Cancer Cell Secretion of the DAMP Protein HMGB1 Supports Progression in Malignant Mesothelioma

Abstract

Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor due to late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern (DAMP) protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in MM cells that influences their proliferation and survival. MM cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in MM patient sera were higher than that found in healthy individuals. The motility, survival and anchorage-independent growth of HMGB1-secreting MM cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products (RAGE), a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of MM xenografts in SCID mice and extended host survival. Taken together, our findings indicate that MM cells rely on HMGB1 and they offer a preclinical proof of principle that antibody-mediated ablation of HMBG1 is sufficient to elicit therapeutic activity, suggesting a novel therapeutic approach for MM treatment.

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

“…HMGB1 contributes to the development of malignant mesotheliomain response to the exposure of mesothelial cells to asbestos. 31,32 Conversely viable mesothelioma cells actively secrete HMGB1: interference with HMGB1 or with the RAGE receptors limits the growth of human xenografts in immunodeficient mice, 33 supporting the contention that the molecule can play cancer-supporting actions in the extracellular environment. 34 Cell death occurring after chemotherapy with cytotoxic agents substantially increases the extent of HMGB1 released from MC-38 cells.…”

Tax is Involved in Up-regulation of HMGB1 Expression Levels by Interaction with C/EBP

“…Generally, HMGB1 is expressed at a basal level as an architectural chromatin-binding protein, but at a slightly elevated level via passive release from damaged or necrotic cells (Beyer et al, 2012;Yi et al, 2013) or active secretion (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Moreover, overexpression of HMGB1 protein is observed in breast, colon, and gastrointestinal cancers, as well as in leukemia and other diseases (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013). ATL is an acute T-cell malignancy modulated by an oncogenic retrovirus, and the virally encoded Tax protein is believed to be critically involved in the development of ALT.…”

“…Aside from these pro-inflammatory functions, HMGB1 protein also promotes regeneration processes and accelerates cell cycle progression. This paradoxical function of HMGB1 protein has been revealed in the growth and spread of many types of tumors such as hepatocellular carcinoma, colon cancer, breast cancer, and leukemia (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013). Thus, HMGB1 has become the focus of recent cancer research and is currently a relevant target for cancer treatment (Ohmori et al, 2011;Yu et al, 2012).…”

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…30,55,56 In contrast, secreted HMGB1 could induce a protumor inflammation to facilitate tumor progression. 57 In addition, HMGB1 expression is significantly associated with overall survival of patients with bladder cancer. 58 As HMGB1 is an intrinsic sensor of oxidative stress, 59 the immunomodulatory properties of HMGB1 might be determined by its redox status.…”