Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma

Main Article Content

Luca Ferrari
Simona Iodice
Laura Cantone
Barbara Dallari
Laura Dioni
Lorenzo Bordini
Alessandro Palleschi
Carolina Mensi
Angela Cecilia Pesatori

Keywords

Malignant Pleural Mesothelioma, Respiratory disease, Asbestos exposure, Circulating Biomarkers

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare highly aggressive tumor strongly associated with asbestos exposure and characterized by poor prognosis. Currently, diagnosis is based on invasive techniques, thus there is a need of identifying non-invasive biomarkers for early detection of the disease among asbestos-exposed subjects. In the present study, we measured the plasmatic concentrations of Mesothelin, Fibulin-3, and HMGB1 protein biomarkers, and of hsa-miR-30e-3p and hsa-miR-103a-3p Extracellular-Vesicles- embedded micro RNAs (EV-miRNAs). We tested the ability of these biomarkers to discriminate between MPM and PAE subjects alone and in combination. Methods: the study was conducted on a population of 26 patients with MPM and 54 healthy subjects with previous asbestos exposure (PAE). Mesothelin, Fibulin-3, and HMGB1 protein biomarkers were measured by the enzyme-linked immunosorbent assay (ELISA) technique; the levels of hsa-miR-30e-3p and hsa-miR-103a-3p EV-miRNAs was assessed by quantitative real-time PCR (qPCR). Results: the most discriminating single biomarker resulted to be Fibulin-3 (AUC 0.94 CI 95% 0.88-1.0; Sensitivity 88%; Specificity 87%). After investigating the different possible combinations, the best performance was obtained by the three protein biomarkers Mesothelin, Fibulin-3, and HMGB1 (AUC 0.99 CI 95% 0.97-1.0; Sensitivity 96%; Specificity 93%). Conclusions: the results obtained contribute to identifying new potential non-invasive biomarkers for the early diagnosis of MPM in high-risk asbestos-exposed subjects. Further studies are needed to validate the evidence obtained, in order to assess the reliability of the proposed biomarker panel.

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References

1. Scherpereel A, Scherpereel A, Opitz I, et al. ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma. Eur Respir J. 2020;55(6):1900953. Doi:10.1183/13993003.00953-2019
2. Fazzo L, Binazzi A, Ferrante D, et al. Burden of Mortality from Asbestos-Related Diseases in Italy. Int J Environ Res Public Health. 2021;18(19):10012. Doi:10.3390/IJERPH181910012
3. International Agency for Research on Cancer (IARC). Mesothelioma. Mesothelioma Globocan 2020. Published 2022. Accessed April 14, 2022. https://gco.iarc.fr/today/data/factsheets/cancers/18-Mesothelioma-fact-sheet.pdf
4. Binazzi A, Marzio D Di, Verardo M, et al. Asbestos Exposure and Malignant Mesothelioma in Construction Workers-Epidemiological Remarks by the Italian National Mesothelioma Registry (ReNaM). Int J Environ Res Public Heal. 2022;19:235. Doi:10.3390/ijerph19010235
5. Schumann SO, Kocher G, Minervini F. Epidemiology, diagnosis and treatment of the malignant pleural mesothelioma, a narrative review of literature. J Thorac Dis. 2021;13(4):2510-2523. Doi:10.21037/JTD-20-2761
6. Bianco A, Valente T, de Rimini ML, Sica G, Fiorelli A. Clinical diagnosis of malignant pleural mesothelioma. J Thorac Dis. 2018;10(Suppl 2):S253-S261. Doi:10.21037/JTD.2017.10.09
7. Wu YB, Xu LL, Wang XJ, et al. Diagnostic value of medical thoracoscopy in malignant pleural effusion. BMC Pulm Med. 2017;17(1):109. Doi:10.1186/S12890-017-0451-1
8. Cinausero M, Rihawi K, Cortiula F, Follador A, Fasola G, Ardizzoni A. Emerging therapies in malignant pleural mesothelioma. Crit Rev Oncol Hematol. 2019;144:102815. Doi:10.1016/J.CRITREVONC.2019.102815
9. Davis A, Ke H, Kao S, Pavlakis N. An Update on Emerging Therapeutic Options for Malignant Pleural Mesothelioma. Lung Cancer (Auckland, NZ). 2022;13:1-12. Doi:10.2147/LCTT.S288535
10. Tsao AS, Pass HI, Rimner A, Mansfield AS. New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options. J Clin Oncol. 2022;40(6):681-692. Doi:10.1200/JCO.21.01567
11. Cavallari I, Urso L, Sharova E, Pasello G, Ciminale V. Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives. Front Oncol. 2019;9(AUG):740. Doi:10.3389/FONC.2019.00740
12. Ferrari L, Carugno M, Mensi C, Pesatori AC. Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation. Front Oncol. 2020;10:445. Doi:10.3389/FONC.2020.00445
13. Poulet G, Massias J, Taly V. Liquid Biopsy: General Concepts. Acta Cytol. 2019;63(6):449-455. Doi:10.1159/000499337
14. Armato SG, Nowak AK, Francis RJ, et al. Imaging in pleural mesothelioma: A review of the 15th International Conference of the International Mesothelioma Interest Group. Lung Cancer. 2022;164:76-83. Doi:10.1016/J.LUNGCAN.2021.12.008
15. Schillebeeckx E, van Meerbeeck JP, Lamote K. Clinical utility of diagnostic biomarkers in malignant pleural mesothelioma: a systematic review and meta-analysis. Eur Respir Rev. 2021;30(162):210057. Doi:10.1183/16000617.0057-2021
16. Tomasetti M, Amati M, Neuzil J, Santarelli L. Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy. Lung Cancer. 2017;107:65-72. Doi:10.1016/J.LUNGCAN.2016.05.023
17. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213-228. Doi:10.1038/nrm.2017.125
18. Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N Engl J Med. Published online 2018. Doi:10.1056/NEJMra1704286
19. Lucchetti D, Ricciardi Tenore C, Colella F, Sgambato A. Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity. Cancers (Basel). 2020;12(1):171. Doi:10.3390/cancers12010171
20. Cavalleri T, Angelici L, Favero C, et al. Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease. PLoS One. 2017;12(5):e0176680. Doi:10.1371/JOURNAL.PONE.0176680
21. Nowak AK, Chansky K, Rice DC, et al. The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol. 2016;11(12):2089-2099. Doi:10.1016/J.JTHO.2016.08.147
22. Rice D, Chansky K, Nowak A, et al. The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol. 2016;11(12):2100-2111. Doi:10.1016/J.JTHO.2016.09.121
23. Pass H, Giroux D, Kennedy C, et al. The IASLC Mesothelioma Staging Project: Improving Staging of a Rare Disease Through International Participation. J Thorac Oncol. 2016;11(12):2082-2088. Doi:10.1016/J.JTHO.2016.09.123
24. Marinaccio A, Binazzi A, Marzio D Di, et al. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J cancer. 2012;130(9):2146-2154. Doi:10.1002/IJC.26229
25. Weber DG, Casjens S, Johnen G, et al. Combination of MiR-103a-3p and Mesothelin Improves the Biomarker Performance of Malignant Mesothelioma Diagnosis. Altomare DA, ed. PLoS One. 2014;9(12):e114483. Doi:10.1371/journal.pone.0114483
26. Tsim S, Alexander L, Kelly C, et al. Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases. J Thorac Oncol. 2021;16(10):1705-1717. Doi:10.1016/j.jtho.2021.05.018
27. Handke N, Rupp A, Trimpop N, von Pawel J, Holdenrieder S. Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients. Diagnostics. 2021;11(2):356. Doi:10.3390/diagnostics11020356
28. Scherpereel A, Scherpereel A, Opitz I, et al. ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma. Eur Respir J. 2020;55(6):1900953. Doi:10.1183/13993003.00953-2019
29. Tang Z, Qian M, Ho M. The role of mesothelin in tumor progression and targeted therapy. Anticancer Agents Med Chem. 2013;13(2):276-280. Doi:10.2174/1871520611313020014
30. Chen Z, Gaudino G, Pass HI, Carbone M, Yang H. Diagnostic and prognostic biomarkers for malignant mesothelioma: an update. Transl lung cancer Res. 2017;6(3):259-269. Doi:10.21037/TLCR.2017.05.06
31. Cristaudo A, Bonotti A, Guglielmi G, Fallahi P, Foddis R. Serum mesothelin and other biomarkers: what have we learned in the last decade? J Thorac Dis. 2018;10(Suppl 2):S353-S359. Doi:10.21037/JTD.2017.10.132
32. Pass HI, Alimi M, Carbone M, Yang H, Goparaju CM. Mesothelioma Biomarkers: A Review Highlighting Contributions from the Early Detection Research Network. Cancer Epidemiol Biomarkers Prev. 2020;29(12):2524-2540. Doi:10.1158/1055-9965.EPI-20-0083
33. Hwang CF, Chien CY, Huang SC, et al. Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity. J Pathol. 2010;222(4):367-379. Doi:10.1002/PATH.2776
34. Pass HI, Levin SM, Harbut MR, et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med. 2012;367(15):1417-1427. Doi:10.1056/NEJMOA1115050
35. Creaney J, Dick IM, Robinson BW. Comparison of mesothelin and fibulin-3 in pleural fluid and serum as markers in malignant mesothelioma. Curr Opin Pulm Med. 2015;21(4):352-356. Doi:10.1097/MCP.0000000000000167
36. Pei D, Li Y, Liu X, et al. Diagnostic and prognostic utilities of humoral fibulin-3 in malignant pleural mesothelioma: Evidence from a meta-analysis. Oncotarget. 2017;8(8):13030-13038. Doi:10.18632/ONCOTARGET.14712
37. Kaya H, Demir M, Taylan M, et al. Fibulin-3 as a diagnostic biomarker in patients with malignant mesothelioma. Asian Pac J Cancer Prev. 2015;16(4):1403-1407. Doi:10.7314/APJCP.2015.16.4.1403
38. Hassan MH, Abuhamdah S, Abdel-Bary M, et al. Circulating and local nuclear expression of survivin and fibulin-3 genes in discriminating benign from malignant respiratory diseases: correlation analysis. Biosci Rep. 2021;41(1): BSR20203097. Doi:10.1042/BSR20203097
39. Jiang Z, Ying S, Shen W, et al. Plasma Fibulin-3 as a Potential Biomarker for Patients with Asbestos-Related Diseases in the Han Population. Dis Markers. 2017;2017:1725354 Doi:10.1155/2017/1725354
40. Creaney J, Dick IM, Meniawy TM, et al. Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. Thorax. 2014;69(10):895-902. Doi:10.1136/thoraxjnl-2014-205205
41. Kirschner MB, Pulford E, Hoda MA, et al. Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis. Br J Cancer. 2015;113(6):963-969. Doi:10.1038/BJC.2015.286
42. Napolitano A, Antoine DJ, Pellegrini L, et al. HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. Clin Cancer Res. 2016;22(12):3087-3096. Doi:10.1158/1078-0432.CCR-15-1130
43. Yang H, Rivera Z, Jube S, et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci U S A. 2010;107(28):12611-16. Doi:10.1073/PNAS.1006542107/-/DCSUPPLEMENTAL/PNAS.201006542SI.PDF
44. Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol. 2020;13(1):1-4. Doi:10.1186/S13045-020-00950-X/FIGURES/1
45. Jube S, Rivera ZS, Bianchi ME, et al. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 2012;72(13):3290-3301. Doi:10.1158/0008-5472.CAN-11-3481
46. Mezzapelle R, De Marchis F, Passera C, et al. CXCR4 engagement triggers CD47 internalization and antitumor immunization in a mouse model of mesothelioma. EMBO Mol Med. 2021;13(6):e12344. Doi:10.15252/EMMM.202012344
47. Ying S, Jiang Z, He X, et al. Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases. Dis Markers. 2017;2017:5756102. Doi:10.1155/2017/5756102
48. Tabata C, Shibata E, Tabata R, et al. Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma. BMC Cancer. 2013;13(1):1-6. Doi:10.1186/1471-2407-13-205/FIGURES/3
49. Napolitano A, Antoine DJ, Pellegrini L, et al. Expression of Concern: HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. Clin Cancer Res. 2020;26(6):1529. Doi:10.1158/1078-0432.CCR-20-0338
50. Han YQ, Xu SC, Zheng WQ, Hu Z De. Diagnostic value of microRNAs for malignant pleural mesothelioma: A mini-review. Thorac cancer. 2021;12(1):8-12. Doi:10.1111/1759-7714.13746
51. Martínez-Rivera V, Negrete-García MC, Ávila-Moreno F, Ortiz-Quintero B. Secreted and tissue miRNAs as diagnosis biomarkers of malignant pleural mesothelioma. Int J Mol Sci. 2018;19(2):595. Doi:10.3390/ijms19020595
52. Filipów S, Łaczmański Ł. Blood Circulating miRNAs as Cancer Biomarkers for Diagnosis and Surgical Treatment Response. Front Genet. 2019;10(FEB):169. Doi:10.3389/FGENE.2019.00169
53. Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021;21(1):22-36. Doi:10.1038/S41568-020-00306-0
54. Jiménez-Ramírez C, Casjens S, Juárez-Pérez CA, et al. Mesothelin, Calretinin, and Megakaryocyte Potentiating Factor as Biomarkers of Malignant Pleural Mesothelioma. Lung. 2019;197(5):641-649. Doi:10.1007/S00408-019-00244-1