MM is particularly frequent (5-10% incidence) in cohorts of asbestos and/or erionite exposed individuals. Genetics also plays a role and in some high-risk MM families in the US and in Cappadocia, Turkey that were exposed to these minerals, over 50% of family members have died of MM. There is a long latency period between the time from initial exposure to MM diagnosis and the precise mechanism(s) of asbestos-induced cell transformation have yet to be elucidated. Previous studies suggest that chronic inflammation may be causally linked to MM and we have shown that asbestos-induced TNF-alpha signaling results in the activation of NF-kB signaling that leads to increased survival of HM, thereby increasing the pool of asbestos-damaged human mesothelial cells (HM) that are susceptible to malignant transformation. However, the potential link between mechanisms of asbestos-induced cytotoxicity and carcinogenesis are unclear. Our most recent publication shows that HM cell death caused by asbestos is a regulated form of necrosis that results in the release of a damage-associated molecular pattern, called HMGB1, into the extra-cellular space, which initiates inflammation. The data suggest that HMGB1 may be the """"""""master switch"""""""" by which the chronic inflammation necessary for asbestos-induced MM is initiated. However, the precise mechanism(s) by which HMGB1 induces the release of TNF-alpha and induces transformation of mesothelial cells is unknown. Furthermore, whether inhibition of HMGB1 can prevent the secretion of inflammatory molecules so as to prevent/delay the onset of MM, or whether this strategy has the potential to be used therapeutically has not been studied. Here, we will elucidate the mechanism(s) by which HMGB1 contributes to asbestos-induced initiation, maintenance and progression of MM. We hypothesize that upon asbestos exposure, the HMGB1-induced inflammatory response is essential to transformation of HM into MM via NF-kB signaling, that HMGB1 is necessary for maintaining the malignant cell phenotype and that inhibition of HMGB1 may be used to prevent or treat MM. To test the hypothesis, the following aims will be addressed: (1) Elucidate the mechanism by which HMGB1 contributes to asbestos-induced transformation of HM cells. (2) Determine whether inhibiting HMGB1 prevents or delays the onset of asbestos-induced MM. (3) Elucidate the role of HMGB1 in the maintenance and progression of MM and evaluate the potential for inhibition of HMGB1 as a therapeutic intervention. To accomplish these aims, we will use both in vitro and in vivo models and determine whether HMGB1 inhibitors prevent the secretion of inflammatory molecules, which HMGB1 receptor(s) play a critical role in transformation of HM cells, whether HMGB1 activates NF-kB signaling and whether specific inhibition of HMGB1 reduces asbestos-induced inflammation and either prevents MM. Finally, we will determine the effects of HMGB1 and HMGB1 inhibitors on the migration, invasion and colony formation of MM cells and assess the potential of inhibiting HMGB1 for MM therapy.

Public Health Relevance

Malignant mesothelioma (MM) is a deadly cancer caused by a variety of risk factors and of these, environmental exposure to asbestos is most highly correlated with development of MM. Due to a poor understanding of how asbestos causes malignant transformation of mesothelial cells, the aggressive and fatal nature of the disease and the very limited types of treatment options available, median survival from diagnosis is only 1 year. Our goal is to study the mechanism by which asbestos causes MM and successful completion of this project will lead the identification of new molecular targets for intervention and the development of novel strategies for the prevention and/or therapy of MM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160715-03
Application #
8468668
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2011-07-28
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$292,575
Indirect Cost
$97,525
Name
University of Hawaii
Department
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Bononi, Angela; Giorgi, Carlotta; Patergnani, Simone et al. (2017) BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546:549-553
Guo, Zhenying; Carbone, Michele; Zhang, Xing et al. (2017) Improving the Accuracy of Mesothelioma Diagnosis in China. J Thorac Oncol 12:714-723
Mao, Weimin; Zhang, Xing; Guo, Zhenying et al. (2017) Association of Asbestos Exposure With Malignant Mesothelioma Incidence in Eastern China. JAMA Oncol 3:562-564
Bononi, Angela; Yang, Haining; Giorgi, Carlotta et al. (2017) Germline BAP1 mutations induce a Warburg effect. Cell Death Differ 24:1694-1704
Szymiczek, A; Carbone, M; Pastorino, S et al. (2017) Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma. Oncogene 36:6501-6507
Pellegrini, Laura; Xue, Jiaming; Larson, David et al. (2017) HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget 8:22649-22661
Chen, Zhongjian; Gaudino, Giovanni; Pass, Harvey I et al. (2017) Diagnostic and prognostic biomarkers for malignant mesothelioma: an update. Transl Lung Cancer Res 6:259-269
Szymiczek, Agata; Pastorino, Sandra; Larson, David et al. (2017) FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model. J Transl Med 15:58
Carbone, Michele; Yang, Haining (2017) Mesothelioma: recent highlights. Ann Transl Med 5:238
Yoshikawa, Yoshie; Emi, Mitsuru; Hashimoto-Tamaoki, Tomoko et al. (2016) High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Acad Sci U S A 113:13432-13437

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