Ovarian cancer tumour cells use two separate mechanisms to evade the body’s defensive reaction - and in so doing also elude a newly discovered counteraction from the surrounding tissue.

Details on these strategies, which have been observed in 65% of the cancer cells tested, are published today in Clinical Cancer Research by a group at the Medical University of Vienna led by Prof. Michael Krainer. The work, supported by the Austrian Science Fund FWF, may be a big help in optimising a new cancer therapy candidate.

One cancer cell does not make a tumour. To do so, the cell must divide many times over, and also develop mechanisms that allow the daughter cells to evade the body’s defences. Two previously unknown mechanisms have now been discovered by Prof. Michael Krainer at the Medical University of Vienna, Department of Internal Medicine I while investigating ovarian cancer cells.

Both mechanisms cause a signal molecule in the body known as TRAIL to remain ineffective in the degenerated cells. This signal molecule causes the death of cells whose functioning is impaired. TRAIL is part of the body’s sophisticated protection program, and drives damaged cells to the suicide known as apoptosis.

Prof. Krainer and his team have now been able to establish that more than 20% of all tumour cells cannot even bind with the TRAIL molecule as they lack the receptors necessary for this, namely DR4 and DR5. Therefore TRAIL cannot activate the mechanisms necessary for apoptosis in these cancer cells. By autumn 2005 the team was able to show that modifications to the gene coding for DR4 lead to decreased production of this receptor in tumour cells, thus shedding light on the molecular mechanisms behind TRAIL resistance in ovarian carcinomas. This mechanism and its clinical significance have now been confirmed by the research reported on in the paper.

The team has also been able to show that a further 40% of the cancer cells produce a protein which hinders the activation of the suicide program itself when binding with TRAIL takes place. This protein, known as FLIP, halts the processes activated by TRAIL in the interior of the cell. FLIP is similar in structure to the enzyme that should be activated by TRAIL, and it is this similarity that causes TRAIL to act on FLIP, instead.

Commenting on the frequency of this protection mechanism, Dr. Peter Horak, a co-author of the paper, said: “We established that 6% of the cancer cells examined actually exhibited both mechanisms. In all, more than 65% of the 68 cancer cells examined have at least one mechanism that allows them to elude the immune surveillance mediated by TRAIL.”

Hot on the Therapy TRAIL
The team also found that increased concentrations of TRAIL appeared in the tissue samples of advanced stage patients, and were particularly prevalent in healthy tissue close to the tumour. Prof. Krainer remarks: “It was previously anticipated that TRAIL is mainly produced by the cancer cells themselves. Healthy ovarian tissue does not normally produce TRAIL. The presence of TRAIL in this healthy tissue, observed by us for the first time, is most probably a reaction to the development of the tumour. The body is fighting back. And our data shows that patients who produce TRAIL in this tissue have a higher life expectancy.” This last finding suggests that TRAIL could have therapeutic uses.

Two innovative therapeutic approaches of this kind are indeed currently being developed. Both are based on the controlled activation of TRAIL-binding receptors. The data published in Clinical Cancer Research provides important information on the potential effectiveness of these strategies, since it will depend both on the production of this signal molecule and on the newly discovered protection mechanisms.

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