Molecular biology of malignant mesothelioma
Environ Health Prev Med
Molecular biology of malignant mesothelioma
Yoshitaka Sekido 0
0 Y. Sekido (&) Division of Molecular Oncology, Aichi Cancer Center Research Institute , 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681 , Japan
Human malignancies develop via a multi-step that involves the accumulation of several key gene alterations with associated genetic and epigenetic events. Although malignant mesothelioma (MM) has been demonstrated to be clearly correlated with asbestos exposure, it remains poorly understood how asbestos fibers confer key gene alterations and induce cellular transformation in normal mesothelial cells, which results in the acquisition of malignant phenotypes, including deregulated cell proliferation and invasion. Malignant mesothelioma presents with the frequent inactivation of tumor suppressor genes of p16INK4a/p14ARF on chromosome 9p21 and neurofibromatosis type 2 (NF2) on chromosome 22q12, with the latter being responsible for the NF2 familial cancer syndrome. In contrast, MM shows infrequent mutation of the p53 gene, which is one of the most frequently mutated tumor suppressor genes in human malignancies. Genetic abnormalities of oncogenes have also been studied in MM, but no frequent mutations have been identified, including the epidermal growth factor receptor (EGFR) and K-RAS genes. Recent studies have suggested the activation of other receptor tyrosine kinases, including Met, and the deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, although the alterations responsible for their activation are still not clear. Thus, further genome-wide
Asbestos; Molecular target therapy; Tumor suppressor gene; Malignant mesothelioma; Oncogene
studies of genetic and epigenetic alterations as well as
detailed analyses of deregulated signaling cascades in MM
are necessary to determine the molecular mechanisms of
MM, which would also provide some clues for establishing
a new molecular target therapy for MM.
Malignant mesothelioma (MM), a highly lethal neoplasm
arising primarily in the pleural, peritoneal, or pericardial
cavity, is thought to develop from surface mesothelial cells
]. In up to 80% of patients, MM occurs within
approximately 30–40 years following exposure to asbestos [
Since patients with MM are usually diagnosed at advanced
stages and MM is refractory to conventional therapy, the
prognosis of patients with MM is very poor. The median
survival of patients with malignant pleural mesothelioma
(MPM) is 7–11 months after diagnosis, despite the recent
advancements in chemotherapeutical modalities combining
cisplatin and antifolates such as pemetrexed or raltitrexed
The regulation of asbestos occurred relatively late in
Japan, with the result that the number of patients with MM
is expected to increase year by year, with the peak
incidence predicted around 2030–2040 [
]. To date, in Japan
approximately 1000 deaths can be attributed to MM. It has
been estimated that 250,000 people will die of MPM in
Europe during the next three decades and in the United
States, 2500–3000 new cases are diagnosed each year [
]. These numbers are attributable to the wide use of
asbestos in various industrial and building materials,
resulting in exposure to asbestos not only among workers
in factories and/or at construction and demolition sites but
also by ordinary citizens including family members of the
workers and local residents near the factories and affected
About 80% of MM develops in the pleura, 20% in the
peritonea, and less than 1% in the pericardium. The
pathologically, epithelial type accounts for about 60% of all
cases, the sarcomatous type for about 20%, and the
biphasic type with both components ranges around 20%.
Since MM is a relatively rare human malignancy, both
basic and clinical studies have lagged far behind those on
other common types of malignancies, such as lung, colon,
and breast cancers. However, many researchers are now
focusing their efforts on identifying the mechanisms and
key genes in MM development with the aim of using this
information to develop new diagnostic tools and target
molecules of new therapy.
Up to 80% of mesothelioma patients have been exposed to
asbestos, thus establishing a clear link between asbestos
exposure and MM development [
]. Many animal models
have also demonstrated the carcinogenicity of asbestos.
There are six types of asbestos: amphiboles-amosite
(brown asbestos), crocidolite (blue asbestos), anthophyllite,
actinolite, and tremolite, the serpentine chrysotile (white
asbestos). However, it has not yet been clearly determined
whether asbestos fibers act directly on the mesothelial cells
or whether they indirectly cause mesothelioma. Several
plausible explanations have been put forward on how
asbestos fibers can cause MPM [
]. One such suggestion
is that asbestos fibers mechanically induce pleural
irritation: long and thin asbestos fibers can be inhaled deeply
into the lungs, penetrating and repeatedly scratching the
mesothelial surface, resulting in prolonged cycles of
damage, repair, and local inflammation. Alternatively,
asbestos fibers can also mechanically interfere with the
mitotic process of the cell cycle by disrupting the mitotic
spindle, which may result in chromosomal abnormalities
and aneuploidy. A third proposal is that highly reactive
oxygen species (ROS) and reactive nitrogen species (RNS)
are induced by asbestos, leading to DNA damage and
strand breaks. A ramification of the interaction of long
fibers with cells is frustrated phagocytosis and a prolonged
oxidative burst. Finally, asbestos can induce cytokines and
growth factors, such as transforming growth factor-b
(TGF-b) and platelet-derived growth factor (PDGF), as
well as transcription factors, such as nuclear factor kappa B
(NF-jB) and activator protein-1 (AP-1). Additionally, in
rat mesothelial cells, crocidolite asbestos was found to
cause autophosphorylation of epidermal growth factor
receptor (EGFR) .
Inactivation of tumor suppressor genes in MPM
The most frequently inactivated tumor suppressor genes
(TSGs) in human malignancies are p53 and p16INK4a/
p14ARF. Most MPMs show frequent inactivation of
p16INK4a/p14ARF, although only 20–25% of these show a
mutation of p53. Analysis of primary samples of MPM
revealed that over 70% of the samples showed
downregulation of p16INK4a/p14ARF [
]. Using established
MPM cell lines, Taniguchi et al.  found that almost all
of the cell lines had a homozygous deletion of the p16INK4a/
p14ARFgene locus. The p16INK4a gene product controls the
cell cycle via the cyclin-dependent kinase 4 (CDK4)/
Cyclin D-RB pathway, while the p14ARF gene product
regulates p53 through inactivation of the human homolog
of mouse double minute 2 (HDM2), which is an upstream
regulator of p53. Thus, the homozygous deletion of
p16INK4a/p14ARF indicates the inactivation of two major
tumor-suppressing pathways of RB and p53 in the cell.
The loss of chromosome 22q12 is frequently detected in
MPM. The neurofibromatosis type 2 (NF2) gene, which
had been initially identified as a target gene of NF2 familial
cancer syndrome, has also been shown to be the target gene
of the 22q12 loss in MPM [
]. Neurofibromatosis type
2 patients frequently develop vestibular schwannoma,
meningioma, and other neuronal malignancies, while
sporadic tumors of these types of cancer also harbor a
NF2 mutation . However, to date, there has been no
published report of NF2 patients showing a higher
susceptibility to MPM. The NF2 gene is inactivated by
homozygous deletion, nonsense mutation, or missense
mutation in MPMs. Bianchi et al. [
] and Sekido et al.
] reported that about 40% of MPMs showed the genetic
mutation of NF2; among the 60% of MPMs without this
NF2 genetic mutation, about 20% showed a
down-regulation of NF2. In total, 50–60% of MPMs showed
inactivation of NF2. In an animal model, an established
line of Nf2 (±) knockout mice were shown to develop
MPMs in the earlier stage and, more frequently, after
asbestos exposure [
]. Remarkably, similar to human
MM, tumors from Nf2 (±) mice showed frequent
homozygous deletions of the p16Ink4a/p19Arf locus and adjacent
p15Ink4b tumor suppressor gene.
The NF2 gene encodes a
membrane–cytoskeletonassociated protein, Merlin, an adaptor protein with a FERM
(four-point-one, ezrin, radixin, and moesin) domain, which
transduces a growth-regulatory signal [
]. Merlin has
been shown to interact with several proteins, including
CD44, ezrin radixin moesin (ERM) proteins, p21-activated
kinase 1 (PAK1), and loses its tumor-suppressing activity
with phosphorylation at serine 518. This serine 518 site is
phosphorylated with RAC/PAK1 and dephosphorylated
with myosin phosphatase targeting subunit 1-protein
phosphatase 1d (MYPT-1-PP1d) [
]. The activity of
Merlin is thought to be regulated by cell-adhesion
(adherence junction), cell-extracellular matrix adhesion, or
extracellular growth signals. The downstream signaling of
Merlin is mediated by Hippo cascade, which was initially
identified via genetic studies in Drosophila [
Merlin is thought to be one of the key molecules in the
signaling cascades that determine the properties of
invasion, cell growth, and survival of malignant mesothelioma
cells (Fig. 1).
Activation of oncogenes in MPM
Simian virus 40 (SV40) is a double-stranded DNA
polyomavirus of monkey origin, which has been suggested to be
associated with MM development [
]. Since the polio
vaccine that was used between 1954 and 1963 was widely
contaminated with SV40, vaccination was proposed as a
plausible vector for the widespread SV40 infection of the
human population. However, even people who had not
received a polio vaccination were found to be infected with
SV40, leaving unanswered the questions as to how SV40
virus infected humans.
Since SV40 expresses large T and small T antigens, and
the large T antigen binds and inactivates the p53 and RB
tumor suppressors, SV40 infection has been recognized as
one of primary mechanisms of mesothelioma development
pathogenetically. Intrapleural infection of SV40 in
hamsters induces mesothelioma development by 6 months after
administration, and SV40 induces Met, Notch-1, and
telomerase activity, which also supports the functional roles of
However, most of the studies showing a strong
relationship between SV40 and MM consisted exclusively of
PCR-based assays in which the simple amplification of
specific segments was considered to indicate a positive
result; otherwise, the data were conflicting and
reproducibility was limited. The results from several more recent
studies suggest that such results were false-positives due to
contamination by plasmids that were in general use in
many of the laboratories common among the studies [
Consequently, the involvement of SV40 in malignant
mesothelioma remains controversial.
The activation of receptor tyrosine kinase (RTK) family
members has been investigated in MM. Among these, the
Met oncogene has been shown to be frequently expressed
Receptor Tyrosine Kinase
AKT, and Hpo (Hippo) cascades, which are regulated by Merlin and
its homologues [ezrin radixin moesin (ERM) proteins], such as Ezrin.
These signaling cascades are often deregulated in malignant
mesothelioma (MM) cells. ECM Extracellular matrix, ERK extracellular
signal-regulated kinase JNK JUN N-terminal kinase, MAPK
mitogenactivated protein, PI3 phospatidylinositol-3
in primary tumors and cell lines of MM [
growth factor (HGF) is a ligand of Met, and HGF-MET
plays a role in the mitogen-activated protein kinase
(MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT
cascades. The PI3K-AKT cascade has also been shown to
be activated in MM. Furthermore, MMs with positive AKT
phosphorylation status show phosphorylated (activated)
mTOR (mammalian target of rapamycin), which is one of
the downstream molecules of AKT. Thus, the activation of
the PI3K-AKT-mTOR signaling cascade in MM is thought
to be induced by activation of the upstream HGF-MET
(Fig. 1). Additionally, although EGFR, another RTK which
is frequently mutated in Asian female adenocarcinoma of
the lung, was shown to be overexpressed in 56% of primary
tumors, no EGFR mutation was documented [
Malignant mesothelioma cell lines produce many other
growth factors and cytokines [
]. Platelet-derived growth
factor, TGF-b, insulin-like growth factor (IGF) have been
studied in depth. In addition, factors involving angiogenic
pathways have also been demonstrated to be expressed in
MM cells, including interleukin (IL)-6, IL-8, fibroblast
growth factors (FGFs), and vascular endothelial growth
factors (VEGFs) [
Searching for new key genes in malignant mesothelioma
Since only a small number of oncogenes or TSGs with
genetic alterations has been identified in MM, other, as yet
unidentified genes may well be responsible for its
development. Traditional allelotyping and karyotype analyses
have revealed nonrandom chromosomal abnormalities,
including 1p, 3p, 4p15.1-p15.3, 4q25-q26, 4q33-q34, 6q,
9p, 14q11.1-q12, 14q23-q24, and 22q [
comparative genomic hybridization (CGH) technique has
recently been introduced to search for additional genes that
are potentially involved in MM biology. New alteration
regions have been identified, including 1q, 4q, 5p, 6p, 7p,
8p, 8q, 10p13-pter, 13q, 14q, 15q, 17p12-pter, 17q, and 20,
in which new cancer-associated genes of MM may be
]. A recent study of array-based CGH
analysis with MMs from a total of 22 individuals identified
high-copy gain at 1p32, which includes the JUN
]. JUN is a transcription factor and functions as
homo- or hetero-dimerization with FOS to form the
transcription factor AP-1, which can bind to the promoter
region of intermediate genes involved in cell division and
other cell functions. Both crocidolite and chrysotile
asbestos reportedly caused increases in the expression of
JUN and FOS in rat pleural mesothelial cells [
the gene amplification of JUN was identified in a subset of
MPM tumors, it was suggested that there were some strong
and persistent factors for JUN activation during the
development of MPM tumor cells. A more recent study
reported an activated mutation of N-RAS in three of 38
Finally, expression profiling using microarray has been
also studied to identify specific gene expression changes in
MM compared with normal mesothelium [
new candidate oncogenes and TSGs of MM were proposed,
and patient prognosis was shown to be predictable with the
differences of gene expression profiling.
Application for molecular target therapy
Malignant mesothelioma is a highly aggressive tumor, and
the patient prognosis with advanced-stage MM is very
poor. Combination chemotherapy with cisplatin and
antifolate has recently been shown to be superior to cisplatin
]. Although several molecular target therapies
have been tested, no satisfactory results have been obtained
to date. For example, a phase II study of an EGFR
inhibitor, gefitinib, was conducted for 43 patients with
previously untreated MM . Although 97% of patients
with MM had EGFR overexpression, gefitinib was not
active in MM and EGFR expression did not correlate with
failure-free survival. Imatinib, another tyrosine kinase
inhibitor known to affect both Kit and PDGFa (and b)
receptors, has also been shown to have limited efficacy for
A recent microarray analysis on 99 MPM detected
advanced-stage, sarcomatous histology and the p16INK4a/
p14ARF homozygous deletion to be significant adverse
prognostic factors [
]. The same study also found that
more aggressive MPM expressed higher levels of Aurora
kinases A and B, which are serine/threonine kinases with
multiple roles in mitotic progression. Thus, the role of
Aurora kinases is of interest due to the recent development
of their small-molecule inhibitors. In addition, a
smallmolecule inhibitor of TGFb type I receptor has been shown
to inhibit murine mesothelioma tumor growth in vivo [
The long latency period between asbestos exposure and
tumor development implies that multiple—and likely
diverse—genetic changes are required for the malignant
transformation of mesothelial cells. Many studies have
been conducted to determine the underlying key genetic
and epigenetic events responsible for the development of
MPM, some of which may be directly caused by asbestos
fibers. New animal models of MM and human MM cell
lines are also being established to present more useful tools
for detailed analyses of the carcinogenesis of MM and the
development of new therapeutic modalities [
more in-depth knowledge of key gene alteration, specific
expression profiling, and other fundamental abnormalities
at the cellular, intercellular, and tissue levels in MM cells
will be of great help in developing future strategies for
potential molecular targets as well as other therapeutic
modalities, such as immunotherapy.
Acknowledgments This work was supported by a Special
Coordination Fund for Promoting Science and Technology from the Ministry
of Education, Culture, Sports, Science and Technology
(H18-1-3-31). I thank Dr. Hideki Murakami, Dr. Yutaka Kondo, Dr. Hirotaka
Osada, and Dr. Tetsuo Taniguchi for their helpful comments. I regret
the lack of citations for many important observations in the text, but
their omission is made necessary by restrictions on the preparation of
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