Dr. Emanuela Felley-Bosco discusses the strength of collaborative work to tackle the understanding and handling of a rare cancer
Malignant mesothelioma is a rare but rapidly fatal, aggressive and highly resilient tumour arising in the thin layer of tissue known as mesothelium that covers many of the important internal organs like the lungs (pleural mesothelioma), peritoneal cavities (peritoneal mesothelioma), and the sacs surrounding the heart (pericardial mesothelioma) and covering the testis (tunica vaginalis mesothelioma). Malignant pleural mesothelioma is the most common type accounting for about 80% of the cases.
The incidence of pleural mesothelioma in 2011-2012 was around three in 100,000 in men in Belgium, Switzerland and Denmark, and four in 100,000 in the Netherlands, while it is between one and two in 100,000 in Austria and Sweden. The incidence in women is similar in all those countries and is much lower (approximately 0.5 per 100,000) (Fig. 1).
The rate reported for the UK is higher with a similar difference between men and women (Fig. 2).
Based on the recognised association of asbestos exposure with mesothelioma development, which originated from observation done in the 1960s, asbestos production and import has been banned in several, but not all, countries. The annual global healthcare cost associated with asbestos-related cancer has been estimated to amount to USD 2.4-3.9bn1 (~€2.0-3.2bn), which, although a hundredfold lower compared to smoking attributable illnesses,2 will not decrease soon as we shall discuss below.
Global asbestos production
Annual asbestos production and consumption had a peak in 1980 with approximately 4.8 million tonnes then decreased to approximately 1.3-1.4 million tonnes by 2016, with Russia being the biggest producer (692,000 tonnes) followed by Kazakhstan, China and Brazil (contributing around 200,000 tonnes), while the biggest consumers are India (308,000 tonnes), China (288,000 tonnes), Russia (234,000 tonnes), followed by Brazil (120,000 tonnes) and Indonesia (114,000 tonnes).
In comparison is the detail of use of asbestos in the United States, which stopped all production of asbestos in 2002. In 2017, domestic consumption of imported asbestos minerals was estimated to be 300 tonnes. The chloralkali industry, which uses asbestos to manufacture semipermeable diaphragms that prevent chlorine generated at the anode of an electrolytic cell from reacting with sodium hydroxide generated at the cathode, accounted for nearly all asbestos mineral consumption in 2017, based on bill of lading information obtained from a commercial trade database. In addition to asbestos minerals, an unknown quantity of asbestos was imported within manufactured products, including asbestos containing brake linings, knitted fabric, rubber sheets for gasket manufacture, and potentially asbestos-cement pipe.3
Therefore, taking into account still producing and consuming countries, asbestos-related diseases are not likely to decrease soon.
Even in countries that never produced asbestos, such Iceland,4 and where the importing of asbestos has been banned since 1983, pleural mesothelioma incidence is still rising, so it is difficult to predict when incidence will start to decrease.
The increase in age
An additional important factor is that the incidence of mesothelioma is higher and plateauing in a population (Fig. 3) age range (70-85+) that is rapidly increasing worldwide (http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2017_Highlights.pdf).
This observation has been used to argument the long latency period between known asbestos exposure and cancer development but may contribute to the observed continuation of increased incidence of mesothelioma.
An aspect that is worth considering is that the knowledge that has been acquired could help challenges to come with the increased production of material that may behave similarly to asbestos fibres. For example, long fibre carbon nanotubes have been recently demonstrated to behave like asbestos.5
Carbon nanotubes are being used in an increasing number of fields ranging from rechargeable batteries to high performance structural materials and confirmed production and use of carbon nanotubes was evaluated to be of 2,000 tonnes in 20116 but is rapidly increasing (http://www.eenewseurope.com/news/carbon-nanotubes-ton).
Of the worldwide mesothelioma deaths reported to the World health Organization between 1998 and 2008, 54% occurred in Europe7 highlighting the problem of under-reporting in some countries, as it is often observed with rare diseases that are difficult to diagnose. But, this also indicates that Europe was one of the continents where it has been possible to acquire knowledge that may benefit other countries/continents.
The Thoracic Oncology Center of the Zurich University Hospital
The Pulmonary and Thoracic Oncology Centre of the Hospital University of Zürich (http://www.cancercenter.usz.ch/ueber-das-zentrum/organzentren/seiten/lungen-und-thoraxonkologiezentrum.aspx) is a major referral centre for patients with malignant pleural mesothelioma in Switzerland.8 We initiated and take part to clinical trials for mesothelioma at different stages and with different approaches (NCT02899299, NCT01722149, NCT01644994, NCT02991482) and are involved in mesothelioma translational research including establishment of a serum/plasma databank9 as well as in ‘MESOscape’, an annotated molecular epidemiology database under the umbrella of the European Thoracic Oncology Platform(http://www.etop-eu.org/index.php?option=com_content&view=article&id=115542&Itemid=410), which has the directors of the Pulmonary and Thoracic Oncology Centre as founding members.
Within the Pulmonary and Thoracic Oncology Centre, the Laboratory of Thoracic Surgery and the Laboratory of Molecular Oncology have a long-term focus on translational research in thoracic malignancies. Because of the unique opportunity provided by the clinical activities in mesothelioma, we focus the research efforts of our laboratory in translational and fundamental research projects in malignant mesothelioma.
The team of the Laboratory of Molecular Oncology aims at understanding the biology of mesothelioma in order to improve secondary prevention and develop novel therapeutic approaches.
Within this programme, we identified cells with stem cells properties in malignant pleural mesothelioma. These cells are characterised by the expression of functional transporter which allows the efflux of some chemotherapeutic drugs, thereby allowing drug resistance.10
We characterised alterations in tumour suppressors such as neurofibromatosis type 2 (NF2) (Fig. 4) and BRCA-associated protein 1 (BAP1), where loss of function has been associated with mesothelioma development.11,12
Alterations of these pathways can be exploited for targeted therapy since loss of NF2 entails activation of mTOR signalling, while loss of BAP1 function results in deficiency in processes involved in DNA damage response which can be exploited as therapeutic strategy.13
Tumour predisposition syndrome
Germline (hereditary) loss of BAP1 function is associated with a tumour predisposition syndrome and we determined that the prevalence of germline mutations in sporadic malignant pleural mesothelioma patients can be estimated around 1-2%, suggesting a minor role of germline BAP1 mutation in the pathogenesis of sporadic malignant pleural mesothelioma.14
In translational research projects, which are conducted in parallel with clinical trials for the treatment of patients with mesothelioma, we developed primary mesothelioma cultures, derived from surgical malignant tissue from mesothelioma patients and established a live-cell biobank.15 We have demonstrated the advantage of having established primary culture in studies where we have used state of the art proteomics methods to achieve the quantitative proteome profiling of malignant pleural mesothelioma biomarkers, based first on the primary cultures that we have developed, and then using serum samples from the patients.9
We explore targeted mesothelioma therapy using 2D and 3D experimental in vitro models16,17 and we are exploring how growth in 3D under different stiffness conditions promotes growth of specific cell populations, which could be particularly resistant to cancer therapy.
We have also developed a unique primary culture model growing in the absence of serum and in 3% oxygen, which mimics oxygenation conditions present in vivo. Using this tool we were able to maintain de-differentiating conditions allowing us to be as close as possible to the original tumour cells. We were also able to explore the potential therapeutic value of G coupled receptor Smoothened inhibition after having determined that the stem cell Hedgehog pathway is reactivated in malignant pleural mesothelioma and is associated with the worst prognosis.18
Our collaboration with clinicians allowed us to explore in situ the response of tumour cells to cisplatin-pemetrexed chemotherapy, which is the standard of care for mesothelioma patients, and we could associate the increase of senescence markers after chemotherapy with worse prognosis.19
Understanding the early steps of mesothelioma development
Within an international project where the Swiss National Science Foundation fosters synergism between different research groups, we performed a study using animal models (mice exposed to asbestos) in order to understand early steps of mesothelioma development.20 As mentioned above, asbestos accumulates in a space delimited by a cell layer that surrounds all internal organs (the mesothelium). The lymphatic system is unable to clear the long and pointed fibres. Consequently, they remain stuck (Fig. 5) and cause persistent tissue injury to the mesothelium, which can lead to cancer.
Indeed, inflammatory signals are sent out mobilising white blood cells. Tissue repair signalling pathways are activated (increased YAP/TAZ signalling) in the inflamed mesothelium, which promote cell proliferation and thereby favour the growth of tumours. Moreover, we found an accumulation of mutations in RNA – the working copy of DNA.
We hypothesise that, amongst other things, these mutations serve to attenuate the immune response. As a result, tumour formation is no longer effectively combatted and cancer can develop. A similar mechanism is at work in humans: analysis of data from The Cancer Genome Atlas database revealed that tumours from patients with poor outcomes also produce large amounts of the enzyme that causes the mutations in the RNA. Exploiting acquired knowledge, we aim at developing sensitive methods detecting pathological changes upon long-term exposure to asbestos or other potentially carcinogenic fibres.
Through our unique mesothelioma mouse model, we could explore synergies between chemotherapy and immunotherapy and identified possible candidates. This has already led to the development of a clinical trial that has received a first approval by the Swiss Group for Clinical Cancer Research.
1. Allen, LP, Baez, J, Stern, MEC, Takahashi, K, George, F. Trends and the economic effect of asbestos bans and decline in asbestos consumption and production worldwide. Int J Environ Res Public Health 2018, 15.
2. Verghese, C, Redko, C, Fink, B. Screening for lung cancer has limited effectiveness globally and distracts from much needed efforts to reduce the critical worldwide prevalence of smoking and related morbidity and mortality. Journal of Global Oncology 2018, 1-7.
3. Asbestos use url. https://minerals.usgs.gov/minerals/pubs/commodity/asbestos/ (April 11, 2018).
4. Tomasson, K, Gudmundsson, G, Briem, H, Rafnsson, V. Malignant mesothelioma incidence by nation-wide cancer registry: A population-based study. J Occup Med Toxicol 2016, 11, 37.
5. Chernova, T, Murphy, FA, Galavotti, S, Sun, XM, Powley, IR, Grosso, S, Schinwald, A, Zacarias-Cabeza, J, Dudek, KM, Dinsdale, D, et al. Long-fiber carbon nanotubes replicate asbestos-induced mesothelioma with disruption of the tumor suppressor gene cdkn2a (ink4a/arf). Curr Biol 2017, 27, 3302-3314 e3306.
6. De Volder, MF Tawfick, SH, Baughman, RH, Hart, AJ, Carbon nanotubes: Present and future commercial applications. Science 2013, 339, 535-539.
7. Delgermaa, V, Takahashi, K, Park, EK, Le, GV, Hara, T, Sorahan, T. Global mesothelioma deaths reported to the world health organization between 1994 and 2008. Bull World Health Organ 2011, 89, 716-724, 724A-724C.
8. Opitz, I, Friess, M, Kestenholz, P, Schneiter, D, Frauenfelder, T, Nguyen-Kim, TD, Seifert, B, Hoda, MA, Klepetko, W, Stahel, RA, et al. A new prognostic score supporting treatment allocation for multimodality therapy for malignant pleural mesothelioma: A review of 12 years’ experience. J Thorac Oncol 2015, 10, 1634-1641.
9. Cerciello, F, Choi, M, Nicastri, A, Bausch-Fluck, D, Ziegler, A, Vitek, O, Felley-Bosco, E, Stahel, R, Aebersold, R, Wollscheid, B. Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring. Clin Proteomics 2013, 10, 16.
10. Frei, C, Opitz, I, Soltermann, A, Fischer, B, Moura, U, Rehrauer, H, Weder, W, Stahel, R, Felley-Bosco, E. Pleural mesothelioma side populations have a precursor phenotype. Carcinogenesis 2011, 32, 1324-1332.
11. Thurneysen, C, Opitz, I, Kurtz, S, Weder, W, Stahel, RA, Felley-Bosco, E. Functional inactivation of nf2/merlin in human mesothelioma. Lung Cancer 2009, 64, 140-147.
12. Meerang, M, Berard, K, Friess, M, Bitanihirwe, BK, Soltermann, A, Vrugt, B, Felley-Bosco, E, Bueno, R, Richards, WG, Seifert, B, et al. Low merlin expression and high survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma. Mol Oncol 2016, 10, 1255-1265.
13. Parrotta, R, Okonska, A, Ronner, M, Weder, W, Stahel, R, Penengo, L, Felley-Bosco, E. A novel brca1-associated protein-1 isoform affects response of mesothelioma cells to drugs impairing brca1-mediated DNA repair. J Thorac Oncol 2017.
14. Rusch, A, Ziltener, G, Nackaerts, K, Weder, W, Stahel, RA, Felley-Bosco, E. Prevalence of brca-1 associated protein 1 germline mutation in sporadic malignant pleural mesothelioma cases. Lung Cancer 2015, 87, 77-79.
15. Oehl, K, Kresoja-Rakic, J, Opitz, I, Vrugt, B, Weder, W, Stahel, R, Wild, P, Felley-Bosco, E. Live-cell mesothelioma biobank to explore mechanisms of tumor progression. Frontiers in oncology 2018, 8, 40.
16. Echeverry, N, Ziltener, G, Barbone, D, Weder, W, Stahel, RA, Broaddus, VC, Felley-Bosco, E. Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual pi3k/mtor inhibitors. Cell Death Dis 2015, 6, e1757.
17. Fischer, B, Frei, C, Moura, U, Stahel, R, Felley-Bosco, E. Inhibition of phosphoinositide-3 kinase pathway down regulates abcg2 function and sensitizes malignant pleural mesothelioma to chemotherapy. Lung Cancer 2012, 78, 23-29.
18. Shi, Y, Moura, U, Opitz, I, Soltermann, A, Rehrauer, H, Thies, S, Weder, W, Stahel, RA, Felley-Bosco, E. Role of hedgehog signaling in malignant pleural mesothelioma. Clin Cancer Res 2012, 18, 4646-4656.
19. Sidi, R, Pasello, G, Opitz, I, Soltermann, A, Tutic, M, Rehrauer, H, Weder, W, Stahel, RA, Felley-Bosco, E. Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: An exploratory analysis. Eur J Cancer 2011, 47, 326-332.
20. Rehrauer, H, Wu, L, Blum, W, Pecze, L, Henzi, T, Serre-Beinier, V, Aquino, C, Vrugt, B, de Perrot, M, Schwaller, B, et al. How asbestos drives the tissue towards tumors: Yap activation, macrophage and mesothelial precursor recruitment, rna editing, and somatic mutations. Oncogene 2018.