Molecular pathways in malignant pleural mesothelioma

doi:10.1016/j.canlet.2005.08.010

Cancer Letters

Volume 239, Issue 2, 8 August 2006, Pages 183-189

https://doi.org/10.1016/j.canlet.2005.08.010 Get rights and content

Abstract

Malignant pleural mesothelioma, although uncommon, is highly lethal. There is a high correlation between associated environmental exposure factors, carcinogens, and its development. Carcinogenesis is also mediated by genetic defects that result in loss of tumor suppressors or over expression of proto-oncogenes. Factors such as the loss of CDK inhibition function, IGF stimulatory pathways, p14^ARF, p15^INK4b, p16^INK4a, p21, and p53 loss or mutation, VEGF and COX over expression are discussed. Correlations to potential therapeutic modalities are made.

Introduction

Malignant pleural mesothelioma is a disease that with a poor prognosis with a median survival time of 1 year [1]. The development of mesothelioma has been associated with asbestos exposure and potentially with SV40 tumor virus [2], [3], [4], [5]. Identification of defects in critical molecular in mesothelioma has facilitated the understanding of the development and prognosis of mesothelioma. The limiting of carcinogen exposure, particularly to asbestos, and the continuing elucidation of the molecular pathways involved in transformation should lead to better disease control and greater therapeutic options in the coming decade.

Section snippets

Loss of CDK inhibitor function

A genetic abnormality that recurs in the development of cancer is the loss of G₁ to S checkpoint control locus [6]. An important moderator of this control is the presence of hypo-phosphorylation of pRb [7]. The phosphorylation of pRb is mediated by cyclin dependent kinases 4 and 6 (CDK4/6) with the corresponding inhibition of the kinase activity regulated by the family of CDK inhibitors. Among the most common deletions in mesothelioma, and other cancers, is at the 9p21 locus, the location

IGF

Among the multiple growth factors associated with tumor proliferation and migration is insulin-like growth factor (IGF) [14]. IGF can behave in an autocrine or paracrine fashion and stimulate either tumor growth or growth of adjacent tissues, respectively. The presence of IGF can also have stimulatory effects on extracellular matrix development [15]. Interestingly, the presence of a functioning IGF receptor is necessary for SV40 induced transformation of mesothelial cells arguing for an

p21, p27, p53 and Rb

Mutations in p53 are among the most common acquired genetic lesions seen in cancers. Nonetheless p53 mutations are rarely seen in mesothelioma [10], [22], [23], [24]. However, this lack of gene mutations does not fully detail the effect of p53 on the natural history of p53. For example, p53 is inactivated by SV40 LT antigen and this possible r method of inactivating p53 may explain the absence of p53 mutations in mesothelioma [5] The SV40 LT tumor antigen binds to and inhibits both p53 and Rb

BCL-2

Apoptosis is strongly mediated by the caspsase and bcl-2 pathways [29]. In particular, bcl-2 over-expression has been identified in many tumors and is associated with resistance to apoptosis. Similar to other tumors, the presence of bcl-2 over-expression has been identified in mesothelioma tumors [30]. Somewhat unexpectedly, lack of bcl-2 expression was associated with a higher apoptotic index in mesothelioma which correlated with poor survival [31]. Whether bcl-2 expression can be a clinically

VEGF and COX-2

A common component to all malignancy is the ability to develop vascular supply to support tumor growth. Vascular Endothelial Growth Factor (VEGF) and its associated receptor family play a significant role in mediating this process. As malignancies grow, they have an increased metabolic demand and need for vascular delivery. In this setting, VEGF stimulates the growth of new blood vessels. Not surprisingly, VEGF is influential in mesothelioma as well. Interestingly, VEGF over-expression is

EGFR expression

Epidermal growth factor receptor (EGFR) has been found to be over-expressed in malignant mesothelioma. The over-expression of EGFR has been associated with increased proliferation and angiogenesis. Gefitinib, a selective inhibitor of EGFR, a receptor tyrosine kinase, has been developed and has entered clinical use. After studies demonstrated that mesothelioma treated with gefitinib had inhibited proliferation while apoptosis increased in mesothelioma cell lines, a phase II study of its

NF2, RASSF1A, and WT1

Population studies have linked the autosomally dominant disease neurofibromatosis type 2 (NF2), to the loss of the function of the gene located on the long arm of chromosome 22 [37], [38], the so called schwannomin protein or merlin (meosin ezrin radixin-like protein). In malignant mesothelioma, the loss of chromosome 22 gene products is an extremely common, recurring occurrence [39]. Analysis of mesothelioma cell lines through protein coding sequencing has revealed that 100% (8/8) of cell

Conclusions

Mesothelioma is associated with environmental exposure to asbestos and potentially with SV40 infection. There are many genetic defects that contribute to the outcome of mesothelioma. Some of the most common are associated with deletion at the 9p21 locus and consequent loss of p15^INK4b, p16^INK4a, and p14^ARF. Identification and quantification of WT1 expression can have diagnostic benefit in histologically difficult tumors. Increasingly, the IGF axis is also being found to be an important

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Cited by (34)

Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma
2016, Lung Cancer
Citation Excerpt :
Although real-time PCR is much more accessible than FISH, the quality of sampling should be carefully considered. The relationship between the tumor suppressor genes and MPM pathogenesis is discussed elsewhere [4,21,22]. The 9p21 locus includes both the p16INK4a and p14ARF genes.
Homozygous deletion (homo-d) of the p16 (CDKN2A) gene, as determined by fluorescence in situ hybridization (FISH), helps differentiate malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH). Heterozygous deletion (hetero-d) has also been identified variably in p16 FISH. This study aimed to investigate the significance of homo-d and hetero-d of p16 in the diagnosis and prognosis of MPM.
p16 FISH was performed in 93 MPMs and 47 RMHs. Real-time polymerase chain reaction (PCR) and methylation specific PCR (MSP) were also performed for cases in which DNA was available. Overall survival (OS) was assessed via the Kaplan-Meier method and logrank test.
Cutoff values for homo-d and hetero-d were set at 10% and 47%, respectively, based on p16 FISH results in RMH. In MPM, 80/93 (86.0%) were homo-d positive, and 15/93 (16.1%) were hetero-d positive. No RMH was homo/hetero-d positive. In nine cases of MPM with the low homo-d (<30%)/high hetero-d (>47%) pattern, FISH with a shorter probe caused a slight increase (from 20.1% to 26.5%) in the mean percentage of homo-d and a decrease in that of hetero-d (from 59.6% to 55.6%). Four cases in which the low homo-d/high hetero-d pattern was maintained with the shorter probe were further analyzed by real-time PCR, which separated them into a two (n = 2) or one allele deletion group (n = 2). MSP revealed no promoter methylation in the two cases with one allele deletion. The OS was significantly shorter in homo-d positive cases (n = 24) than homo-d negative cases (n = 5, p = 0.0002) in the 29 MPM cases with follow-up data. Also, low homo-d/high hetero-d cases (n = 5) had a significantly better prognosis than high homo-d (≥30%) cases (n = 17, p = 0.011).
Within p16 homo-d positive MPMs with poorer prognosis, the low homo-d/high hetero-d pattern may belong to a better prognostic subgroup in homo-d positive MPMs.
The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma
2014, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
Regarding anti-VEGF therapy, erlotinib and bevacizumab in combination with chemotherapy were also evaluated in MM [158]. Insulin growth factor (IGF) and Insulin growth factor receptors (IGFR) are expressed by MM [159], and by normal mesothelial cell lines [27]; however, dysregulation of IGF pathway may lead to malignant transformation [27]. Stimulation by IGF-I resulted in enhanced activation of IGFR leading to cell proliferation [160].
Malignant Mesothelioma (MM) is a very aggressive cancer with low survival rates and often diagnosed at an advanced stage. Several players have been implicated in the development of this cancer, such as asbestos, erionite and the simian virus 40 (SV40). Here, we have reviewed the involvement of erionite, SV40, as well as, the role of several genes (p16^INK4a, p14^ARF, NF2, LATS2, SAV, CTNNB1 and among others), the pathways (RAS, PI3K, Wnt, BCL and Hippo), and their respective roles in the development of MM.
Did we progress in mesothelioma knowledge, diagnosis and treatment?
2011, Revue des Maladies Respiratoires Actualites
Le mésothéliome pleural malin reste une tumeur rare consécutive à l’exposition professionnelle aux fibres d’amiante. Son incidence semble avoir atteint un plateau en France, plus tôt que prévu. Elle est de 100 cas/million/an dans la population exposée à l’amiante contre moins de 1 cas/million d’habitants et par an dans la population générale non exposée, soit 800 à 1 000 cas/an en France. La carcinogenèse moléculaire reste imparfaitement comprise, impliquant les gènes NF2, c-met, WT1, RASSF1 et p16, qui régulent l’invasion et la motilité cellulaire, le contrôle de la division cellulaire et l’apoptose. Le rôle de certaines molécules d’adhésion et d’invasion tumorale (c-met, CD44, FAK), s’est fait jour plus récemment. La thoracoscopie est l’examen diagnostique de base, permettant des biopsies profondes. Le diagnostic histologique reste difficile, et repose sur une analyse immunohistochimique. La thérapeutique repose sur l’irradiation précoce des trajets de ponction, et parfois, chez des patients sélectionnés, sur une chirurgie de « debulking ». La chimiothérapie par le doublet pemetrexed et sel de platine, reste le standard de traitement des formes inopérables. L’apport du bevacizumab est testé dans l’essai de phase 3 MAPS coordonné par l’Intergroupe Francophone de Cancérologie Thoracique (IFCT) qui, avec actuellement 200 inclusions/445, doit s’achever à la mi-2014.
Malignant Pleural Mesothelioma (MPM) is a rare tumor secondary to professional asbestosis exposure. MPM incidence has increased continuously since last thirty years, but has reached a plateau in France earlier than anticipated. MPM incidence reaches 100 cases/million/year in a professionally exposed population versus less than 1 case/million/year in general population, leading to 800 to 1,000 cases in France. Molecular carcinogenesis of MPM is incompletely understood, but involved NF2, c-met, WT1 RASSF1, and p16 gene alterations. These genes are involved in cell invasion and motility, cell division and apoptosis control. The role of adhesion and invasion molecules recently emerged, those molecules (c-met, CD44, FAK) being targeted by new putative therapeutic agents currently in development. Diagnosis relies on thoracoscopy and large pleural biopsies. Histological diagnosis remains an actual dilemma, relying on immunohistochemical analysis as described by the French Mesopath group. Therapeutic strategy includes precocious irradiation following drainage or thorascopy, to prevent permeation nodules developing along drainage tracts. In selected patients, debulking surgery can still be discussed. Firstline chemotherapy is based on a doublet of pemetrexed and cisplatin, that demonstrated overall survival and quality of life improvement in phase 3 trials. Bevacizumab (Avastin^®) is currently tested in association with pemetrexed-cisplatin in an on-going randomized phase 3 trial, Mesothelioma Avastin Pemetrexed Study (MAPS) sponsored by the French Intergroup (IFCT), with more than 200 patients/445 already included with an anticipated end in mid 2014.
A phase II study of sorafenib in malignant mesothelioma: Results of Cancer and Leukemia Group B 30307
2010, Journal of Thoracic Oncology
Malignant mesotheliomas (MMs) express vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and cKIT. Sorafenib is a potent inhibitor of the ras/raf/MEK pathway and also targets VEGFR and cKIT. We evaluated the activity of sorafenib in patients with unresectable mesothelioma.
MM patients who had received 0 to 1 prior chemotherapy regimens were treated with sorafenib 400 mg orally twice daily continuously. The primary end point was objective response. ERK1/2 phosphorylation in archival tissues was correlated with response and survival.
A total of 51 patients were enrolled, 50 were evaluable and included in the analysis. Three patients had a partial response (6% [95% confidence interval = 1.3–16.6%]), and 27 (54% [95% confidence interval = 39.3–68.2%]) had stable disease. Median progression-free survival and median overall survival (OS) were 3.6 and 9.7 months, respectively. Median survival was superior in epithelioid histology versus other types (10.7 versus 3.7 months, p = 0.0179). The difference in median OS between pretreated and chemonaive patients was not statistically significant (13.2 versus 5 months, p = 0.3117). Low/negative baseline tumor phospho-ERK1/2 levels were associated with improved OS (13.9 versus 5.2 months, p = 0.0066).
Sorafenib has limited activity in advanced MM patients, similar to that seen with other VEGFR tyrosine kinase inhibitors. Additional studies of sorafenib in MM are not warranted.
Inhibition of the insulin-like growth factor 1 receptor pathway enhances the antitumor effect of cisplatin in human malignant mesothelioma cell lines
2009, Cancer Letters
Citation Excerpt :
The presence of a functional IGF receptor is essential for SV40-induced transformation of mesothelial cells, suggesting an important role for the IGF-1 pathway in the development of mesothelioma [17]. The IGF-1R pathway has been found to be an important regulator of tumorigenesis and growth in HMM [4]. Tyrphostins are a family of synthetic protein tyrosine kinase inhibitors that selectively inhibit receptor autophosphorylation [18].
Human malignant mesothelioma (HMM) is a fatal tumor and is poorly responsive to current therapeutic regimens. The insulin-like growth factor 1 receptor (IGF-1R) pathway is activated in HMM cell lines and tissues. Treatment with AG1024, an inhibitor of the IGF-1R pathway, significantly decreased cell proliferation and attenuated the phosphorylation of Akt and p44/42. In addition, it significantly enhanced the cytotoxic effects of cisplatin in HMM cell lines. This study supports the conjecture that inhibition of the IGF-1R pathway may be a useful target for reducing toxicity and alleviating chemoresistance to traditional anticancer drugs in HMM patients.
A redox-silent analogue of tocotrienol acts as a potential cytotoxic agent against human mesothelioma cells
2009, Life Sciences
Malignant mesothelioma is an aggressive cancer with no effective treatment options. A redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) is a new potential anti-carcinogenic agent with less toxic effect on non-tumorigenic cells. Here, we evaluated the effect of T3E on killing of chemoresistant mesothelioma cell (H28).
The cytotoxic effect of T3E was evaluated by a WST-1 assay, and cell cycle and apoptosis analysis were done by FACS. Each signal molecule's activity was determined by protein array and immunoblot analysis.
T3E effectively inhibited H28 cell growth at practical pharmacological concentrations (10–20 μM) without any effect on non-tumorigenic mesothelial cell (Met-5A). Inhibition of H28 cell growth by T3E mediated through G2/M arrest in cell cycle and induction of apoptosis. Protein array and immunoblot analyses revealed that T3E inhibited the activation of epidermal growth factor receptor (EGFR) via the inactivation of the Src family of protein tyrosine kinases (Src). However, the blockade of the EGFR signaling was not associated with the T3E-dependent H28 cell growth control. In addition to Src inactivation, T3E inhibited signal transduction and activation of transcription Stat3. A combination of an Src inhibitor, PP2, and a Stat3 inhibitor, AG490, induced G2/M arrest and enhanced apoptosis compared with PP2 alone. These results suggest that T3E suppresses H28 cell growth via the inhibition of Src activation and Src-independent Stat3 activation.
T3E can be a new effective therapeutic agent against chemoresistant mesothelioma cells.

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Mini-reviewMolecular pathways in malignant pleural mesothelioma

Abstract

Introduction

Section snippets

Loss of CDK inhibitor function

IGF

p21, p27, p53 and Rb

BCL-2

VEGF and COX-2

EGFR expression

NF2, RASSF1A, and WT1

Conclusions

Chest

Mutat. Res.

Semin. Oncol.

Lung Cancer

Biochimie

Chest

Cell

Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells

Cancer Res.

SV40 expression in human neoplastic and non-neoplastic tissues: perspectives on diagnosis, prognosis and therapy of human malignant mesothelioma

Dev. Biol. Standard.

Cancer cell cycles

Science

Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma

J. Natl Cancer Inst.

Alterations of the p16(INK4) locus in human malignant mesothelial tumors

Carcinogenesis

Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas

Int J. Oncol.

Codeletion of p15 and p16 in primary malignant mesothelioma

Oncogene

Re-expression of p16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression

Oncogene

Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells

J. Natl Cancer Inst.

Chemotaxis and chemokinesis of malignant mesothelioma cells to multiple growth factors

Anticancer Res.

The growth-stimulatory effect of simian virus 40 T antigen requires the interaction of insulinlike growth factor 1 with its receptor

Mol. Cell. Biol.

Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors

Thorax

The effect of an antisense expression plasmid to the IGF-1 receptor on hamster mesothelioma proliferation

Dev. Biol. Stand.

Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes

Cancer Res.

Characterization of the IGF system and analysis of the possible molecular mechanisms leading to IGF-II overexpression in a mesothelioma

Horm. Metabol. Res.

Mini-review
Molecular pathways in malignant pleural mesothelioma