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HMGB1 is normally present in the nucleus of the cells, where it functions as a non-histone chromatin binding protein that regulates nucleosome assembly and chromatin structure. HMGB1 can gain entry to the extracellular space by passive release from necrotic cells or by active secretion by macrophages and Malignant Mesothelioma cells (Fig 1). 6,20. Extracellular HMGB1 functions as a DAMP to initiate and perpetuate the inflammatory response.20 Active secretion of HMGB1 requires acetylation of specific lysine residues in the nuclear localization sequence. Asbestos deposition in tissues leads to a chronic inflammatory reaction that over the years may cause Malignant Mesothelioma.1,19 

Dr. Carbone’s team discovered that this inflammatory reaction is largely triggered by the release of HMGB1 in the extracellular space by mesothelial cells and macrophages that undergo programmed cell necrosis as they attempt to phagocytize asbestos fibers.6<,20 They are now studying how BAP1 germline mutations increase susceptibility to asbestos and the role of HMGB1 and of other mediators of innate immunity in this process. Moreover, Dr. Carbone’s team found that different isoforms of HMGB1 are produced in response to asbestos exposure and in patients with Malignant Mesothelioma.17

Strikingly, the acetylation status of serum HMGB1 differs between patients with Malignant Mesothelioma versus asbestos exposed individuals,17 raising the possibility that analyzing HMGB1 isoforms may enable identification of individuals with early stage Malignant Mesothelioma among cohorts of asbestos-exposed individuals and BAP1+/- families at high risk for Malignant Mesothelioma. Dr. Carbone’s team will conduct prospective clinical trials to challenge/validate our findings. A biomarker for mineral fiber exposure would allow us to identify those among mineral fiber-exposed cohorts, in which sufficient quantities of fibers have been inhaled and deposited in the lung and pleura to induce HMGB1 release into the serum. They will test their hypothesis 15 that individuals with sustained high levels of serum HMGB1 could be monitored for early signs of disease, a task that would be facilitated by a biomarker whose value changes during the early stages of Malignant Mesothelioma development, i.e. acetylated HMGB1. Dr. Carbone’s team also hypothesize that monitoring blood levels of HMGB1 in family members who carry BAP1 mutations may facilitate early detection of Malignant Mesothelioma.

 

Future Research Plans

Identify Mechanisms of Asbestos Carcinogenesis and Biomarkers for Early Detection

Together with Dr. Haining Yang, an internationally recognized expert in mesothelioma, Dr. Carbone’s team are testing the hypothesis that 1) non-acetylated, disulfide HMGB1SS released by mesothelial cells undergoing necrosis due to asbestos exposure, induces chronic inflammation leading over the course of years to the development of Malignant Mesothelioma; 2) the acetylation status of HMGB1, which directs trafficking of HMGB1, drives the growth of Malignant Mesothelioma; and III) these different HMGB1 isoforms can be used to identify asbestos exposed individuals and among them Malignant Mesothelioma at the earliest stages of disease progression.

REFERENCES

  1. Carbone M, Ly BH, Dodson RF, Pagano I, Morris PT, Dogan UA, Gazdar AF, Pass HI, Yang H. Malignant mesothelioma: Facts, myths and hypotheses. Malignant mesothelioma: Facts, myths and hypotheses. Journal of  Cellular Physiology, 227: 44-58, 2012 Jan. PMCID: PMC3143206.
  2. Henley SJ, Larson TC, Wu M, et al. Mesothelioma incidence in 50 states and the District of Columbia, United States, 2003-2008. International Journal of Occupational and Environmental Health 2013;19:1-10.
  3. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural Pneumonectomy Versus Pleurectomy Decortication in the Surgical Management of Malignant Pleural Mesothelioma. Journal of Thoracic Cardiovascular Surgery, 2008.
  4. Carbone M, Baris YI, Bertino P, Brass B, Comertpay S, Dogan AU, Gaudino G, Jube S, Kanodia S, Partridge CR, Pass HI, Rivera ZS, Steele I, Tuncer M, Way S, Yang H, Miller A. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proceedings of the National Academy of Science USA, 108:13618-23, 2011.
  5. Baumann F, Buck BJ, Metcalf RV, McLaurin BT, Merkler D, and Carbone M. The presence of asbestos in the natural environment is likely related to mesothelioma in young individuals and women from Southern Nevada. Journal of Thoracic Oncology, 10:731-7, 2015.
  6. Yang H, Rivera Z, Jube S, Nasu M, Bertino P, Goparaju C, Franzoso G, Lotze MT, Krausz T, Pass HI, Bianchi ME, and Carbone M. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proceedings of the National Academy of Science USA, 107: 12611-12616, 2010. PMCID: PMC2906549.
  7. Carbone M, Emri S, Dogan U, Steele I, Tuncer M, Pass HI, Baris YI. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nature Reviews Cancer, 7:147-154, 2007.
  8. Roushdy-Hammady I, Siegel J, Emri S, Testa JR and Carbone M. A genetic-susceptibility factor malignant mesothelioma in the Cappadocian region of Turkey. The Lancet, 357:444-445, 2001.
  9. Dogan UA, Baris YI, Dogan M, Emri S, Steele I, Elmishad AG, and Carbone M. Genetic Predisposition to Fiber Carcinogenesis Causes a mesothelioma Epidemic in Turkey. Cancer Research, 66:5063-5068, 2006.
  10. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox N, Dogan AU, Pass, HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, and Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics, 43: 1022-25, 2011.
  11. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. Bap1 and cancer. Nature Review Cancer, 13:153-159, 2013.
  12. Napolitano A, Pellegrini L, Dei A, Larson D, Tanji M, Flores EG, Kendrick B, Lapid D, Powers A, Kanodia S, Pastorino S, Pass HI, Dixit V, Yang H, and Carbone M. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene, Advance online publication, June 29, 2015.
  13. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nature Genetics, 2012;44:751-759.
  14. Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, Gaudino G, Powers A, Bryant-Greenwood  P, Krausz T, Hyjek E, Tate R, Friedberg J, Weigel T, Pass HI, Yang H.  BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.  Journal of Translational Medicine, 10:179, 2012.
  15. Baumann F, Flores E, Napolitano A, Kanodia A, Taioli E, Pass H, Yang H, and Carbone M. Mesothelioma Patients with Germline BAP1 Mutations Have Seven-Fold Improved Long-term Survival. Carcinogenesis, 36:76-81, 2015.
  16. Carbone M, Flores EG, Emi M, Johnson TA, Tsunoda T, Behner D, Hoffman H, Hesdorffer M, Nasu M, Napolitano A, Power A, Minaai M, Baumann F, Bryant-Greenwood P, Lauk O, Kirschner MB, Weder W, Opitz I, Pass HI, Gaudino G, Pastorino S, Yang H. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. PLoS Genetics, Advance online publication, Dec 18, 2015
  17. Napolitano A, Antoine DJ , Pellegrini L, Baumann F, Pagano IS , Pastorino S, Goparaju CM, Prokrym K, Canino C, Pass HI, Carbone M.  and Yang H. HMGB1 and its hyper-acetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients. Clinical Cancer Research, Advance online publication, Jan 5, 2016.
  18. Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Baumann F, Zhang YA, Gazdar A, Kanodia S, Tiirikainen M, Flores E, Gaudino G, Becich GJ, Pass HI, Yang H, and Carbone M. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. Journal of Thoracic Oncology, 10:565-76, 2015.
  19. Carbone M., et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma. Journal of Thoracic Oncology, accepted
  20. Carbone M and Yang H. Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clinical Cancer Research, 18:598-604, 2012.
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