Cancer Cell Secretion of the DAMP Protein HMGB1 Supports Progression in Malignant Mesothelioma
High Mobility Group Box 1 protein (HMGB1) is a Damage-Associated Molecular Pattern (DAMP) protein and a key mediator of inflammation. 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 in response to specific stimuli. The authors previously showed that HMGB1 is involved in the early stages of mesothelial cell transformation upon exposure to asbestos and erionite, starting a chronic inflammatory process that leads to the development of malignant mesothelioma (MM).
In this paper, the authors demonstrated that HMGB1 establishes an autocrine circuit in MM cells influencing tumor cell proliferation and survival. MM cells express and secrete HMGB1. Accordingly, HMGB1 levels in biopsies and sera of MM patients were significantly higher than in those of healthy individuals, suggesting that HMGB1 may be a novel biomarker for MM. In addition, inhibiting HMGB1 by a HMGB1 monoclonal antibody (mAb), by the recombinant HMGB1 antagonist BoxA and by a mAb against the HMGB1 main receptor RAGE impaired the survival, invasiveness and anchorage-independent growth of HMGB1-secreting MM cells in vitro. Moreover, inhibition of HMGB1 with HMGB1 antagonists reduced the growth of MM xenografts in SCID mice and extended animal survival.
The authors indicate that HMGB1-secreting MM cells become “addicted” to HMGB1 and propose that targeting HMGB1 may represent a novel and promising therapeutic approach for MM.
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