Human malignant mesothelioma (MM) arises from the neoplastic transformation of mesothelial cells lining the pleural, peritoneal and pericardial cavities. MM has been linked to occupational and environmental exposure to asbestos, causing over 100,000 deaths per year worldwide (1
). Moreover, in rapidly industrializing countries, such as India and China where the use of asbestos is unrestricted, the incidence of MM is expected to rise dramatically (2
). Erionite, a natural mineral fiber that can be dispersed in the environment by human activities also causes MM (3
). We have recently discovered extensive erionite exposure in the US (4
). It has been estimated that over 25 million people have been exposed to asbestos in the US, while the number of those exposed to erionite is still unknown (1
MM is a very aggressive cancer, usually diagnosed at late stages, when it is refractory to most therapeutic modalities, leading to poor prognosis with a patients’ median survival of 8–12 months from diagnosis. MM is considerably resistant to all current treatments, and survival may only be extended by about 11 weeks in patients treated with Cisplatin/Alimta as the standard of care (5
). However, in the 5% of patients diagnosed at an early stage (Stage Ia) survivals of 5 or more years are not uncommon (5
). Therefore, the development of new biomarkers for early detection and of novel targets for preventive and therapeutic approaches to MM are most needed. Moreover, recently we discovered a novel cancer syndrome caused by BAP1 germline mutations, characterized by the development of uveal melanoma and mesothelioma and possibly other cancers (8
). When individuals with BAP1 mutations are exposed to asbestos or erionite, mesothelioma predominates. Thus, it has become possible to identify within asbestos and erionite exposed cohorts those individuals at the highest risk of mesothelioma for early diagnosis.
We recently showed that asbestos- and erionite-exposed primary human mesothelial cells (HM) release High Mobility Group Box 1 protein (HMGB1), which plays a critical role in the carcinogenesis of these mineral fibers (4
). HMGB1 is a Damage Associated Molecular Pattern (DAMP) and a key mediator of inflammation (10
). Although HMGB1 is a nuclear protein, it is detected in the cytoplasm of cells undergoing necrosis and in some cell types that can actively secrete it, such as macrophages. Once in the extracellular space, HMGB1 binds to the Receptor for Advanced Glycation Endproducts (RAGE) (11
) and to the Toll-like Receptors (TLRs 2 and 4) (12
) starting the inflammatory process (13
). HMGB1 induces the secretion of tumor necrosis factor-alpha (TNF-α) by macrophages, and activation of nuclear factor-kappa B (NF-κB), a key regulator of oncogenesis (9
). Activation of NF-κB promotes cell proliferation and inhibits cell death, leading to enhanced survival of HM that have accumulated DNA alterations following asbestos exposure, thus facilitating their malignant transformation (18
MM biopsies often show a marked inflammatory infiltrate that contains a large number of tumor-associated macrophages. Here we show that HMGB1 is highly expressed and secreted by MM cells, establishing an autocrine circuit. Consistently, MM patients have elevated HMGB1 serum levels, suggesting that HMGB1 may be a novel MM biomarker. In addition, inhibition of HMGB1 impaired the motility, survival and anchorage-independent growth of HMGB1-secreting MM cells in vitro. Finally, a monoclonal antibody against HMGB1 reduced tumor growth in xenografted SCID mice, extending their survival.
Our data indicate that the sustained release of HMGB1 by MM cells, along with its secretion by surrounding inflammatory cells, supports the MM malignant phenotype. These findings provide the rationale for inhibiting HMGB1 as a novel molecular targeted therapy of MM.