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65% Of Ovarian Cancer Cells Sideline Body's Defences, Study
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.
TRAIL & Error
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.
Original publication: Perturbation of the TRAIL cascade in ovarian cancer:
Overexpression of FLIPL and deregulation of the functional TRAIL receptors
DR4 and DR5. Horak et al., Clin Can Res., Vol.: pp: ol.: pp: 8585-8591 DOI:
10.1158/1078-0432.CCR-05-1276
Campus Vienna Biocenter 2
A-1030 Vienna, Austria
http://www.prd.at
65% din Cancer ovarian Celule linie colateralã de organismul de apãrare, de studiu - 65% Of Ovarian Cancer Cells Sideline Body's Defences, Study - articole medicale engleza - startsanatate