Asbestos a tragic story and a challenge for exemplary research
We
publish the authoritative intervention of Prof. Luciano Mutti , a
member of the National Scientific and Technical Committee , and Director
of the Department ONA Research and Treatment of mesothelioma.
The properties of asbestos have been known since the times of ancient civilizations that have always made extensive use .Pliny
the Elder reported the circumstance to which the slaves assigned to
work in asbestos mines had health problems much more frequently than
other slaves .The
first evidence of two disease states , most likely attributable to
mesothelioma occurred in 1769 , attributed to the French physician who
practiced Joseph Lieutad 3000 autopsies (fig 1 ), while E. Wagner in 1870 is attributed to the first definition of malignant mesothelioma as a distinct disease entity .fig 1The
industrial revolution led to a tremendous increase in the use of '
asbestos in the course of the 18th and 19th century heavily used in
steam engines, technology hub of the revolution .Yet
the existence of pleural mesothelioma was placed in doubt until the
beginning of the 19th century when some relationship between the damage
to health and exposure to asbestos fibers became progressively more
evident.Unfortunately,
these years saw the great prevalence of tuberculosis as a major
respiratory illness and subsequent lung fibrosis and pleural long
confused the doctors in the course of autopsies interpreted as scars
tuberculous fibrosis pleuropulmonary from asbestos and mesothelioma same
.Only in 1930 it began to correlate cases of pulmonary fibrosis with exposure to asbestos.Unfortunately,
over the years, with the outbreak of the two world wars , the demand
for and use of asbestos increased dramatically.Asbestos was used heavily in ships , buildings and almost all of the weapons used in those years.From
there began a gradual and increasingly widespread civilian use of
asbestos : public buildings ( eg schools ) and private in a ' wide range
of everyday objects .Yet
only in 1960, Wagner and co-workers reported 47 cases of mesothelioma
observed during the previous five years in a part of South Africa where
there were small companies that dealt with asbestos.Many
of the deceased had had a kind of professional exposure to asbestos (
including a railroad ) many years ago , some were played by children on
piles of asbestos deposited in the vicinity of the companies , one had
lived in the immediate vicinity of a factory which used the ' asbestos .1965
is , however, the date on which the international scientific community
finally sealed the ' existence of cancerogenetici effects of ' asbestos :
in fact published in 1965 were published in the proceedings of the
conference organized in 1964 by the New York Academy of Sciences on the
biological effects of ' asbestos . ( Annals of the New York Academy of Sciences 1965)In
the meantime , unfortunately, in the United States , it is estimated
that between 1940 and 1979, 27.5 million people were exposed to asbestos
fibers for reasons lavorativi.Ora we then face what has been called "
Epidemic European Pleural mesothelioma , J . Peto
, 1999) with very few effective weapons due to a too incomplete
understanding of the molecular mechanisms that determine the appearance
and development of this cancer .Just
this knowledge has , however, allowed great strides in the treatment of
other cancers (such as breast , colon , urinary tract and leukemias /
lymphomas ), of which a significant part is currently treated with drugs
that inhibit the molecular mechanisms discovered especially in the last 15 years.There
is therefore no doubt that the same knowledge should be acquired
quickly even on the molecular mechanisms of cancer from asbestos and in
particular of Pleural Mesothelioma . Only
way to achieve the purpose of designing new , more effective therapies ,
In short, we are faced with a big challenge for research.The
principles which led the research of our group as the other teams of
research on mesothelioma in the world were largely borrowed from the
fields of research previously conducted for the study of cancer
incidence and are at increased slowly the wide gap of knowledge between the pleural mesothelioma ( in particular) and other cancers .In
particular, we focused on the study of how to increase the sensitivity
of tumor cells to Mesothelioma to the most common anticancer drugs used
for this cancer and how to reduce or eliminate the characteristic
resistance of all tumor cells ( in particular in those of Mesothelioma )
to cell death (necrosis) or programmed cell death ( apoptosis).To
better understand these features should be considered as a valid
therapeutic targets to recall here the most accredited mechanisms as
responsible for the transformation of normal cells in pleural
mesothelioma cells ( mesothelial cells )Asbestos fibers exert their ability 'to carcinogenesis primarily through three main mechanisms :a)
Rupture of chromosomes with mechanical action that leads to a stable
radical change of ' " trim " gene of mesothelial cells to which these
cells end up with more express genes that lead to' increased
proliferation and resistance to stimulus normally capable of kill the cells .b ) genetic damage due to oxidative stress associated with iron contained in asbestos fibers. This type of oxidative damage leads to an abnormal gene expression similarly to the mechanical action described previously .c)
Proliferation of mesothelial cells damaged that favors the selection of
abnormal mesothelial cells , are resistant to toxic stimuli and
represent the first step towards their transformation into cancer cells.d)
The ability of the asbestos fibers to induce growth factors with the
activation of specific biochemical signals of resistance to necrosis and
apoptosis represent a further , crucial mechanism of neoplastic
transformation of mesothelial cells (Fig 2 )From
these general considerations on the mechanisms of carcinogenesis is
easy to understand how our attention is focused on the biochemical
signals considered able to increase the resistance of the cells to toxic
stimuli and promote , as an event, the final appearance of neoplastic
cells through the state of from transformed cells ' exposure to asbestos. The
"transformation" then , as a prelude intermediate state , through the
progressive acquisition of resistance to cell death , the formation of
cancer cells induced by ' exposure to asbestos.They
go back about 10 years ago, our first data that led us to focus on the
release of growth factors and activation of its biochemical signals as a
crucial mechanism in carcinogenesis of Mesothelioma .In
2001, our group published in fact the first article in the prestigious
journal Proceedings of the National Academy of Sciences (PNAS) on a
series of experiments which showed that in a model of co- carcinogenesis
virus / asbestos, mesothelioma and mesothelial cells produce high
amounts of
growth factor called Hepatocyte growth Factor ( HGF) is well known as
being able to contribute to the survival of cells exposed to toxic
stimuli of different nature.This
first work that opened new perspectives to the study of the biochemical
signals induced by growth factors in the onset and progression of
pleural mesothelioma .In
particular, for some years the study of their proliferative signal has
gradually developed and has been extensively studied both from our own
and other groups in the world.In
particular, our attention has focused on biochemical signals involving
different proteins whose activation plays an essential role in the
survival of normal cells exposed to toxic agents and / or
cancerogeneticiPI3K/AKT . The
activity of PI3K is well known as being able to activate a protein
called AKT including main biological effects is considered crucial to
the ability of cells to confer increased resistance to toxic stimuli . The
activation of this protein is significantly related to the action of
HGF as well as other growth factors such as Platelet Derived Growth
Facor (PDGF ) and Vascular Endothelial Growth Factor (VEGF ) whose
release by the cells of Mesothelioma associated with the presence of the respective receptors on the same cells has been demonstrated (Fig 2)The
research has therefore focused on the role of AKT in both mesothelial
cells grown experimentally in cells exposed to asbestos is mesothelioma .Since
the early experiments it was evident as indeed asbestos fibers were
able to induce activation of AKT (Fig 3 ) and how this activation was
significantly responsible for the process of transformation and
resistance to the toxicity exerted by the fibers . Indeed the ' experimental use of inhibitors of AKT was again able to induce such toxicity .So
AKT has been considered a key protein in the process that leads to the
selection of mesothelial tumor cells after exposure to asbestos fibers .The
next step was to identify a method potentially applicable in clinical
practice that it was able to induce the same inhibitory effect of AKT in
cells of Mesothelioma .The
focus has then again focused on growth factors able to activate AKT and
on the identification of specific inhibitors of their effect on this
protein .In
particular, the intense expression of the PDGF receptor ( PDGFR ) on
mesothelioma cells has suggested the use of a specific inhibitor of the
biological effects induced by the interaction between PDGF and PDGFR .The
availability on the market a drug on the market ( whose active
ingredient is Imatinib Mesylate , trade name, Gleevec ®) , which can
interfere with the binding of PDGF / PDGFR has therefore prompted the
research to test what effect Imatinib was able to exercise on ' activation of AKT .It
is thus shown as Imatinib Mesylate is able to induce selective
inhibition of the activation of AKT and also a very significant increase
in the sensitivity to certain chemotherapeutic drugs such as
gemcitabine .This
set of in vitro data has thus justified the use del'associazione
gemcitabine / Imatinib also on experimental animals that had been
experimentally induced human mesothelioma .The
treatment of these experimental tumors induced a significant
improvement in the survival of animals tested with a reduction or
stability of the size of the tumor (Fig 5 )The
logical conclusion of these preclinical studies has been to induce the
scientific world and our group to assess the real possibility that these
results could and should also be tested on patients with mesothelioma .Initially,
patients were treated with very extensive disease and were refractory
to previous therapy nel'ambito every one administration called "
compassionate."The
ability of the treatment to induce responses very significant both in
terms of reduction in tumor mass that of improving the quality of life
as well as the perception that these effects to be passed also on a
longer survival ( Fig 6 ) , ultimately prompted to begin a ' further
clinical trials on patients selected from those with a lack of response
to chemotherapy or relapse after an initial response to chemotherapy
(unfortunately almost constant conditions in patients with mesothelioma )
.
Fig 2 . When
a population of mesothelial cells exposed to asbestos fibers some of
these cells become resistant to the toxic agents and are progressively
transformed and induced the proliferation inducing the appearance of
mesothelioma cells .Population of cells
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