Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors
Shoshana J Weiner1, Siyamek Neragi-Miandoab2
1 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH, USA
2 University Hospitals, Case Western Reserve University School of Medicine, 11100 Euclid Avenue LKS Building 7th floor, Cleveland, OH, USA
|Date of Submission||13-Sep-2007|
|Date of Acceptance||28-Jul-2008|
|Date of Web Publication||28-Jul-2008|
University Hospitals, Case Western Reserve University School of Medicine, 11100 Euclid Avenue LKS Building 7th floor, Cleveland, OH
Source of Support: None, Conflict of Interest: None
Clinical trial registration None
Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes.
|How to cite this article:|
Weiner SJ, Neragi-Miandoab S. Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors. J Carcinog 2008;7:3
|How to cite this URL:|
Weiner SJ, Neragi-Miandoab S. Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors. J Carcinog [serial online] 2008 [cited 2020 Jul 6];7:3. Available from: http://www.carcinogenesis.com/text.asp?2008/7/1/3/42488
| Introduction|| |
Malignant pleural mesothelioma (MPM) is a solid, locally aggressive tumor of the pleura that encases and invades the lung parenchyma in late stages of the disease (see [Figure 1]) causing clinically significant morbidities such as dyspnea and chest pain [1,2]. Without treatment, MPM is associated with a poor median survival, ranging from 4 to 12 months .
The single term MPM can be misleading in that these tumors present with substantial phenotypic variability and are, therefore, classified according to the relative proportions of epithelial and spindle cells. The three major histological types include epithelial (see [Figure 2]), sarcomatous (see [Figure 3]), and mixed types. In all of these types of malignant mesothelioma, the cells are more frequently bi- or multi-nucleated, arranged in clumps, and the nuclear and nucleolar sizes are proportionally larger .
Epithelium-derived mesothelioma consists of large spherical cells arranged in solid masses and columns that form mainly within the lymphatics. These cells may also form glandular structures that resemble adenocarcinoma (see [Figure 2]). The epithelial cells contain large numbers of desmosomes, tonofilaments, and long, slender branching microvilli that may have contact with extracellular collagen because the basement membranes are incomplete [4,5]. The sarcomatoid type originates from the deep connective tissue of the mesothelium. These tumors are characterized by ovoid-to-spindle-shaped cells similar to cells seen in fibrosarcomas (see [Figure 3]) . Epithelial mesothelioma is the most prevalent type, followed by mixed/biphasic, sarcomatous, and, rarely, desmoplastic types . In a large study, epithelial cell type was observed in 61.5% of specimens (n = 930), followed by biphasic in 22% (n = 334) and sarcomatous in 16.4% (n = 247) . Additional subtypes of epithelia histology include: tubular, papillary, solid, large/giant cell, small cell, clear cell, signet cell, glandular, microcystic, myxoid, and adenoid cystic [9,10].
Unlike some other tumors, there is no evidence for the existence of a premalignant, non-invasive phase for MPM . This has made it difficult to determine which risk factors and molecular changes are responsible for the initiation and further progression of MPM development. However, through the use of cell culture, animal models, and epidemiology, an active field of research and debate has uncovered many players in MPM pathogenesis. The first part of this review considers the genetic and molecular changes that have been identified in the development of MPM. The second section will provide a more detailed review of the known risk factors that may cause these molecular changes and the controversies that surround these risk factors.
| Genetic and molecular processes in MPM|| |
In the development of cancer, a cell acquires alterations in gene expression and protein function that allow the cell to surpass its normal growth limits. One way of acquiring these alterations is through changes to the genome itself. Abnormal karyotypes, often with extensive aneuploidy and structural rearrangements, have been described for a number of genetic loci in MPM [12,13]. The effects of these mutations and additional effects from environmental risk factors have begun to explain how malignant mesothelioma cells form malignant tumors. Additional details about many of these pathways can be found in earlier reviews [14-16].
Tumor suppressor genes (TSGs) play vital roles in regulating the cell cycle in response to DNA damage and other stressors. The loss of TGS function is one of the fundamental events in tumorigenesis . Loss of heterozygosity (LOH) seems to be a consistent feature of MPMs, which commonly lead to the loss and/or inactivation of multiple TSGs. Pylkkanen et al.  demonstrated frequent deletions at specific sites within chromosomal arms 1p, 3p, 6q, 9p, 13q, 15q, and 22q. p16/CDKN2A , p15/CDKB2B and p14ARF at 9p21, FHIT gene at 3p and neurofibromatosis 2 (NF2) at 22q12 are frequently altered TSGs that account for some of these deleted sites in MPMs [18-22]. Epigenetic methods may also contribute to TSG inactivation. Promoter hypermethylation has been demonstrated for p16/CDKN2A in MPM tumor samples and cell lines, and for another TSG candidate RASSF1A located at 3p21 in cell lines [23,24]. Wilms tumor suppressor gene (WT1), another TSG associated with MPM, will be discussed in the section on pediatric mesothelioma.
A surprising finding in mesothelioma research is the lack of frequent mutations in the two most notorious TSGs: p53 and pRb. Although p53 mutations have been found in MPM cell lines [21,25], there is a general sense that the contributions of p53 mutations in MPM pathogenesis are minor [21,26-28]. However, the importance of p53 deregulation is well-recognized. p53 is essential for cell cycle arrest in response to DNA damage and in genomic instability. When Vaslet et al.  induced mesothelioma growth in heterozygous p53 +/- mice with crocidolite asbestos fibers, the mice that had lost the functioning allele of p53 had shorter latent periods and more aggressive tumors than the mice that still maintained one copy. Outside of this model, p53 function is more commonly affected by mutations in upstream and downstream members of the p53 pathways [16,25]. The most well-known mechanism is the inactivation of p53's upstream regulator p14ARF . With the loss of p14ARF, the cell loses its ability to inhibit MDM2. This allows MDM2 to inhibit p53, which can no longer induce cell cycle arrest and apoptosis.
The loss of pRb function occurs in a similar manner to p53. This time p16/CDKN2A is mutated. In brief, p16/CDKN2A can no longer inhibit cyclin-dependent kinases 4 and 6, which are responsible for the G1–S phase transition of the cell cycle. Left unchecked, these kinases can phosphorylate and thereby inactivate pRb, which allows an uncontrolled entry into S phase . Homozygous deletion of p16/CDKN2A has been reported in >70% of malignant mesotheliomas, and has been associated with poor prognosis [30,31]. In addition to proteins within the p53 and pRb pathways, the role of a viral protein has also been shown to inactivate these TSGs. The large tumor antigen protein (SV40Tag) of the SV40 virus can bind to and inactivate both p53 and pRb [32-37]. However, the role of SV40 virus in mesothelioma is still a matter of debate, as discussed below.
Not only must malignant tumors continue their growth, but they must also be able to move and invade. A recent paper by Poulikakos et al.  proposes a mechanism through which merlin, the product of NF2 , may help mesothelioma cells acquire this ability. Through the use of in vitro assays, Poulikakos et al.  found that the re-expression of merlin in two human malignant mesothelioma cell lines significantly decreased cell motility and invasion. Furthermore, merlin may mediate its effects through the phosphorylation of focal adhesion kinase. Further evidence is needed in order to determine if merlin functions in this particular way in vivo .
While the loss of TSGs allows the cell to grow in light of aberrant changes in cellular DNA and function, it is the activation of oncogenes that inspires cell growth and proliferation. AP–1 and β-catenin transcription factors are implicated in MPM pathogenesis. The AP–1 family of transcription factors is known for mediating a wide range of processes including proliferation, apoptosis and transformation in response to a variety of stimuli . The activation and expression of AP–1 proteins are regulated by different mitogen-activated protein kinases (MAPK) . Fra–1, a member of the Fos family of AP–1 transcription factors, has been implicated in MPM pathogenesis. Ramos-Nino et al.  found a high level of AP–1 DNA binding activity and an increased expression of Fra–1 in mesothelioma cell lines. In addition, rat mesothelial cells exposed to either asbestos or epidermal growth factor (EGF) showed an increase in Fra–1 expression. This expression was abrogated when cells were pretreated with an inhibitor to the MAPK, extracellular-signal-regulated kinase (ERK). When mesothelioma cell lines were treated with either the ERK inhibitor or were transfected with a vector carrying a dominant negative fra–1, there was a reversal of the transformed phenotype of the cells . Previous work also examined the role of asbestos and the EGF receptor in ERK activation . Zanella et al. [42,43] hypothesized that asbestos may activate the EGF receptor itself or may also induce the ERK pathway through the formation of reactive oxygen species. Hepatocyte growth factor (HGF) and signaling through its receptor, c-Met, may also activate ERKs in addition to the Akt pathway . Furthermore, the small tumor antigen (SV40tag) protein of the SV40 virus may activate ERK. SV40tag is known to inhibit protein phosphatase 2A (PP2A). Due to this inhibition, PP2A can no longer dephosphorylate and inactivate members of the MAPK family [32,41].
The transcription factor β-catenin is regulated by an ubiquitin ligase pathway. In the absence of Wnt signaling, glycogen synthase kinase 3B (GSK3β) phosphorylates adenomatous polyposis coli (APC) and axin, which increases their affinity for β-catenin. GSK3β can then phosphorylate β-catenin, marking it for destruction. When Wnt is present, GSK3β phosphorylation is inhibited, allowing β-catenin to escape ubiquination, and enter the nucleus where it can bind to T-cell factor/lymphoid-enhancer factor (Tcf/Lef) transcription factor proteins thereby activating transcription of downstream effectors . The role of this oncogenic pathway has been previously reviewed by Lee et al.  Here we briefly discuss the concerns surrounding the activation of β-catenin in MPM. It is interesting that activating mutations in the GSK3β phosphorylation sites of β-catenin have not been detected  since mutations in the p53 and pRb tumor suppressors also do not appear to play an important role in MPM pathogenesis as discussed above. Just as with these TSGs, we may need to look to upstream regulators in order to find our answer as to how β-catenin is activated. For example, an increase in disheveled expression has been observed in patient samples and mesothelioma cell lines,  and a lack of staining in some mesotheliomas for the C-terminus of APC has led to the hypothesis that inactivating mutations of APC may be involved . A group of upstream negative-regulators of the Wnt pathway have also been implicated. Wnt inhibitory factor 1 (WIF–1) , Dickkopf–1 , and secreted frizzle-related proteins (sFRP) [50,51] have the ability to inhibit Wnt signaling at the level of cell membrane receptor activation. Thus far, data has demonstrated a possible role for promoter methylation in the inactivation of WIF–1 and sFRPs [48,50], a mechanism also described for TSG inactivation. Lee et al.  has also hypothesized that some of these mediators may have a role outside of the canonical Wnt-β-catenin pathway. Lastly, SV40tag may also be involved in the activation of the Wnt pathway, in addition to its role of ERK activation . In this case, the inhibited PP2A cannot inactivate the transcription factor β-catenin, making entrance to the nucleus possible.
The role of growth factors in carcinogenesis has already been suggested above in the case of MAPK pathway activation by EGF. Growth factors can stimulate proliferative pathways through their contact with membrane receptors. They may also play a role in the process of tumor invasion and metastasis, which has been demonstrated by their ability to stimulate chemotactic and/or chemokinetic motility in mesothelioma cell lines . Moreover, they can act on stromal cells in order to provide an environment favorable to tumor growth. For example, endothelial cells proliferate during the process of angiogenesis, which supplies the growing tumor with necessary oxygen and nutrients. Another important family of landscaper genes is the matrix metalloproteases (MMPs), which help to degrade the extracellular matrix that surrounds the tumor [53-57]. This process is also important in angiogenesis as well as in tumor migration and invasion. Here we also mention that the expression of cyclooxygenase 2 (COX–2) has been recognized as a prognostic factor in MPM as reviewed elsewhere [15,16]. It is possible that COX–2 may play a role in angiogenesis and/or resistance to apoptosis .
Many growth factors, such as insulin-like growth factor–1 (IGF–1) [16,59], hepatocyte growth factor (HGF) [44,60], basic fibroblast growth factor (b-FGF) , TNF-α , EGF [14,63], VEGF [14,64-68] and platelet-derived growth factor (PDGF) A and B , have been implicated in the development and progression of malignant mesothelioma. Growth factors may come from a variety of sources during the course of MPM pathogenesis such as the surrounding lung parenchyma , macrophages , and from the mesothelial cells themselves [44,62] in response to a number of stimuli including inflammatory cytokines [62,70], asbestos , and SV40 infection [64,65]. Some of these stimuli may also induce ectopic signaling through growth factor receptors without the need for ligand stimulation  and/or activating mutations of these receptors may result in signaling . The role of growth factors in oncogenesis has become a provocative subject in cancer therapy since the development of cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma [67,71]. Here we discuss the role of VEGF, HGF, and TNF-α in more detail. Additional growth factors are reviewed elsewhere [14-16].
VEGF is an angiogenic peptide, which is an independent prognostic factor in MPM . Higher VEGF levels were found in the pleural effusions of patients with MPM compared to its level in the effusions of patients with non-malignant pleural disease . While VEGF is a fairly specific angiogenic factor, it has also been shown to increase the growth of mesothelioma cells in vitro . The use of antisense oligonucleotides (ODN) to inhibit the production of both VEGF and VEGF-C slowed mesothelioma cell growth. In addition, antibodies to VEGF receptor (VEGFR–2) and VEGF-C receptor (VEGFR–3) had a synergistic effect in inhibiting mesothelioma cell growth . One mechanism that may increase the production of VEGF in MPM is SV40 infection. Production and release of VEGF was greater in SV40Tag-positive MPM cells than in MPM cells that did not show evidence of SV40 infection . It appears that this effect is mediated through more than just SV40Tag, since mesothelial cells transfected with the full length SV40 genome produced higher levels of VEGF as compared to cells transfected with SV40Tag only .
HGF has many possible roles in MPM pathogenesis. It may stimulate morphological changes , promote cell growth and migration [44,64] and induce angiogenesis by itself or through an increase in the production of VEGF . Some of these effects may be mediated by downstream signaling via Akt and ERK pathways . The mechanisms by which HGF and its receptor are activated are not fully understood. Cacciotti et al. proposes an SV40–mediated activation that is dependent on SV40Tag binding to pRb. The HGF that is produced in response to SV40 infection signals through autocrine and paracrine mechanisms . HGF may also come from neighboring lung tissue that has been damaged by asbestos exposure and inflammation . Lastly, signaling through c-Met may be caused through activating mutations .
TNF-α may help to explain the survival of mesothelial cells after exposure to asbestos . Human mesothelial cells are sensitive and often die after phagocytosis of asbestos fibers . The dilemma caused by this finding is well stated by Yang et al. : "How can asbestos cause MM [malignant mesothelioma] if HM [human mesothelial cells] exposed to asbestos die?" They show in vitro that asbestos induces the expression of TNF-α and its receptor in human mesothelial cells, and that cell survival may be mediated by the NF-κB pathway downstream of receptor activation. They also propose that other cells, macrophages in particular, may be important contributors of TNF-α in vivo . More research is needed in order to test this hypothesis.
Apoptosis frequently occurs in response to signals from outside the cell. For example, TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand and a lack of growth factor stimulation may result in programmed cell death . However, it is a couple of intracellular mediators of apoptosis that have thus far been implicated in MPM. The over-expression of BCL–2 helps to protect the cell from apoptosis as reviewed elsewhere [14-16]. MPM cells may also be protected from apoptosis by the ectopic expression of telomerase , and SV40 infection may be one way mesothelial cells activate this protein . In the absence of telomerase, telomeres located at the terminal segments of chromosomes shorten with each cell division. At first, these segments protect the coding regions of chromosomal DNA from degradation. When the telomeres become too short, apoptosis ensues. The activation of telomerase allows MPM cells to escape this mechanism of cell death and to perpetuate mutations that might have otherwise been discarded in the normal process of "cell aging."
| Risk factors of MPM: Their contributions and controversies|| |
Many risk factors have been identified as contributors to MPM pathogenesis. Above, we began the discussion surrounding the contribution of genetics, asbestos, and SV40 infection. Here we will complete our discussion of these factors and further introduce concerns surrounding the relationship of MPM to radiation and to the pediatric population.
Asbestos' contribution to the pathogenesis of MPM is multifaceted with effects ranging from direct to indirect, genetic to molecular. Asbestos induces mutations in mesothelial cells. The more direct mechanism of injury includes deposition of asbestos fiber in the pleura. Longer fibers can penetrate deeply into parietal pleura and have a high likelihood of causing cancer . Asbestos fibers may also damage the mitotic spindle of cells and thereby disrupt mitosis, resulting in aneuploidy and DNA damage [78,79]. In a less direct fashion, asbestos can lead to the formation of reactive oxygen species (ROS). The production of ROS can be catalyzed by the iron content of the fibers or can occur through additional reactions on the fiber surface [80,81]. Macrophages that have phagocytosed asbestos fibers release ROS and lymphokines, which can damage DNA and possibly suppress the immune system [82,83]. Asbestos and/or the resulting ROS may also directly activate cell-signaling pathways [42,43].
The response of mesothelial cells to asbestos and ROS is an important factor in MPM pathogenesis. Above, we described the possible role of TNF-α in protecting mesothelial cells from death after asbestos exposure . The ability to manage oxidative damage may be another mechanism mesothelial cells use to protect themselves . Ferritin heavy chain (FHC) is a subunit of ferritin involved in iron sequestration. Aung et al.  found that when two mesothelioma cell lines were treated with asbestos, the cells that expressed higher levels of FHC had a smaller percentage increase in hydrogen peroxide generation and experienced less apoptosis as compared to cells that expressed lower levels. In addition, polymorphisms in some genes of important free radical scavenging enzymes such as mitochondrial manganese superoxide dismutase (MnSOD), glutathione-S-transferase M1 and mEH have been associated with MPM [85,86].
The Asbestos Controversy: Which Fiber is Responsible?
The use of the single term "asbestos" to describe at least five unique fibrous silicate minerals (see [Table 1]) hides the underlying controversy as to which fibers truly carry carcinogenic potential. The asbestos fibers, with regard to their bio-persistence and dimensional properties, have been stratified into two main groups: serpentine fibers (mainly chrysotile), and amphibole fibers (consisting of crocidolite, tremolite, anthrophylite and amosite). Nearly 95% of asbestos used internationally is chrysotile, and only 5% is amosite and crocidolite , although these groups of fibers are commonly found mixed together. New members of the asbestos family and new fiber species have been found to have carcinogenetic potential [88,89]. Exposure to these fibers may help to explain why some communities experience a high incidence of MPM without any known evidence of asbestos exposure .
The two different theories dealing with carcinogenicity of asbestos fibers are the Amphibole Hypothesis and Stanton's Theory. The Amphibole Hypothesis claims that only amphibole fibers can cause cancer, since chrysotile fibers are broken down and cleared too quickly to provoke carcinogenesis . This is in contrast to amphibole fibers, which persist in the body for a longer period of time as a result of their durability and biopersistance . The Stanton Theory suggests that long and thin fibers (≥ 8 micrometer in length and ≤ 0.25 microm in width) are strongly carcinogenic regardless of their physicochemical nature , since they can penetrate further into the pleura .
There is data that both supports and opposes these theories. In his recent reviews [93,94], Yarborough concludes that the epidemiological evidence for the role of chrysotile fibers in MPM pathogenesis is weak and that chrysotile may not play a significant role in this disease process. However, he does admit that a threshold for chrysotile most likely exists though it has not yet been adequately detected by epidemiological research . Although Yarborough's conclusions mainly support the Amphibole Hypothesis, they do not completely rule out a role for chrysotile fibers in MPM pathogenesis. Conclusions concerning the Stanton Hypothesis are also mixed. A recent expert panel concluded that longer fibers have more carcinogenic potential  although an earlier review of animal and in vitro studies by Jaurand  did not find this correlation. The role of the different fiber types and the quantity of exposure necessary to cause MPM are still controversial. The data are complicated by the variability in study designs and definitions as well as by the role of other risk factors such as genetics, industrial hygiene, and concomitant smoking [96-99]. However, the general consensus holds that longer fibers and amphibole fibers have more carcinogenic potential than their shorter and chrysotile counterparts in regards to MPM.
Recent advances in cancer treatment involve multimodality approaches that include surgery, chemotherapy, and irradiation. Although these combined therapies increase survival in certain types of cancer, they can also cause the development of new malignancies [2, 100, 101]. Ionizing radiation, in particular, has been shown to play an important role in secondary benign and malignant tumors [102,103]. Post-radiation malignant mesothelioma has been reported after radiation therapy for breast cancer [102, 104, 105], Hodgkin's disease , cervical cancer . Wilm's tumor [108-110], and seminoma . In order to rule out previous asbestos exposure as a risk factor in these cases, Wissman  measured the levels of ferruginous bodies in the lung of a patient who developed MPM after radiation for Hodgkin's disease. The lung tissue showed 250 ferruginous bodies per gram of lung tissue, which is consistent with no significant prior asbestos exposure. In addition, Cavazza et al.  reviewed the National Cancer Institute's SEER data for 30 patients who developed malignant mesothelioma after radiation therapy. According to Cahan's criteria, these cases of mesothelioma may be considered as treatment-related post-radiation mesothelioma or sarcoma . Radiation seems to contribute to MPM development in a small percentage of patients after radiation therapy. This low incidence may be explained by a multifactorial cause of secondary malignancies. In addition to radiation, exposure to chemotherapy, genetic predisposition, environmental cocarcinogens and other factors may be needed in their development . As the frequent use of radiation therapy has raised concerns about future increases in the incidence of these secondary malignancies [116-118], future research to recognize these additional risk factors may be useful in identifying and modifying the treatment of patients who are likely to develop these secondary cancers.
SV40 is a poliomavirus with double-stranded circular DNA [33,119]. The virus has two regions, early and late. The early region encodes SV40Tag, SV40tag, and 17 KT. The late region encodes structural proteins of the virus . Important roles of the early proteins in TSG, oncogene and growth factor regulation were described above. Briefly, SV40Tag can bind to and inhibit p53 and pRb TSGs, and SV40tag has been shown to inhibit PP2A, which may lead to the activation of Wnt and ERK signaling pathways. SV40 infection may also increase autocrine and paracrine signaling through a variety of growth factor pathways and induce the expression of telomerase . Another possible role of SV40 in MPM that was not stated above is that SV40 infection may increase the transcription and activation of Notch–1, which may have an important role in mesothelial cell transformation and proliferation . Lastly, SV40 has been hypothesized to work as a cocarcinogen with asbestos [73,122-125]. SV40 may provide another mechanism by which mesothelial cells escape asbestos' cytotoxic effects . Cacciotti et al.  found that mesothelial and mesothelioma cells infected with SV40 were more resistant to asbestos treatment. They concluded that this effect may be mediated by the activation of the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. This pathway may become activated downstream of SV40's ability to induce growth factor signaling pathways or through other mechanisms. They provided in vivo evidence from mesothelioma samples. 10 out of 11 tumors with detectable SV40Tag expression also stained positively for activated Akt. After helping mesothelial cells survive asbestos exposure, SV40 may also work with asbestos to cause DNA damage  and to transform cells [73, 122, 124]. When Bocchetta et al.  expressed SV40Tag and SV40tag in human mesothelial and fibroblast cells, cells that had been treated with asbestos showed a larger number of transformed foci as compared to cells that only expressed SV40.
Controversy about SV40: Does SV40 really play a role?
Not only does the above data supply strong mechanistic support for the role of SV40 infection in MPM pathogenesis, but in vitro experiments have also demonstrated a high susceptibility of mesothelial cells to develop stable infections by SV40 as compared to human fibroblasts, which quickly lyse after only semipermissive infection . Despite this collection of mainly in vitro data, a role of SV40 infection in MPM pathogenesis has not been established due to the conflicting results of epidemiological studies.
From 1955 to 1963, the polio vaccine supplied to the United States, Canada, Europe, Asia and Africa was contaminated with SV40. Furthermore, the possibility of horizontal transmission may have enlarged this exposure . Many studies [123,126-130] have found evidence of SV40 infection. A meta-analysis conducted by Vilchez  reviewed molecular, pathological, and clinical data from 1,793 cancer patients. He concluded that there is significant data to support a role for SV40 infection in human brain cancers, bone cancers, malignant mesothelioma, and non-Hodgkin's lymphoma. However, whether these results can be attributed to polio virus contamination is not completely clear [128, 129, 132, 133]. Populations in Finland and Turkey were not exposed to the contaminated vaccine. In these cases, SV40 contamination was not observed in MPM as would be expected if the source of infection was primarily vaccination. On the other hand, Engels et al.  reported that although a contaminated poliovirus vaccine was administered to most children in Denmark from 1955 to 1961, there was no increase in malignant mesothelioma incidence . Additional studies argue against the significance of SV40 infection [135,136]. In a study by Manfredi et al. , SV40Tag DNA was not detectable in tumor tissue of 69 mesothelioma patients. SV40Tag protein was also undetectable in tumor samples and mesothelioma cell lines by immunohistochemistry. Perhaps the standardization of SV40-detection techniques and more comprehensive studies will determine if SV40 will be a worthwhile target for preventative measures in the future .
Pediatric mesothelioma, familial cases and genetic predisposition
Mesothelioma is very rare in childhood with an estimated 2%–5% of all cases occurring in the first two decades of life. The diagnosis may be challenging because of its rarity and its pathologic similarities to other papillary or spindle cell neoplasms in the pediatric age group [137,138]. To date, little is known about the pathogenesis of MPM in children. Frair et al.  reviewed the risk factors in a series of 80 pediatric patients with malignant mesothelioma. Only four of the 80 children had exposure to known risk factors (two had history of exposure to asbestos, one had received radiation therapy, and one was exposed to isoniazid in utero ). A causal relationship between malignant mesothelioma and asbestos exposure, radiation, and/or isoniazid could not be established. As far as asbestos is concerned, the long latency of asbestos-related mesothelioma makes a role for this risk factor in pediatric MPM unlikely [140,141] unless the natural history of asbestos-related cancer in children is very aggressive and rapidly progresses .
Pediatric and familial cases may open an avenue for the study of genetic contributions to MPM. Small case studies have found that pediatric patients with Wilm's tumor who were treated with radiation may be at an increased risk for mesothelioma [110,142]. This risk may represent a role of WT1 as a TSG in MPM pathogenesis. However, this picture is complicated by data that reports a lack of inactivating mutations in MPM [143-145]. Also, one study has reported a de novo activating-mutation in WT1 in a 45–year old woman with a perotineal mesothelioma , and many studies have demonstrated the expression of WT1 in mesothelioma as reviewed by Whitson et al. . It may be possible that the WT1 plays different roles in pediatric versus adult mesotheliomas, or that the association of Wilm's tumor with mesothelioma is confounded by the exposure to radiation and other risk factors. The study of pediatric patients who have not been exposed to known risk factors may provide a key opportunity to evaluate WT1 involvement in MPM in addition to the role of other genetic contributors.
Familial cases also support the role of genetic predisposition to MPM [146,147]. However, the interpretation of these studies may be complicated by the presence of common environmental exposures. Ascoli et al.  found that most of the familial cases in their study had been exposed to asbestos. One might conclude that this common exposure outweighs any contribution of genetics. On the other hand, these cases provide a resource to examine genetics-asbestos interactions in MPM pathogenesis, and may help to explain why less than 10% of people exposed to asbestos develop mesothelioma . Already, various studies have begun to apply modern genetic association techniques to the study of mesothelioma [31, 85, 86, 148, 149]. However more rigorous studies with larger sample sizes will be needed in order to make the most out of these techniques. Ohar et al.  has also offered other demographic information that may be taken into consideration when planning and analyzing genetic studies.
| Conclusion|| |
MPM has a complex etiology in which asbestos, ionizing radiation, viruses, genetic factors, and even diet  may act alone or in concert to activate the molecular processes necessary for carcinogenesis. A multi-step process is supported by the observation that numerous chromosomal deletions accumulate in most malignant mesotheliomas, many of which result in the loss and/or inactivation of TSGs [18,22]. However, uncovering the temporality of these steps has been difficult. Although many experimental techniques have been employed, the study of MPM is complicated by its late stage at diagnosis and its rarity. The long latency between asbestos exposure and MPM diagnosis exemplifies these problems. It is unclear if the time lag between asbestos exposure and diagnosis reflects a slow-growing tumor after early genetic mutations, or if the accumulation of genetic changes reaches a threshold of malignant transformation  since the late stage of diagnosis makes it difficult to determine the temporality of various genetic and molecular events. In addition, the long latency and the rarity make asbestos-induced MPM a poor candidate for comprehensive cohort studies. Through the application of innovative animal models [21, 124, 152], in vitro studies, and epidemiology, we may be able to gain a better understanding of which risk factors and molecular targets are the most important for future preventative and therapeutic measures.
| Competing interests|| |
The authors declare that they have no competing interests.
| Authors' contributions|| |
SJW and SNM both contributed to the research and writing. All authors read and approved the final manuscript.
| References|| |
Ismail-Khan R, Robinson LA, Williams CC Jr, Garrett CR, Bepler G, Simon GR: Malignant pleural mesothelioma: a comprehensive review. Cancer Control 2006, 13(4):255-263.
Neragi-Miandoab S: Multimodality approach in management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2006, 29(1):14-19.
KT BF: The Pleura. Oxford: Oxford University Press; 1992.
Dewar A, Valente M, Ring NP, Corrin B: Pleural mesothelioma of epithelial type and pulmonary adenocarcinoma: an ultrastructural and cytochemical comparison. The Journal of pathology 1987, 152(4):309-316.
Oury TD, Hammar SP, Roggli VL: Ultrastructural features of diffuse malignant mesotheliomas. Human pathology 1998, 29(12):1382-1392.
Thurlbeck WMR: The Respiratory system, disease of the pleura. Philadelphia: Lippincott; 1988.
Boutin C, Schlesser M, Frenay C, Astoul P: Malignant pleural mesothelioma. Eur Respir J 1998, 12(4):972-981.
Suzuki Y: Pathology of human malignant mesothelioma - preliminary analysis of 1,517 mesothelioma cases. Industrial health 2001, 39(2):183-185.
Adams VI, Unni KK: Diffuse malignant mesothelioma of pleura: diagnostic criteria based on an autopsy study. American journal of clinical pathology 1984, 82(1):15-23.
Corson JM: Pathology of diffuse malignant pleural mesothelioma. Seminars in thoracic and cardiovascular surgery 1997, 9(4):347-355.
Carbone M, Pass HI: Re: Debate on the link between SV40 and human cancer continues. Journal of the National Cancer Institute 2002, 94(3):229-230.
Balsara BR, Bell DW, Sonoda G, De Rienzo A, du Manoir S, Jhanwar SC, Testa JR: Comparative genomic hybridization and loss of heterozygosity analyses identify a common region of deletion at 15q11.1-15 in human malignant mesothelioma. Cancer research 1999, 59(2):450-454.
Bjorkqvist AM, Tammilehto L, Anttila S, Mattson K, Knuutila S: Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. British journal of cancer 1997, 75(4):523-527.
Lee AY, Raz DJ, He B, Jablons DM: Update on the molecular biology of malignant mesothelioma. Cancer 2007, 109(8):1454-1461.
Spugnini EP, Bosari S, Citro G, Lorenzon I, Cognetti F, Baldi A: Human malignant mesothelioma: molecular mechanisms of pathogenesis and progression. The international journal of biochemistry & cell biology 2006, 38(12):2000-2004.
Whitson BA, Kratzke RA: Molecular pathways in malignant pleural mesothelioma. Cancer letters 2006, 239(2):183-189.
Kops GJ, Weaver BA, Cleveland DW: On the road to cancer: aneuploidy and the mitotic checkpoint. Nature reviews 2005, 5(10):773-785.
Pylkkanen L, Sainio M, Ollikainen T, Mattson K, Nordling S, Carpen O, Linnainmaa K, Husgafvel-Pursiainen K: Concurrent LOH at multiple loci in human malignant mesothelioma with preferential loss of NF2 gene region. Oncology reports 2002, 9(5):955-959.
Apostolou S, De Rienzo A, Murthy SS, Jhanwar SC, Testa JR: Absence of BCL10 mutations in human malignant mesothelioma. Cell 1999, 97(6):684-686. discussion 686-688
De Rienzo A, Jhanwar SC, Testa JR: Loss of heterozygosity analysis of 13q and 14q in human malignant mesothelioma. Genes, chromosomes & cancer 2000, 28(3):337-341.
Lecomte C, Andujar P, Renier A, Kheuang L, Abramowski V, Mellottee L, Fleury-Feith J, Zucman-Rossi J, Giovannini M, Jaurand MC: Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma. Cell cycle (Georgetown, Tex) 2005, 4(12):1862-1869.
Murthy SS, Testa JR: Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma. Journal of cellular physiology 1999, 180(2):150-157.
Toyooka S, Carbone M, Toyooka KO, Bocchetta M, Shivapurkar N, Minna JD, Gazdar AF: Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells. Oncogene 2002, 21(27):4340-4344.
Wong L, Zhou J, Anderson D, Kratzke RA: Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung cancer (Amsterdam, Netherlands) 2002, 38(2):131-136.
Kumar K, Rahman Q, Schipper H, Matschegewski C, Schiffmann D, Papp T: Mutational analysis of 9 different tumour-associated genes in human malignant mesothelioma cell lines. Oncology reports 2005, 14(3):743-750.
Kitamura F, Araki S, Suzuki Y, Yokoyama K, Tanigawa T, Iwasaki R: Assessment of the mutations of p53 suppressor gene and Ha- and Ki-ras oncogenes in malignant mesothelioma in relation to asbestos exposure: a study of 12 American patients. Industrial health 2002, 40(2):175-181.
Ni Z, Liu Y, Keshava N, Zhou G, Whong W, Ong T: Analysis of K-ras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos. Mutation research 2000, 468(1):87-92.
Papp T, Schipper H, Pemsel H, Bastrop R, Muller KM, Wiethege T, Weiss DG, Dopp E, Schiffmann D, Rahman Q: Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas. International journal of oncology 2001, 18(2):425-433.
Vaslet CA, Messier NJ, Kane AB: Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53+/- mice. Toxicol Sci 2002, 68(2):331-338.
Illei PB, Rusch VW, Zakowski MF, Ladanyi M: Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res 2003, 9(6):2108-2113.
Lopez-Rios F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, Illei PB, Hussain S, Krug L, Zakowski MF, et al.: Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer research 2006, 66(6):2970-2979.
Barbanti-Brodano G, Sabbioni S, Martini F, Negrini M, Corallini A, Tognon M: Simian virus 40 infection in humans and association with human diseases: results and hypotheses. Virology 2004, 318(1):1-9.
Carbone M: Simian virus 40 and human tumors: It is time to study mechanisms. Journal of cellular biochemistry 1999, 76(2):189-193.
Kops SP: Oral polio vaccine and human cancer: a reassessment of SV40 as a contaminant based upon legal documents. Anticancer research 2000, 20(6C):4745-4749.
Pipas JM, Levine AJ: Role of T antigen interactions with p53 in tumorigenesis. Seminars in cancer biology 2001, 11(1):23-30.
Testa JR, Giordano A: SV40 and cell cycle perturbations in malignant mesothelioma. Seminars in cancer biology 2001, 11(1):31-38.
Vivo C, Lecomte C, Levy F, Leroy K, Kirova Y, Renier A, Kheuang L, Piedbois P, Chopin D, Jaurand MC: Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation. British journal of cancer 2003, 88(3):388-395.
Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR: Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 2006, 25(44):5960-5968.
Shaulian E, Karin M: AP-1 as a regulator of cell life and death. Nature cell biology 2002, 4(5):E131-136.
Whitmarsh AJ, Davis RJ: Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. Journal of molecular medicine (Berlin, Germany) 1996, 74(10):589-607.
Ramos-Nino ME, Timblin CR, Mossman BT: Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. Cancer research 2002, 62(21):6065-6069.
Zanella CL, Posada J, Tritton TR, Mossman BT: Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. Cancer research 1996, 56(23):5334-5338.
Jimenez LA, Zanella C, Fung H, Janssen YM, Vacek P, Charland C, Goldberg J, Mossman BT: Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2. The American journal of physiology 1997, 273(5 Pt 1):L1029-1035.
Jagadeeswaran R, Ma PC, Seiwert TY, Jagadeeswaran S, Zumba O, Nallasura V, Ahmed S, Filiberti R, Paganuzzi M, Puntoni R, et al.: Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer research 2006, 66(1):352-361.
Polakis P: Wnt signaling and cancer. Genes & development 2000, 14(15):1837-1851.
Abutaily AS, Collins JE, Roche WR: Cadherins, catenins and APC in pleural malignant mesothelioma. The Journal of pathology 2003, 201(3):355-362.
Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin BM, McCormick F, Jablons DM: Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of beta-catenin. Cancer research 2003, 63(15):4547-4551.
Batra S, Shi Y, Kuchenbecker KM, He B, Reguart N, Mikami I, You L, Xu Z, Lin YC, Clement G, et al.: Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethylation in malignant pleural mesothelioma. Biochemical and biophysical research communications 2006, 342(4):1228-1232.
Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N, Mikami I, Batra S, Jablons DM: Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma. Biochemical and biophysical research communications 2004, 323(4):1246-1250.
He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, Mazieres J, Mikami I, McCormick F, Jablons DM: Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer research 2005, 65(3):743-748.
Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM: Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene 2004, 23(39):6672-6676.
Liu Z, Klominek J: Chemotaxis and chemokinesis of malignant mesothelioma cells to multiple growth factors. Anticancer research 2004, 24(3a):1625-1630.
Edwards JG, McLaren J, Jones JL, Waller DA, O′Byrne KJ: Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura. British journal of cancer 2003, 88(10):1553-1559.
Hirano H, Tsuji M, Kizaki T, Sashikata T, Yoshi Y, Okada Y, Mori H: Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinase, collagens, and Ki67 antigen in pleural malignant mesothelioma: an immunohistochemical and electron microscopic study. Med Electron Microsc 2002, 35(1):16-23.
Liu Z, Ivanoff A, Klominek J: Expression and activity of matrix metalloproteases in human malignant mesothelioma cell lines. International journal of cancer 2001, 91(5):638-643.
Liu Z, Klominek J: Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors. Thorax 2003, 58(3):198-203.
Zhong J, Gencay MM, Bubendorf L, Burgess JK, Parson H, Robinson BW, Tamm M, Black JL, Roth M: ERK1/2 and p38 MAP kinase control MMP-2, MT1-MMP, and TIMP action and affect cell migration: a comparison between mesothelioma and mesothelial cells. Journal of cellular physiology 2006, 207(2):540-552.
Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM: Cyclooxygenases in cancer: progress and perspective. Cancer letters 2004, 215(1):1-20.
Lee TC, Zhang Y, Aston C, Hintz R, Jagirdar J, Perle MA, Burt M, Rom WN: Normal human mesothelial cells and mesothelioma cell lines express insulin-like growth factor I and associated molecules. Cancer research 1993, 53(12):2858-2864.
Harvey P, Warn A, Dobbin S, Arakaki N, Daikuhara Y, Jaurand MC, Warn RM: Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology. British journal of cancer 1998, 77(7):1052-1059.
Asplund T, Versnel MA, Laurent TC, Heldin P: Human mesothelioma cells produce factors that stimulate the production of hyaluronan by mesothelial cells and fibroblasts. Cancer research 1993, 53(2):388-392.
Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, et al.: TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proceedings of the National Academy of Sciences of the United States of America 2006, 103(27):10397-10402.
Destro A, Ceresoli GL, Falleni M, Zucali PA, Morenghi E, Bianchi P, Pellegrini C, Cordani N, Vaira V, Alloisio M, et al.: EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico-pathological correlations. Lung cancer (Amsterdam, Netherlands) 2006, 51(2):207-215.
Cacciotti P, Libener R, Betta P, Martini F, Porta C, Procopio A, Strizzi L, Penengo L, Tognon M, Mutti L, et al.: SV40 replication in human mesothelial cells induces HGF/Met receptor activation: a model for viral-related carcinogenesis of human malignant mesothelioma. Proceedings of the National Academy of Sciences of the United States of America 2001, 98(21):12032-12037.
Cacciotti P, Strizzi L, Vianale G, Iaccheri L, Libener R, Porta C, Tognon M, Gaudino G, Mutti L: The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor. Am J Respir Cell Mol Biol 2002, 26(2):189-193.
Demirag F, Unsal E, Yilmaz A, Caglar A: Prognostic significance of vascular endothelial growth factor, tumor necrosis, and mitotic activity index in malignant pleural mesothelioma. Chest 2005, 128(5):3382-3387.
Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS: Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. International journal of cancer 2003, 104(5):603-610.
Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, Puntoni R, Mutti L, Procopio A: Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. The Journal of pathology 2001, 193(4):468-475.
Versnel MA, Hagemeijer A, Bouts MJ, Kwast TH, Hoogsteden HC: Expression of c-sis (PDGF B-chain) and PDGF A-chain genes in ten human malignant mesothelioma cell lines derived from primary and metastatic tumors. Oncogene 1988, 2(6):601-605.
Adamson IY, Bakowska J: KGF and HGF are growth factors for mesothelial cells in pleural lavage fluid after intratracheal asbestos. Experimental lung research 2001, 27(7):605-616.
Kindler HL: Moving beyond chemotherapy: novel cytostatic agents for malignant mesothelioma. Lung cancer (Amsterdam, Netherlands) 2004, 45(Suppl 1):S125-127.
Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, et al.: Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Laboratory investigation; a journal of technical methods and pathology 1999, 79(4):427-438.
Bocchetta M, Di Resta I, Powers A, Fresco R, Tosolini A, Testa JR, Pass HI, Rizzo P, Carbone M: Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97(18):10214-10219.
Riedl SJ, Shi Y: Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 2004, 5(11):897-907.
Dhaene K, Wauters J, Weyn B, Timmermans JP, van Marck E: Expression profile of telomerase subunits in human pleural mesothelioma. The Journal of pathology 2000, 190(1):80-85.
Foddis R, De Rienzo A, Broccoli D, Bocchetta M, Stekala E, Rizzo P, Tosolini A, Grobelny JV, Jhanwar SC, Pass HI, et al.: SV40 infection induces telomerase activity in human mesothelial cells. Oncogene 2002, 21(9):1434-1442.
Sebastien P, Janson X, Gaudichet A, Hirsch A, Bignon J: Asbestos retention in human respiratory tissues: comparative measurements in lung parenchyma and in parietal pleura. IARC scientific publications 1980, (30):237-246.
Ault JG, Cole RW, Jensen CG, Jensen LC, Bachert LA, Rieder CL: Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer research 1995, 55(4):792-798.
Kamp DW, Israbian VA, Preusen SE, Zhang CX, Weitzman SA: Asbestos causes DNA strand breaks in cultured pulmonary epithelial cells: role of iron-catalyzed free radicals. The American journal of physiology 1995, 268(3 Pt 1):L471-480.
Gulumian M, van Wyk JA: Hydroxyl radical production in the presence of fibres by a Fenton-type reaction. Chemico-biological interactions 1987, 62(1):89-97.
Hansen K, Mossman BT: Generation of superoxide (O2-.) from alveolar macrophages exposed to asbestiform and nonfibrous particles. Cancer research 1987, 47(6):1681-1686.
Choe N, Tanaka S, Kagan E: Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells. Am J Respir Cell Mol Biol 1998, 19(2):226-236.
Rosenthal GJ, Simeonova P, Corsini E: Asbestos toxicity: an immunologic perspective. Reviews on environmental health 1999, 14(1):11-20.
Aung W, Hasegawa S, Furukawa T, Saga T: Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis. Carcinogenesis 2007.
Landi S, Gemignani F, Neri M, Barale R, Bonassi S, Bottari F, Canessa PA, Canzian F, Ceppi M, Filiberti R, et al.: Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma. International journal of cancer 2007, 120(12):2739-2743.
Neri M, Filiberti R, Taioli E, Garte S, Paracchini V, Bolognesi C, Canessa PA, Fontana V, Ivaldi GP, Verna A, et al.: Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure. Mutation research 2005, 592(1-2):36-44.
Mancuso TF: Relative risk of mesothelioma among railroad machinists exposed to chrysotile. American journal of industrial medicine 1988, 13(6):639-657.
Bertino P, Marconi A, Palumbo L, Bruni BM, Barbone D, Germano S, Dogan AU, Tassi GF, Porta C, Mutti L, et al.: Erionite and asbestos differently cause transformation of human mesothelial cells. International journal of cancer 2007, 121(1):12-20.
Comba P, Gianfagna A, Paoletti L: Pleural mesothelioma cases in Biancavilla are related to a new fluoro-edenite fibrous amphibole. Archives of environmental health 2003, 58(4):229-232.
Nicholson WJ: The carcinogenicity of chrysotile asbestos - a review. Industrial health 2001, 39(2):57-64.
McDonald JC, Armstrong BG, Edwards CW, Gibbs AR, Lloyd HM, Pooley FD, Ross DJ, Rudd RM: Case-referent survey of young adults with mesothelioma: I. Lung fibre analyses. The Annals of occupational hygiene 2001, 45(7):513-518.
Stanton MF, Wrench C: Mechanisms of mesothelioma induction with asbestos and fibrous glass. Journal of the National Cancer Institute 1972, 48(3):797-821.
Yarborough CM: The risk of mesothelioma from exposure to chrysotile asbestos. Current opinion in pulmonary medicine 2007, 13(4):334-338.
Yarborough CM: Chrysotile as a cause of mesothelioma: an assessment based on epidemiology. Critical reviews in toxicology 2006, 36(2):165-187.
Jaurand MC: Observations on the carcinogenicity of asbestos fibers. Annals of the New York Academy of Sciences 1991, 643:258-270.
Huuskonen MS, Karjalainen A, Tossavainen A, Rantanen J: Asbestos and cancer in Finland. La Medicina del lavoro 1995, 86(5):426-434.
Marchevsky AM, Harber P, Crawford L, Wick MR: Mesothelioma in patients with nonoccupational asbestos exposure. An evidence-based approach to causation assessment. Annals of diagnostic pathology 2006, 10(4):241-250.
Neuberger M, Kundi M: Individual asbestos exposure: smoking and mortality - a cohort study in the asbestos cement industry. British journal of industrial medicine 1990, 47(9):615-620.
Inoue YZ, Frassica FJ, Sim FH, Unni KK, Petersen IA, McLeod RA: Clinicopathologic features and treatment of postirradiation sarcoma of bone and soft tissue. Journal of surgical oncology 2000, 75(1):42-50.
Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, et al.: Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. The Journal of thoracic and cardiovascular surgery 1999, 117(1):54-63. discussion 63-55
Hill JK, Heitmiller RF 2nd, Askin FB, Kuhlman JE: Localized benign pleural mesothelioma arising in a radiation field. Clinical imaging 1997, 21(3):189-194.
Neragi-Miandoab S, Gangadharan SP, Sugarbaker DJ: Cardiac sarcoma 14 years after treatment for pleural mesothelioma. The New England journal of medicine 2005, 352(18):1929-1930.
Kawashima A, Libshitz HI, Lukeman JM: Radiation-induced malignant pleural mesothelioma. Canadian Association of Radiologists journal = Journal l′Association canadienne des radiologistes 1990, 41(6):384-386.
Shannon VR, Nesbitt JC, Libshitz HI: Malignant pleural mesothelioma after radiation therapy for breast cancer. A report of two additional patients. Cancer 1995, 76(3):437-441.
Lerman Y, Learman Y, Schachter P, Herceg E, Lieberman Y, Yellin A: Radiation associated malignant pleural mesothelioma. Thorax 1991, 46(6):463-464.
Babcock TL, Powell DH, Bothwell RS: Radiation-induced peritoneal mesothelioma. Journal of surgical oncology 1976, 8(5):369-372.
Huncharek M: Non-asbestos related diffuse malignant mesothelioma. Tumori 2002, 88(1):1-9.
Anderson KA, Hurley WC, Hurley BT, Ohrt DW: Malignant pleural mesothelioma following radiotherapy in a 16-year-old boy. Cancer 1985, 56(2):273-276.
Austin MB, Fechner RE, Roggli VL: Pleural malignant mesothelioma following Wilms′ tumor. American journal of clinical pathology 1986, 86(2):227-230.
Gilks B, Hegedus C, Freeman H, Fratkin L, Churg A: Malignant peritoneal mesothelioma after remote abdominal radiation. Cancer 1988, 61(10):2019-2021.
Weissmann LB, Corson JM, Neugut AI, Antman KH: Malignant mesothelioma following treatment for Hodgkin′s disease. J Clin Oncol 1996, 14(7):2098-2100.
Cavazza A, Travis LB, Travis WD, Wolfe JT 3rd, Foo ML, Gillespie DJ, Weidner N, Colby TV: Post-irradiation malignant mesothelioma. Cancer 1996, 77(7):1379-1385.
Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer 1998, 82(1):8-34.
Miracco C, Materno M, De Santi MM, Pirtoli L, Ninfo V: Unusual second malignancies following radiation therapy: subcutaneous pleomorphic rhabdomyosarcoma and cutaneous melanoma. Two case reports. Journal of cutaneous pathology 2000, 27(8):419-422.
Hussussian CJ, Mackinnon SE: Postradiation neural sheath sarcoma of the brachial plexus: a case report. Annals of plastic surgery 1999, 43(3):313-317.
Hofmann J, Mintzer D, Warhol MJ: Malignant mesothelioma following radiation therapy. The American journal of medicine 1994, 97(4):379-382.
Mesurolle B, Qanadli SD, Merad M, Mignon F, Baldeyrou P, Tardivon A, Lacombe P, Vanel D: Unusual radiologic findings in the thorax after radiation therapy. Radiographics 2000, 20(1):67-81.
Testa JRPH, Carbone M: Molecular biology of mesothelioma. Philadelphia: Lippincott; 2001.
Carbone M, Kratzke RA, Testa JR: The pathogenesis of mesothelioma. Seminars in oncology 2002, 29(1):2-17.
Bocchetta M, Miele L, Pass HI, Carbone M: Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells. Oncogene 2003, 22(1):81-89.
Cacciotti P, Barbone D, Porta C, Altomare DA, Testa JR, Mutti L, Gaudino G: SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure. Cancer research 2005, 65(12):5256-5262.
Cristaudo A, Foddis R, Vivaldi A, Buselli R, Gattini V, Guglielmi G, Cosentino F, Ottenga F, Ciancia E, Libener R, et al.: SV40 enhances the risk of malignant mesothelioma among people exposed to asbestos: a molecular epidemiologic case-control study. Cancer research 2005, 65(8):3049-3052.
Robinson C, van Bruggen I, Segal A, Dunham M, Sherwood A, Koentgen F, Robinson BW, Lake RA: A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent. Cancer research 2006, 66(22):10786-10794.
Pietruska JR, Kane AB: SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells. Cancer research 2007, 67(8):3637-3645.
Pepper C, Jasani B, Navabi H, Wynford-Thomas D, Gibbs AR: Simian virus 40 large T antigen (SV40LTAg) primer specific DNA amplification in human pleural mesothelioma tissue. Thorax 1996, 51(11):1074-1076.
Butel JS, Jafar S, Stewart AR, Lednicky JA: Detection of authentic SV40 DNA sequences in human brain and bone tumours. Developments in biological standardization 1998, 94:23-32.
Klein G, Powers A, Croce C: Association of SV40 with human tumors. Oncogene 2002, 21(8):1141-1149.
Pass HI, Donington JS, Wu P, Rizzo P, Nishimura M, Kennedy R, Carbone M: Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences. The Journal of thoracic and cardiovascular surgery 1998, 116(5):854-859.
Testa JR, Carbone M, Hirvonen A, Khalili K, Krynska B, Linnainmaa K, Pooley FD, Rizzo P, Rusch V, Xiao GH: A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas. Cancer research 1998, 58(20):4505-4509.
Vilchez RA, Kozinetz CA, Arrington AS, Madden CR, Butel JS: Simian virus 40 in human cancers. The American journal of medicine 2003, 114(8):675-684.
Carbone M, Pass HI, Rizzo P, Marinetti M, Di Muzio M, Mew DJ, Levine AS, Procopio A: Simian virus 40-like DNA sequences in human pleural mesothelioma. Oncogene 1994, 9(6):1781-1790.
Griffiths DJ, Nicholson AG, Weiss RA: Detection of SV40 sequences in human mesothelioma. Developments in biological standardization 1998, 94:127-136.
Engels EA, Katki HA, Nielsen NM, Winther JF, Hjalgrim H, Gjerris F, Rosenberg PS, Frisch M: Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. Journal of the National Cancer Institute 2003, 95(7):532-539.
Manfredi JJ, Dong J, Liu WJ, Resnick-Silverman L, Qiao R, Chahinian P, Saric M, Gibbs AR, Phillips JI, Murray J, et al.: Evidence against a role for SV40 in human mesothelioma. Cancer research 2005, 65(7):2602-2609.
Mayall F, Barratt K, Shanks J: The detection of Simian virus 40 in mesotheliomas from New Zealand and England using real time FRET probe PCR protocols. Journal of clinical pathology 2003, 56(10):728-730.
Coffin CM, Dehner LP: Mesothelial and related neoplasms in children and adolescents: a clinicopathologic and immunohistochemical analysis of eight cases. Pediatr Pathol 1992, 12(3):333-347.
Vanneuville G, Escande G, Dechelotte P, Demeocq F, Nebout P, Scheye T, Goddon R, Campagne D: Malignant pleural tumor in a child mimicking a mesothelioma. Eur J Pediatr Surg 1993, 3(6):362-365.
Fraire AE, Cooper S, Greenberg SD, Buffler P, Langston C: Mesothelioma of childhood. Cancer 1988, 62(4):838-847.
Hubbard R: The aetiology of mesothelioma: are risk factors other than asbestos exposure important? Thorax 1997, 52(6):496-497.
Niggli FK, Gray TJ, Raafat F, Stevens MC: Spectrum of peritoneal mesothelioma in childhood: clinical and histopathologic features, including DNA cytometry. Pediatric hematology and oncology 1994, 11(4):399-408.
Antman KH, Ruxer RL Jr, Aisner J, Vawter G: Mesothelioma following Wilms′ tumor in childhood. Cancer 1984, 54(2):367-369.
Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J, Van Broeckhoven C, Van Marck E: WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis. The Journal of pathology 1997, 181(1):67-74.
Langerak AW, Williamson KA, Miyagawa K, Hagemeijer A, Versnel MA, Hastie ND: Expression of the Wilms′ tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression. Genes, chromosomes & cancer 1995, 12(2):87-96.
Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D, Fletcher J, Shipman R, Rheinwald J, Demetri G, et al.: The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nature genetics 1993, 4(4):415-420.
Ascoli V, Cavone D, Merler E, Barbieri PG, Romeo L, Nardi F, Musti M: Mesothelioma in blood related subjects: report of 11 clusters among 1954 Italy cases and review of the literature. American journal of industrial medicine 2007, 50(5):357-369.
Bianchi C, Brollo A, Ramani L, Bianchi T, Giarelli L: Familial mesothelioma of the pleura - a report of 40 cases. Industrial health 2004, 42(2):235-239.
Nymark P, Lindholm PM, Korpela MV, Lahti L, Ruosaari S, Kaski S, Hollmen J, Anttila S, Kinnula VL, Knuutila S: Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC genomics 2007, 8:62.
Dianzani I, Gibello L, Biava A, Giordano M, Bertolotti M, Betti M, Ferrante D, Guarrera S, Betta GP, Mirabelli D, et al.: Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study. Mutation research 2006, 599(1-2):124-134.
Ohar JA, Ampleford EJ, Howard SE, Sterling DA: Identification of a mesothelioma phenotype. Respiratory medicine 2007, 101(3):503-509.
Bianchi C, Bianchi T: Malignant mesothelioma: global incidence and relationship with asbestos. Industrial health 2007, 45(3):379-387.
Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K, Jhanwar SC, McClatchey AI, Kane AB, Testa JR: A mouse model recapitulating molecular features of human mesothelioma. Cancer research 2005, 65(18):8090-8095.
[Figure 1], [Figure 2], [Figure 3]
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