

"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 10 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,” explained Prof. Krainer. It was confirmed in additional testing that these cells respond poorly to TRIAL. This confirms that the missing receptor and not the missing signal can considerably contribute to tumor growth.

Additional assessment validated why there was such a small proportion of receptors. "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,” stated Prof. Krainer. It proved to be precisely the latter. Prof. Krainer and his coworkers discovered that in 75% of the specimens containing only a few DR4 receptors, the responsible gene was altered. Some components of this gene were modified by attaching methyl groups. Methylation is a typical process in which cells silence genes, but in the affected tumor cells, it noticeably occurs at the wrong time.

To conclude their study, Prof. Krainer and his coworkers retested their results. Their findings were validated by evaluating 36 different tumor tissues taken directly from patients. In comparison, these cells signify the real causes of disease much better than cell cultures typically used for experimental research. It was determined that in 20% of the tissues studied, the gene responsible for DR4 was methylated to a higher extent and DR4 was missing.

This research provides insights for future treatment through the significant finding that the methylation of the gene for DR4 can contribute to the formation of tumor formation. These therapies could manipulate the faulty signal transfer system, DR4-TRAIL, to make cancer cells return to the originally programmed cell death.