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Institut Curie/CNRS/INSERM
Joint Press Release
Although cells generally tend to
"stay at home", they may sometimes wish to take a look elsewhere,
and this wandering has a whole range of consequences. During embryonic
development, cells must migrate to give birth to new tissues. This roving
spirit is essential to the modeling of the future living organism. In
contrast, when tumor cells acquire the capacity to move around and invade
other tissues, there is a risk that metastases will develop, thus rendering
the treatment of cancer more difficult.
At the Institut Curie, Inserm research scientists in a CNRS unit have
just shown that Akt kinase is a "fuel" which enables epithelial
cells to move. This discovery, published in Cancer Research of May 1,
2003, opens up new therapeutic perspectives since it may prove possible
to curb the formation of metastases by modifying Akt.
United we stand, divided we fall: such is the watchword of epithelial
cells. Organized into layers, they cover an external surface, like the
skin or a body cavity such as the intestinal mucosa, and must remain within
their tissue to fulfill their functions. This cohesion is therefore indispensable
for the good functioning of the organism and, like good little soldiers,
the epithelial cells are supposed to remain "faithful" to their
original tissue till death. But no system is perfect and dysregulation
can occur.
This generally occurs through a series of genetic accidents that initiate
the cellular "mutiny". Anomalies accumulate in the genes that
govern vital processes (division, differentiation, apoptosis, repair).
The cell that has become abnormal escapes all regulation and the process
of oncogenesis begins. An initial mutated cell gives rise to all cancer
cells, which then form a tumor which becomes increasingly aggressive for
its environment and inevitably eludes all control.
When cells escape…
Certain cancer cells do not stop at the invasion
of a single original tissue, but instead propagate throughout the body.
This long march of tumor cells is only possible at the price of numerous
mutations. Progressive loss of function or increased activity of certain
proteins allows these cells to penetrate another tissue, to pass into
a blood or lymph vessel, to propagate, to adhere to a capillary wall,
to invade a new tissue. The route taken by "circulating" tumor
cells and the organs they target generally vary according to the nature
and location of the primary cancer.
As long as the cells remain together, the tumor is considered to be localized
and containable. The patient is generally cured by local treatment, either
surgical removal or radiotherapy. However, when the cells acquire the
capacity to disseminate through the body, the tumor is then considered
to be metastatic and is more difficult to eradicate.
Lionel Larue1 and his team at the
Institut Curie are studying how cells, and in particular epithelial cells,
acquire their capacity to move around the body.
This phenomenon occurs during both embryonic development and in certain
tumor cells, which in part explains why oncogenesis is sometimes described
as the "mirror image" of embryogenesis.
Akt, which is already implicated in numerous processes vital for the cell,
is continually activated in numerous cancers, including cancers of the
ovary, pancreas, breast and thyroid.
Lionel Larue and his group, in collaboration with international teams,
have therefore sought to elucidate the role of this protein and the consequences
of an increase in its activity in tumor cells.
Akt, mainstay of the metastatic transformation
Anchoring proteins found in the cell membrane
ensure the cohesion of tissues. Yet if these proteins receive the order
to move into the cell, the moorings are broken and the cell can then leave
its original tissue.
Sylvia Julien Grille in Lionel Larue's team, in close collaboration with
the group of Alfonso Bellacosa in Philadelphia, has just shown that continuous2
and not alternating activation of Akt leads to modified expression and
relocation of anchoring proteins to the inside of the cell, loss of adhesion
between cells, and an increase in the speed at which cells move.
In animal models in which Akt is continually activated in the trachea,
researchers at the Institut Curie have also observed an acceleration of
cell division and a migration of cells beyond the trachea.
The abnormal continuous activation of Akt
therefore confers on cells the mobility required to go and invade other
tissues and form metastases.
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Akt at the heart of cellular imbalance
The Akt pathway is one of the protein cascades
that pass messages to the inside of cells.
The message from outside, in this case IGF (insulin growth factor),
is received at the cell surface by a receptor and is then relayed
from protein to protein within the cell until the desired effect
is produced.
Akt stands at the crossroads of this relay and controls several
of the cell's fundamental mechanisms, such as proliferation, apoptosis,
transcription and migration. When Akt activation is disrupted, cancer
cells lose their ability to self-destruct and thus become harmful
to the organism.
Akt acts as a biological switch oscillating between an active state,
in which it triggers protein cascades that relay the signal, and
an inactive state.
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Biologists, but also chemists, at the Institut
Curie now face the challenge of discovering molecules likely to restore
cohesion to cells where Akt is continually activated. Akt
thus constitutes a promising target for new treatments since by acting
on this protein it may be possible to limit the invasion of other tissues
by tumor cells. This discovery holds out
hope to oncologists since at present one of their major challenges is
to curb the formation of metastases.
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Further information on : Embryonic development, a " mirror
image" of oncogenesis
Embryo formation and the development of
a cancer have various points in common. These two processes are
characterized by the transformation of a single cell into a group
of several cells. So, just like a growing tumor, the cells of a
fertilized egg divide at a high rate. They then migrate to give
form to future organs, whereas tumor cells that escape from their
original tumor will generate metastases. These similarities make
embryonic development a "mirror image" of tumor transformation,
albeit a rather distorted image. The study of embryogenesis thus
enhances understanding of how cancers start and progress. Researchers
studying basic oncology and specialists in the biology of development
have therefore joined forces. This joint effort has now shown that
the same genes are often involved in both embryonic development
and tumor growth.
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Reference
The protein kinase Akt induces epithelial mesenchymal transition and
promotes enhanced motility and invasiveness of squamous carcinoma lines.
Sylvia Julien Grille1, Alfonso
Bellacosa2, John Upson2, Andres J. Klein-Szanto2,
Frans Roy3, Whaseon Lee-Know4, Mark Donowitz4,
Philip N. Tsichlis5 and Lionel Larue1
Cancer Research, 1st May 2003,
vol. 63 - http://intl-cancerres.aacrjournals.org/
1 - Developmental Genetics of Melanocytes,
UMR 146 CNRS/Institut Curie, France
2 - Fox Chase Cancer Center, Philadelphia, USA
3 - Department for Molecular Biomedical Research, Ghent University, Belgium
4 - Hopkins Center for Epithelial Disorders, Johns Hopkins School of Medicine,
Baltimore, USA
5- Molecular Oncology Research Institute, Tufts-New England Medical Center,
Boston, USA
1 - Lionel Larue is an Inserm research
scientist and head of the "Developmental Genetics of Melanocytes"
team in CNRS/Institut Curie Joint Research Unit 146 "Cell Regulation
and Oncogenesis".
2 - In fact, "activated" Akt protein is overexpressed.
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