Biologic, Molecular and Cytogenetic Factors in Mesothelial Proliferations
Texas Children's Hospital
Baylor College of Medicine, Houston, TX
Mesotheliomas tend to be aggressive tumors that arise from the serosal surface cells lining the
pleura, peritoneum and pericardium. The majority (80%) of these tumors are associated with exposure to
asbestos fibers, either in the environment or work place. Although asbestos has been banned for use in
most developed countries and asbestos abatement programs have been in place for the past several decades,
over 2,000 cases are diagnosed in the United States each year. This is due to the long latency period
from time of exposure to development of mesothelioma (20 to 40 years). Males are at a much higher risk
for mesothelioma than females due to occupational exposure (plumbers, pipe fitters, insulation
installers, shipyard workers). Although mesothelioma incidence in the United States peaked in the
mid-1990's, it is estimated that over 70,000 mesothelioma cases will occur in US males between 2003 and
2054. It must be realized that less than 5% of those exposed to asbestos will develop mesothelioma.
Commercial asbestos fibers are subgrouped as chrysolite and amphibole. Chyrsolite is a long curly
serpentine fiber. This fiber accounts for 90% of the world's asbestos production. Amphibole is a short
rod-like fiber, and includes crocridolite, amosite and tremolite. Amphibole fibers account for the
remaining 5 to 10% of asbestos commercial production. The majority of mesotheliomas occur with amphibole
fiber exposure. In general, a much smaller fiber burden is associated with mesotheliomas induced by
amphibole (1/400th asbestos burden) compared with chrysolite. Naturally occurring air-borne
fibers of the zeolite mineral erionite and several asbestos minerals account for endemic mesotheliomas in
south central Turkey.
Although asbestos has been banned in developed countries, asbestos continues to be used at an alarming
rate in Southeast Asia and China. With expansion of industrialization, it is expected that within the
next few decades a "mesothelioma epidemic" may be seen in this region.
Tumorigenesis and Asbestos
Asbestos fibers tend to accumulate near the pleural surface and interact with the mesothelial cell
layer. It appears that asbestos fibers lead to neoplasia through the generation of reactive oxygen
species and the formation of free radicals. These fibers also induce cytokine and growth factor
production due to an inflammatory response (Table 1):
Table 1: Growth Factors and Cytokines in Mesothelial Proliferations
Type IV Collagen
This results in mesothelial cell proliferation.
It has been suggested that the generation of free radicals and cytokines secondary to asbestos fiber
accumulation causes DNA damage. Proto-oncogene activation may be induced and this leads to DNA
synthesis, cell proliferation and susceptibility to mutations.
The process of tumor formation is a prolonged event with many oncologic steps occurring over many
decades. Asbestos is thought to act as a tumor promoter and may facilitate tumorigenesis in synergy with
other carcinogens. Aneuploidy with mesothelial cells has been shown to occur due to interference with
chromosomal segregation by asbestos. Over time, structural alterations and numerical losses and gains
in chromosomes occurs with mesothelial cells exposed to asbestos.
Cytogenetics and Mesothelioma
During the past several decades, cytogenetic studies have been performed in an attempt to identify
specific nonrandom alterations that may prove to be of diagnostic value (Table 2):
Table 2: Cytogenetics and Molecular Genetics of Mesothelioma
| ||No specific chromosomal anomaly|
| ||Monosomy Chromosomes 4 and 22|
| ||Polysomy Chromosomes 5, 7 and 20|
| ||Chromosome Loss at 1p21-22 (85%), 3p21 (65%), 4q33-34, 4q25-26,4p15.1-15.3, 6q, 6q15-21, 9p21-22, 22q12(possible tumor suppressor loci)|
| ||Chromosome Losses Occurring in Combination: 1p, 3p, 6q, 9p and 22q|
|Fluorescence In Situ Hybridization|
| ||Extra Copies of 1, 3, 6, 7, 11 and 15|
| ||Loss of 1p21-22|
| ||Loss of Heterozygosity (LOH) at 1p22|
|Comparative Genomic Hybridization|
| ||Losses Detected|
| ||9p21 (34%, 22q (32%), 4q31-32 (29%), 4p21-13 (25%), 14q12-24 (23%), 1p21 (21%), 13q12-14 (19%), 3p21 (16%), 6q22 (16%), 10p13-pter (16%), 17;12-pter (16%), 8p21-pter, 15q11.1-21.1, 3p21|
| ||Gains Detected|
| ||8q22-23 (18%), 1q23/1q32 (16%), 7p14-15 (14%), 15q22-25 (14%) 3p12-13, 7q, 5p|
| ||Allelic Loss at 1p21-22 (70%)|
| ||LOH at 1p36 (45%)|
| ||Loss of 3p21 (69% at 3p21.3, F3F15S2; 62% at 3p21.2, D3S2)|
| ||Loss of 6q15-21 (45%)|
| ||LOH from 6q (61%; 6q14-21, 6q16.6-21, 6q21-23.2, 6q25)|
| ||Loss of 9p (83%, particularly 9p21-22 [p16/CDKN2A locus])|
| ||Allelic Loss at 13q (67%)|
| ||Allelic Loss at 14q (32%, LOH at 14q11.2-13.2, 14q22.3-24.3, 14q32.12)|
| ||Loss at 15q (15q11.1-15)|
|Adenocarcinoma vs. Mesothelioma|
| ||Gains in X, 1p, 10q an d18q|
| ||Amplification in 8q|
| ||N-cadherin negative|
| ||WT-1 negative|
| ||Losses in 10q and 18q|
| ||Bcl-X, Mcl-1, Bax Overexpressed|
| ||N-cadherin Expression|
| ||WT-1 Expression|
| ||Myc(myelocytomatosis virus family)|
| ||Ras(rat sarcoma virus)|
| ||Raf(ras-activated fragment)|
| ||Rassf1a(3p21.3, Ras GTPase family)|
| ||Erb-b1(erythroblastomatosis virus)|
| ||MDR(multidrug-resistance gene, p-glycoprotein gene)|
| ||GPC3(glypian 3 gene, x-linked recessive overgrowth gene)|
| ||G5TM-1(glutathione-5-transferase M1)|
| ||NAT-2(N-acetyl transferase 2)|
| ||HGF(hepatocyte growth factor/scatter factor)|
| ||NOS2(nitric oxide synthease)|
| ||PDGF-BB(platelet-derived growth factor-BB)|
| ||SV40 Large T-Antigen (Tag)|
|Tumor Suppressor Genes|
| ||P16(9p21-22, CDKN2A, 70%)|
| ||P15(9p21, CDK4, 70%)|
| ||NF2(22q12, 41-72%)|
| ||TP53(17p, not related to asbestos)|
| ||WT1(uncommon, SV40)|
| ||RB1(downstream inactivation)|
| ||MDM2(12q14.3-q15, overexpression)|
| ||FHIT(3p14.2, inactivation)|
efforts, karyotyping of mesotheliomas has not provided specific diagnostic anomalies. Monosomy
(chromosomes 4, 22) and polysomy (chromosomes 5, 7, 20) of certain chromosomes does occur more frequently
with mesotheliomas; however these can not be used as sensitive and specific markers for mesothelioma.
Chromosomal losses at specific regions or loci implicate that certain tumor suppressor genes have been
altered or lost. Chromosome loss at 1p21-2 and 3p21 are found in a high proportion of mesotheliomas.
Many of the tumors have several chromosomal losses that occur in combination.
Fluorescent in situ hybridization (FISH) and comparative genomic
hybridization (CGH) evaluation of mesotheliomas confirmed the karyotype findings (Table 2). CGH and
deletion mapping identified even more chromosomal losses and gains than either conventional cytogenetics
or FISH. These methods have defined more specific chromosomal loci that have undergone losses, gains or
loss of heterozygosity. With the information from these studies, certain differences between
adenocarcinoma of the lung and mesothelioma could be discerned (Table 2).
With the evolution of the human genome project, it has been possible to identify many different
oncogenes and tumor suppressor genes that are involved in the multistep process from mesothelial
proliferation to mesothelioma development (Table 2). The oncogenes that have been found are not
exclusive to mesothelioma, but are shared with many other malignant human tumors. Similarly, tumor
suppressor genes that are deleted, altered or inactivated in mesothelioma are those seen in other tumors
The complex cytogenetics and molecular events in mesothelioma development attest to the long latency
period and the multistep process from a benign proliferation to a malignant neoplasm. During the past
several years, evolving molecular techniques, such as tumor suppressor gene methylation, microarray gene
profiling and proteomics, have yielded insight into mesothelioma oncogenesis, diagnosis, prognosis and
SV40 and Mesothelioma
Prior to reviewing recent molecular findings with mesothelioma, it is important to discuss the role of
SV40 in mesothelioma (Table 3):
Table3: Mesothelioma and SV40 Infection
|Contamination of polio (1955-63) and adenovirus (1961-65) vaccines with SV40|
|SV40 Seroprevalence || || 2 to 20% worldwide|
| Adult kidney transplant patients || 18%|
| HIV-Infected patients || 16%|
| Non-HIV infected patients || 11%|
| Hospitalized Children || 6%|
| Czech Republic || 4%|
| Hungary || 9%|
| United Kingdom || 5%|
|SV40 Transmission |
Oral-Fecal (fecal shedding)
|SV40 Reservoir |
Tubular epithelium of kidney
|DNA tumor virus with transforming ability (2A carcinogen)|
|SV40 large tumor antigen (T-ag) |
Essential replication protein
Stimulate infected host cell to enter S phase and undergo DNA synthesis
Major transforming protein of SV40
Binds cellular tumor suppressor gene proteins (p53, pRb, p107, p130/Rb2)
Activation of EF2 to induce expression of growth-stimulatory genes
|SV40 T-ag Associated with Tumors in Animals and Humans |
|SV40 and Primary Human Mesothelial Cells |
Highly susceptible to SV40 transformation
p53/T-ag complexes high levels
Notch-1 and met (hepatocyte growth factor receptor) upregulated
RASSF1A tumor suppressor gene inhibited
1,000-fold rate of transformation compared with human fibroblasts
|SV40 Detection in Human Cancers|
| ||SV40 Detection ||Odds Ratio for|
|Mesothelioma ||49.6% ||16.8|
|Controls ||5.5% ||1.0|
| || || |
|Primary Brain Tumors ||21.3% ||3.9|
|Controls ||9.9% ||1.0|
| || || |
|NonHodgkin Lymphoma ||35.8% ||5.4|
|Controls ||4.7% ||1.0|
SV40 is a DNA tumor virus with transforming ability that contaminated
polio and adenovirus vaccines in the 1950's and 1960's. Seroprevalence of SV40 varies from 2 to 20%
worldwide. SV40 infection is highest among immune suppressed and compromised individuals. SV40 is found
in both adults and children and is thought to be transmitted via maternal-fetal and oral-fecal routes.
The SV40 large tumor antigen (T-ag) stimulates host cells to replicate by entering into the S phase of
the cell cycle, and is considered the major SV40 transforming protein. This protein binds and
inactivates several tumor suppressor genes (p53, Rb) that are responsible for regulation of the cell
SV40 T-ag is found in a high proportion of mesotheliomas (about 50%), primary brain tumors (21%),
non-Hodgkins lymphomas (36%) and osteosarcomas (Table 3). Of particular interest to mesothelioma
development, normal mesothelial cell cultures transform readily when infected with SV40. This appears to
be related to inactivation of cell regulatory genes by the SV40 T-ag protein (p53, RASSFIA tumor
suppressor genes). Other cell signaling and transduction factors are also upregulated (Notch-1, met).
Of interest is the synergy between asbestos and SV40. Asbestos exposure without SV40 leads to
mesothelioma in animal models. The combination of asbestos and SV40 results in more rapid development of
mesothelioma. With SV40 infection in the absence of asbestos exposure, mesotheliomas in animal models do
Tumor Suppressor Gene Methylation and Mesothelioma
Gene promoter methylation, along with resultant histone deacetylation, does not alter chromatin
structure, but inactives or silences the methylated gene. Inactivation of tumor suppressor genes by
aberrant methylation leads to tumor development and progression. Gene silencing by methylation has been
shown to occur in about 20% of mesotheliomas. SV40 virus is a DNA tumorigenic infectious agent that
inactivates both p53 and Rb, induces telomerase activity, and induces oncogene activation and growth
factor secretion. SV40 utilizes methylation as a means to inactive tumor suppressor genes and to bypass
the regulatory pathways of the cell. Over the past few years, several genes in regulatory and signaling
pathways have been discovered to be methylated to a high degree in SV40-infected mesotheliomas.
It is well known that the SV40-Tag protein interacts with p53 and pRb to inactivate their tumor
suppressor functions. Other genes that may be inactivated in SV40-infected mesotheliomas via methylation
are lesser-known regulators of cell signaling pathways. At least 8 genes have been identified that are
methylated in over 20% of mesotheliomas by the "silencing" mechanism (Table 4):
Table 4: Methylation of Regulatory Pathway Genes in Mesotheliomas and SV40 Infection
| ||Gene Methylation|
|All Tumors || SV40 (+) ||SV40 (-)|
|DcR1 (8q21.2) ||65% ||74% ||56%|
|DRM/Gremlin (15q13.3) ||60% ||71% ||50%|
|RRAD (16q22.1) ||56% ||71% ||50%|
|DcR2 (8p21.2) ||41% ||48% ||34%|
|Cyclin 2 (12p13.32) || 35% || 52% ||19%|
|HPP1 (2q32.3) ||35% ||52% ||19%|
|RASSF1A (3p21.3) || 32% || 48% ||16%|
|HIC-1 (17p13.3) ||22% ||23% ||22%|
|RIZ1 (1p36.21) ||16% ||16% ||16%|
|CRBP1 (3q23) ||11% ||23% || 6%|
|TMS1 (16p11.2) ||6% ||13% || 0%|
|NOREA1 (1q32.1) || 3% || 3% || 3%|
DcR1 and DcR2 are
anti-apoptotic decoy receptors that bind TRAIL (tumor necrosis factor-related apoptosis-inducing
ligand). Both these genes are silenced in some pediatric tumors. Cyclin D2 is a critical cell cycle
regulatory gene that is inactivated via methylation in prostate and lung cancer, as well as in several
other cancers. HPP1 is silenced in hyperplastic colon polyps, colorectal carcinoma and lung cancers.
HIC1 (hypermethylated in cancer-1) has a p53-binding site that activates this zinc-finger transcription
factor gene. It is frequently methylated in several human cancers. NOREA1A is a member of the RAS
family of oncogenes, and undergoes inactivation in mesothelioma. CRBP1 (cellular retinol-binding protein
1) carries the alcohol form of vitamin E, participates in the retinoid signaling pathway, and is silenced
by methylation in several cancers. RIZ1 (retinoblastoma protein-interacting zinc finger gene) is a
nuclear histone protein methyltransferase gene and is commonly methylated in liver and breast cancer.
RRAD is a GTPase gene initially identified in skeletal muscle in type II diabetes. Inactivation of RRAD
plays a role in tumor growth in breast cancer. DRM/Gremlin is silenced in many types of cancers, and is
a homolog to the rat drm gene. The silencing of these genes in SV40-infected mesotheliomas is
significantly increased, and several of these genes are methylated in over 40% of tumors (Table 5):
Table 5: Stepwise Process to Mesothelioma Development: A Several Decades Oncogenesis
|Normal Mesothelial Cell |
Loss of Chromosome 9p (p15, p16, CDKN2)
Asbestos Exposure in 80%
|Increased Cell Growth |
Loss of Chromosome 22q (NF2)
|Early Phase of Mesothelial Proliferation* |
Loss of Chromosome 11p (WT1)
|Intermediate Phase of Mesothelial Proliferation |
Loss of Chromosome 6p and 12p (FHIT) => SV40 T-ag**
|Later Phase of Mesothelial Proliferation |
Loss Chromosome 3p
Loss of Chromosome 13q and 14q
|Aggressive Mesothelioma |
Loss of Chromosomes 1q, 1p and 4q
**SV40 identified in about 50% of mesotheliomas.
Adapted from: Sandberg AA, Bridge JA, Cancer Genet Cytogenet 2001;127:93-110
Of interest is the finding that SV40-infected mesotheliomas demonstrate progressive methylation of
several genes (RASSFIA, HPP1, DcR1, TMS1, CRBP1, HIC-1, RRAD) during serial passage of mesothelial cell
lines. With mesotheliomas analyzed from 50 patients with follow-up (range 2 to 68 months, median 14.5
months), it was noted that methylation of TMS1 or HIC1 lead to a significant decrease in survival. Loss
of HIC-1 function in medulloblastoma, and lung and breast cancers also correlates with poor prognosis. A
novel caspase recruitment domain (CARD) is encoded by TMS1. With silencing of TMS-1, apoptosis
mechanisms are inactivated. TMS1 is aberrantly methylated in breast and lung cancers. The ability of
SV40 infection to silence genes is noted by mammalian cell cultures infected with SV40. SV40 infection
induces expression of methyltransferase enzymes (DNMT1, DNMT3b) that leads to global genomic DNA
methylation and tumor suppressor gene inactivation.
Gene Profiling and Mesothelioma
Gene profiling studies are still within their infancy in the investigation of mesotheliomas. There
are confusing results with many studies providing a myriad of known, little known and unknown genes that
are overexpressed and underexpressed in mesothelioma. For example, one study provides a list of 166
genes that are up-regulated and 26 genes that are down-regulated out of over 4,000 genes studied.
Typical analyses reveal genes that participate in glucose metabolism, mRNA translation, and
cytoskeletal remodeling. Perhaps more importantly, these studies are beginning to identify upregulated
genes that have potential diagnostic, therapeutic and prognostic implications for patients. Some of
these upregulated genes in mesothelioma will be discussed. Adenotin (gp96) is expressed on the cell
surface and in the cytoplasm and is closely related to hsp90. This gene is considered to be an important
factor in inducing tumor-specific immunity. Lung-related resistance protein gene is up-regulated in
mesothelioma and may be partially responsible for chemoresistance. This protein acts as a transporter
and removes cytotoxic drugs from the cell (doxorubicin, vincristine, VP-16, taxol, gramicidine-D).
Galectin-3 binding protein is a beta-galactoside binding protein that participates in cell growth,
differentiation, adhesion and malignant transformation. Increased expression in tumors has been linked
to advanced tumor stage, progression, metastases and poor outcome. Laminin receptor (67,000
Mr) plays a role in tumor development, progression and metastasis. It has been associated
with decreased survival in breast, lung and ovarian cancers. Voltage-dependent anion channel genes
(VDAC1, VDAC2) provide the primary pathway for metabolite diffusion across mitochondrial outer membranes.
VDAC participates in the apoptotic pathway through interactions with the bcl-2 family of proteins.
Mesotheliomas express high levels of bax and bcl-xl, and VDAC overexpression may be an attempt to
suppress the anti-apoptotic effects of bax and bcl-xl. Ku80 gene participates in DNA double-strand break
repair, and its overexpression has been identified in mesothelioma. The protein from this gene opposes
anticancer drug-induced apoptosis.
Genes involved in cell signaling pathways have also been reported as up-regulated. The
mitogen-activated protein kinase cascade (JNK1, NIK, TRAF2, PAK1, ERK5 genes), notch signaling pathway
(JAGGED1, JAGGED2 genes) and Wnt-frizzled signaling pathway (SARP1, FRIZZLED, Dickkopf-1, Disheveled,
beta-catenin, n-cadherin genes) are activated in many neoplastic processes. Mesothelioma upregulates
these genes and uses these pathways to sustain tumor growth. The cell cycle in mesothelial tumors is
also activated via up-regulation of cyclin genes (cyclin D1 11p13, cyclin D3 6q21, CDK phosphatase)
Certain gene profiling studies have compared expression between mesothelioma and lung cancer. Results
have been encouraging in differentiating between mesothelioma and lung cancer using such methods. Using
15 ratios between up-regulated genes expressed in mesotheliomas (5 genes, calretinin, VAC-beta, MRX OX-2,
PTGIS, KIAA0977) and adenocarcinomas of the lung (TACSTD1, claudin-7, TITF-1), it was possible to
accurately categorize the tumors as mesotheliomas or lung cancers in over 90% of cases using just a
single expression ratio. When using a two or three gene expression ratio, it was possible to accurately
classify mesotheliomas and adenocarcinomas of the lung in 95% and 99% of the cases.
Gene Expression Ratio Outcome Prediction in Mesothelioma
A gene profiling study illustrates the utility of gene expression in predicting outcome
with mesotheliomas, regardless of histologic type. A total of 46 genes were identified that were
considered to be of prognostic value. From these 46 genes, four upregulated genes that had the highest
statistically significant values were chosen for each of the good and poor outcome groups. Genes that
were overexpressed in the good outcome tumor group, compared with the poor outcome group, were
selenium-binding protein, KIAA0977 protein, EST (similar to L6 tumor antigen), and leukocyte
antigen-related protein. The upregulated genes in the poor outcome group, compared with the good outcome
group, were cytosolic thyroid hormone-binding protein, calgizzarin, insulin-like growth factor-binding
protein-3, and GDP-dissociation inhibitor 1. Five expression ratios (KIAA0977 protein/insulin-like
growth factor-binding protein-3; KIAA0977 protein/ GDP-dissociation inhibitor 1; EST (similar to L6 tumor
antigen)/ cytosolic thyroid hormone-binding protein; EST (similar to L6 tumor antigen)/ GDP-dissociation
inhibitor 1; and leukocyte antigen-related protein/ GDP-dissociation inhibitor 1) each independently
correctly placed the mesothelioma cases into the correct good and poor outcome groups. Ratio values
greater than 1 predicted good outcome, and ratio values below 1 predicted poor outcome. A test set of an
additional 29 patients with mesothelioma was used to validate the gene profiling ratio model. Almost 90%
of patients were place in the correct good and poor outcome groups based upon the gene profiling ratio
model. The median survival for those determined to be in the good outcome group by this model was 35
months vs only 7 months for those placed in the poor outcome group by this model.
Stepwise Process to Mesothelioma Development
As noted previously, the road to mesothelioma development is thought to be a long and winding road.
There are many cytogenetic and molecular events that occur along the way (Table 5). The normal
mesothelial cell undergoes loss of chromosome 9p, which contains several cell cycle regulation genes.
This leads to cell growth and proliferation. Loss of chromosome 22q, which houses NF2, the most
frequently lost tumor suppressor gene in mesotheliomas, then occurs. This results in the early phase of
mesothelial cell proliferation. Chromosome 11p with several important genes, as well as WT1, is lost,
and this leads to further proliferation. Late phase mesothelial cell proliferation is proceeded by the
loss of 6p (several tumor suppressor genes) and loss of 12p (FHIT tumor suppressor gene). Mesothelioma
with its malignant potential develops after loss of chromosome 3p. Loss of 13q (retinoblastoma gene,
several other tumor suppressors) and loss of 14q (several tumor suppressor genes) provides an aggressive
phenotype to the mesothelioma. Loss of chromosome 1q, 1p and 4q are thought to herald the ability to
metastasize to other sites. SV40 virus interacts with asbestos fibers and facilitates chromosomal
damage and gene mutations in about 50% of mesotheliomas. The process from increased cell growth to
mesothelial proliferation to mesothelioma occurs over many decades.
Recent Prognostic Markers for Mesothelioma
A newly discovered tumor marker, mesothelin, is expressed in normal mesothelial cells, and
highly expressed in mesotheliomas, pancreatic cancers, nonmucinous ovarian cancers and certain squamous
cell carcinomas. Mesothelin is a 40kDa cell surface glycoprotein that is shed into the serum and can be
detected by serologic assays using a monoclonal antibody (K1). This serum marker is found in a high
percentage of patients with epithelial and sarcomatoid mesotheliomas (60/69). Non-mesothelial pleural
disease and malignant non-pleural lung disease rarely have detectable serum mesothelin levels (1/68).
Only 2 of 92 patients with inflammatory non-pleural disease have detectable mesothelin in their serum.
In a five-year study, serum mesothelin detection is 84% sensitive and 100% specific for identification of
patients with mesotheliomas. Mesothelin levels were increased for individuals with larger tumors
(>3cm). Epithelial mesotheliomas had higher serum concentrations of mesothelin than sarcomatoid
types. There was no correlation with the mesothelin level at diagnosis and survival. With surgical
debulking, serum mesothelin concentrations decreased by about 40%. Interestingly, 7 of 40 "healthy"
individuals with prior exposure to asbestos and no evidence of tumor had elevated serum mesothelin.
Three of these seven individuals developed mesotheliomas from 15 to 69 months after the detection of
elevated serum mesothelin levels. Mesothelin may act as a longitudinal surrogate serum marker for
mesothelioma development in individuals exposed to asbestos. There are current proposals to utilize
mesothelin as a target for immunotherapy in mesothelin-expressing tumors, including mesothelioma.
Syndecan-1 is a heparin sulphate proteoglycan family member. This protein binds basic
fibroblastic growth factor, modulates neovascularization, upregulates WT1 and plays a role in epithelial
differentiation. It has been noted in immunocytochemical studies that epithelial mesotheliomas that
express syndecan-1 predict longer survival times. Gene therapy to induce syndecan-1 expression may have
a positive effect on survival.
Cyclooxygenase-2 (COX-2) is associated with development of colon polyps, colorectal
carcinoma, non-small cell lung cancer and gastric cancer. COX-2 participates in regulation of
cell-mediated immunity, promotion of angiogenesis, inhibition of apoptosis and formation of carcinogens.
Recently, immunocytochemical studies have shown that high levels of COX-2 expression are associated with
decreased survival and more aggressive mesotheliomas. Although recently maligned for a suspected role in
myocardial infarctions and strokes, COX-2 inhibitors may provide an additional means to improve survival
and prolong life for patients suffering from mesothelioma.
Epidermal growth factor receptor has been found to be present in less than 5% of reactive
mesothelial proliferations compared with almost 50% of mesotheliomas. Epidermal growth factor (EGF)
receptor is a cell membrane receptor that participates in cell signal transduction and growth. The
ligand for this receptor is TGF-alpha, which is often times overexpressed in mesothelioma. Binding of
TGF-alpha to the EGF receptor creates an autocrine loop that results in unregulated cell proliferation.
Interference with this autocrine loop may reduce cell proliferation significantly in mesotheliomas. An
EGF receptor tyrosine kinase inhibitor (ZD1839) has recently been described. In a murine model, the
effect of the combination of this EGF receptor inhibitor and radiation therapy on human mesothelioma
cells has been tested. Radiation alone reduced tumor volume by approximately 50%, with complete
regression in 4 of 22 tumors. The combination of the EGF receptor inhibitor and radiation resulted in a
98% reduction in volume, with complete regression in 15 of 22 tumors. Assessment of mesotheliomas for
EGF receptor expression may become a standard of care in the future in order to determine if the
combination of EGF receptor inhibitor administration and radiation therapy would be feasible in
individuals with mesothelioma.
Factors in Predicting Poor Prognosis with Mesothelioma
Factors that are predictive of poor outcome in mesothelioma may be divided into
host-related, tumor-related, biology-related and environmental-related factors (Table 6):
Table 6: Mesothelioma: Factors in Predicting Poor Prognosis
| ||Poor WHO Performance Status|
| ||Weight Loss|
| ||Male Gender|
| ||High Leukocyte and Platelet Counts|
| ||Low Hemoglobin (Anemia)|
| ||Chest Pain|
| ||High Serum Lactate Dehydrogenase (LDH)|
| ||Nonepithelial Cell Type (sarcomatoid, mixed)|
| ||Local Tumor Burden|
| ||Invasion of Visceral Pleura|
| ||Extension Through Diaphragm|
| ||Mediastinal Lymph Node Involvement|
| ||Tumor at Resection Margins|
| ||Proliferation and Cell Cycle Control|
| ||Proliferation Index High (DNA flow cytometry)|
| ||Mitotic Index High|
| ||Apoptotic Count High|
| ||MIB-1 High|
| ||p27kip1 Low|
| ||p21 Low|
| ||C0X2 High|
| ||P53 low|
| ||Mesothelin Serum Levels High|
| ||Basal Lamina Reduplication|
| ||Microvessel Count and Density Increased|
| ||Syndecan-1 Low|
| ||Fibroblast Growth Factor-2 High|
| ||Thrombospondin-1 High|
| ||Catalase Low|
| ||Mn SOD Low|
| ||Tumor Metabolism|
| ||High Uptake on PET Scan|
| ||SV40 Sequences Detected|
| ||Serum and Pleural Fluid Markers|
| ||Cyfra 21-1 High|
| ||Pleural Hyaluron High|
| ||Chromosome 7p Gains (increased copy numbers)|
| ||Socioeconomic Status Low|
| ||Education Level Low|
| ||Long Distance from Medical Centers|
factors indicative of poor outcome include poor WHO performance status, weight loss and male gender.
Tumor-related factors include non-epithelial mesothelioma, local tumor burden, tumor invasion and
extension through the diaphragm, lymph node involvement and positive resection margins. Biology-based
factors involve proliferation and cell cycle control, promotion of angiogenesis, low anti-oxidants, high
tumor metabolism, presence of SV40, and chromosome 7p gains. The environmental factors in poor prognosis
are related to low socioeconomic group, low education level and impaired access to specialized medical
Although mesothelioma cases may have peaked in the 1990's in developed countries, it is
expected that there will be over 70,000 cases diagnosed in the United States over the next 5 decades.
With the industrial expansion in Southeast Asia and China and the continued use of asbestos, an epidemic
of mesothelioma cases is anticipated over the next several decades. A considerable amount has been
learned about the cytogenetic and molecular genetics of mesotheliomas. However, indepth studies are
needed to further define specific factors that may provide for early diagnosis, surgical treatment,
oncologic management and gene therapy. Serologic markers for surveillance of those with asbestos
exposure and at risk for mesothelioma are needed. Targeted therapy using molecular markers and gene
therapy may provide a means to reverse mesothelial proliferations or stabilize tumor growth and allow for
surgical resection. The future holds great promise in identifying mesothelioma gene expression profiles
(genomics, gene microarrays) and proteins (proteomics) that may produce the key to dealing with this
dismal and devastating neoplasm.
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